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Pathological changes in the Alzheimer's disease (AD) brain include amyoid-β (Aβ) plaques, and neurofibrillary tangles, as well as neuronal death and synaptic loss. Matrix metalloproteinases MMP-2 and MMP-9 are known to degrade Aβ, and their expressions are increased in the AD brain, in particular in the astrocytes surrounding amyloid plaque. To investigate a possible association between plasma metalloproteinases and AD, we quantified MMP-2 and MMP-9 activities in the plasma of healthy controls (HC, n = 56), cases with mild cognitive impairment (MCI, n = 45), and AD (n = 50). All cases had previously been imaged with Pittsburgh compound B (PiB) and had a Mini-Mental Status Examination (MMSE) assessment. MMP-2 and MMP-9 activity was determined using gelatine-zymography. There was a significant 1.5-fold decrease in MMP-2 activity in the AD group compared to HC (p < 0.001) and a 1.4-fold decrease compared to MCI (p < 0.01). There was no difference in MMP-9 levels between the three groups. A positive correlation was identified between MMP-2 plasma activity and MMSE score (r = 0.16, p < 0.05), but there was no association with PiB. This is the first report of a change in MMP-2 activity in AD plasma and these findings may provide some insight into AD pathogenesis. [ABSTRACT FROM AUTHOR]

This clinical report describes the prosthodontic management of a 5-year-old boy with ectodermal dysplasia who had been followed for 31 years. During the first 15 years, several interim removable overdentures were fabricated and modified according to his skeletal growth. At age 20, after the completion of jaw development, 4 endosseous dental implants were inserted in the mandible with a nerve repositioning procedure. After a 6-month healing period, maxillary and mandibular double crown removable partial dentures (RPDs) using a gold electroforming system were delivered. In the 16 years since delivery, the implants and abutment teeth have shown no pathologic signs. The double crown RPDs supported by implants and natural teeth were found to be an effective, long-term stable treatment option for this patient with hypodontia. The authors are unaware of a longer follow-up period of dental rehabilitation in a patient with ectodermal dysplasia providing satisfactory functional and esthetic results., (Copyright © 2024 Editorial Council for The Journal of Prosthetic Dentistry. Published by Elsevier Inc. All rights reserved.)

Purpose: The management of pressure ulcers (PUs) poses challenges due to their chronic nature and the lack of established conservative treatment methods. In this clinical trial, our objective was to examine the validity and safety of using a light-emitting diode device contained four wavelengths in the treatment of grade 2 sacral PUs., Method: A total of 38 patients were randomly assigned to two groups: sham device (Sham) and experimental device (LED) group. The treatment sessions were conducted over a period of four weeks, with a frequency of three times per week. The study was conducted in a double-blinded manner. The study assessed the primary validity by measuring wound size and re-epithelialization after 0 and 4 weeks. Secondary evaluations included epidermal regeneration, collagen density, and immunological markers. Safety was evaluated by monitoring adverse reactions throughout the trial., Result: The presence of eschar was found to have a significant impact on wound healing. Sham consisted of 15 wounds without eschar, while LED had nine. After treatment in without eschar situation, the post-treatment size of wounds in Sham was 13.80 ± 20.29%, while it was 3.52 ± 6.68% in LED. However, there was no significant difference (p = 0.070). And analysis of epidermal thickness showed a significant increase in LED (495.62 ± 327.09 μm) compared to Sham (195.36 ± 263.04 μm) (p < 0.0001)., Conclusion: While LED treatment had a potential for wound reduction in PUs without eschar, we could not uncover evidence to support the efficacy of LED treatment in grade 2 PUs., Competing Interests: Choi YW is a chief executive officer and has stock in Linkoptics corporation. our competing interests do not alter our adherence to PLOS ONE policies on sharing data and materials. However, the data are not publicly available due to ethical and legal restrictions because data contain potentially identifying patient information. Therefore, data may be accessed upon authorization from the Institutional Review Board that may be contacted through ‘chyohu@dkuh.co.kr’, (Copyright: © 2024 Lim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The traditional view of plus (+)-strand RNA virus transcriptomes is that infected cells contain a limited variety of viral RNAs, such as full-length (+)-strand genomic RNA(s), (-)-strand replication intermediate(s), 3' co-terminal subgenomic RNA(s), and viral recombinant defective (D)-RNAs. To ascertain the full complement of viral RNAs associated with the simplest plant viruses, long-read direct RNA nanopore sequencing was used to perform transcriptomic analyses of two related umbra-like viruses: citrus yellow vein-associated virus (CY1) from citrus and CY2 from hemp. Analysis of different timepoints/tissues in CY1- and CY2-infected Nicotiana benthamiana plants and CY2-infected hemp revealed: (i) three 5' co-terminal RNAs of 281 nt, 442 nt and 671 nt, each generated by a different mechanism; (ii) D-RNA populations containing the 671 fragment at their 5'ends; (iii) many full-length genomic RNAs and D-RNAs with identical 3'end 61 nt truncations; (iv) virtually all (-)-strand reads missing 3 nt at their 3' termini; (v) (±) foldback RNAs comprising about one-third of all (-)-strand reads and (vi) a higher proportion of full-length gRNAs in roots than in leaves, suggesting that roots may be functioning as a gRNA reservoir. These findings suggest that viral transcriptomes are much more complex than previously thought., (© The Author(s) 2024. Published by Oxford University Press on behalf of NAR Genomics and Bioinformatics.)

Pathological dermal scars such as keloids present significant clinical challenges lacking effective treatment options. Given the distinctive feature of highly stiffened scar tissues, deciphering how matrix mechanics regulate pathological progression can inform new therapeutic strategies. Here, it is shown that pathological dermal scar keloid fibroblasts display unique metamorphoses to stiffened matrix. Compared to normal fibroblasts, keloid fibroblasts show high sensitivity to stiffness rather than biochemical stimulation, activating cytoskeletal-to-nuclear mechanosensing molecules. Notably, keloid fibroblasts on stiff matrices exhibit nuclear softening, concomitant with reduced lamin A/C expression, and disrupted anchoring of lamina-associated chromatin. This nuclear softening, combined with weak adhesion and high contractility, facilitates the invasive migration of keloid fibroblasts through confining matrices. Inhibiting lamin A/C-driven nuclear softening, via lamin A/C overexpression or actin disruption, mitigates such invasiveness of keloid fibroblasts. These findings highlight the significance of the nuclear mechanics of keloid fibroblasts in scar pathogenesis and propose lamin A/C as a potential therapeutic target for managing pathological scars., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Background: Skin grafting is a common method of treating damaged skin; however, surgical complications may arise in patients with poor health. Currently, no effective conservative treatment is available for extensive skin loss. Mature adipocytes, which constitute a substantial portion of adipose tissue, have recently emerged as a potential source of stemness. When de-lipidated, these cells exhibit fibroblast-like characteristics and the ability to redifferentiate, offering homogeneity and research utility as "dedifferentiated fat cells.", Methods and Results: We conducted an in vitro study to induce fibroblast-like traits in the adipose tissue by transdifferentiating mature adipocytes for skin regeneration. Human subcutaneous fat tissues were isolated and purified from mature adipocytes that underwent a transformation process over 14 days of cultivation. Microscopic analysis revealed lipid degradation over time, ultimately transforming cells into fibroblast-like forms. Flow cytometry was used to verify their characteristics, highlighting markers such as CD90 and CD105 (mesenchymal stem cell markers) and CD56 and CD106 (for detecting fibroblast characteristics). Administering dedifferentiated fat cells with transforming growth factor-β at the identified optimal differentiation concentration of 5 ng/mL for a span of 14 days led to heightened expression of alpha smooth muscle actin and fibronectin, as evidenced by RNA and protein analysis. Meanwhile, functional validation through cell sorting demonstrated limited fibroblast marker expression in both treated and untreated cells after transdifferentiation by transforming growth factor-β., Conclusion: Although challenges remain in achieving more effective transformation and definitive fibroblast differentiation, our trial could pave the way for a novel skin regeneration treatment strategy., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Methods to access chiral sulfur(VI) pharmacophores are of interest in medicinal and synthetic chemistry. We report the desymmetrization of unprotected sulfonimidamides via asymmetric acylation with a cinchona-phosphinate catalyst. The desired products are formed in excellent yield and enantioselectivity with no observed bis-acylation. A data-science-driven approach to substrate scope evaluation was coupled to high throughput experimentation (HTE) to facilitate statistical modeling in order to inform mechanistic studies. Reaction kinetics, catalyst structural studies, and density functional theory (DFT) transition state analysis elucidated the turnover-limiting step to be the collapse of the tetrahedral intermediate and provided key insights into the catalyst-substrate structure-activity relationships responsible for the origin of the enantioselectivity. This study offers a reliable method for accessing enantioenriched sulfonimidamides to propel their application as pharmacophores and serves as an example of the mechanistic insight that can be gleaned from integrating data science and traditional physical organic techniques.

Background: Low muscle mass is associated with adverse health outcomes such as functional decline and all-cause mortality. This study investigated the relationship between the risk of low muscle mass and the training period and/or frequency of resistance training (RT)., Methods: We included 126,339 participants (81,263 women) from nationwide cohorts in Korea. Low muscle mass was defined based on the fat-free mass index. To investigate the presence of an inverse dose-response relationship between RT levels and the risk of low muscle mass, the training period (months) and frequency (per week) of RT were used. Multiple logistic regression models were used to assess the risk of low muscle mass according to the RT levels., Results: Prevalence rates for low muscle mass in our study population were 21.27% and 6.92% in men and women, respectively. When compared with not performing RT, performing RT for 3-4 days/week and ≥5 days/week decreased the risk of low muscle mass by 22% and 27%, respectively, and performing RT for 12-23 months and ≥24 months decreased the risk by 19% and 41%, respectively. When simultaneously considering both training period and frequency, performing RT for either 3-4 days/week or ≥5 days/week was significantly related to risk reduction, provided that the training period was at least 1 year. Importantly, performing RT for more than 2 years resulted in an additional risk reduction. However, there was no additional effect of performing RT for ≥5 days/week compared to 3-4 days/week, regardless of whether the RT duration was 1-2 years or more than 2 years., Conclusions: Since performing RT for 5 days/week or more did not yield any additional effects on the risk of low muscle mass, performing RT for 3-4 days/week was sufficient to prevent low muscle mass. The effectiveness of this preventive measure can be further enhanced by engaging in long-term RT, specifically for more than 2 years., (© 2024. The Author(s).)

Si has the highest theoretical capacity (4200 mA h g -1 ) among conventional anode materials, such as graphite (372 mA h g -1 ), but its large volume expansion leads to deterioration of the battery performance. To overcome this problem (issue), we investigated the use of polysaccharide-based 3D cross-linked network binders for Si anodes, in which the polysaccharide formed an effective 3D cross-linked network around Si particles via cross-linking of polysaccharide with citric acid (CA). Sodium alginate (SA), a natural polysaccharide extracted from brown algae, is a suitable binder material for Si anodes because its abundant hydroxyl (-OH) and carboxyl (-COOH) groups form hydrogen and covalent bonds with the -OH groups present on the Si surface. We found that CA-cross-linked (CA-SA) could effectively prevent the volume expansion of Si anodes through the formation of 3D cross-linked network structures. In addition, the CA-SA binders provide enhanced adhesion strength, enabling the fabrication of more robust electrodes than those prepared using binders with linear structures ("linear binders"). In particular, the fabricated Si-based electrode (high mass loading of 1.5 mg cm -2 ) with CA-SA binder exhibited outstanding areal capacity (∼2.7 mA h cm -2 ) and excellent cycle retention (∼100% after 100 cycles).

Migrant workers face challenging working conditions, resulting in physical and mental vulnerability. The objective is to identify their health vulnerabilities and ensure their right to health. Health records of 163 migrant workers (113 males and 50 females) (Group A) and 163 Korean citizens (Group B) visiting our institution were analyzed from August 2021 to July 2022. Both groups underwent urine analysis, chest radiography, and various blood tests. Statistical analysis using independent t -tests and χ² tests was performed. Group A had a significantly higher rate of hepatitis B virus surface antigen-positive patients, lower vaccination rates for hepatitis B, and poorer nutritional status compared to Group B. Group B generally exhibited higher levels of albumin, glucose, total cholesterol, and thyroid-stimulating hormone. There were significant quantitative differences in multiple blood cell and hemoglobin measurements between the two groups. These findings emphasize the need for policy support and public awareness to protect the health rights of migrant workers., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2023 The Korean Academy of Medical Sciences.)

New methods for the general asymmetric synthesis of sulfonimidamides are of great interest due to their applications in medicinal chemistry, agrochemical discovery, and academic research. We report a palladium-catalyzed cross-coupling method for the enantioselective aryl-carbonylation of sulfonimidamides. Using data science techniques, a virtual library of calculated bisphosphine ligand descriptors was used to guide reaction optimization by effectively sampling the catalyst chemical space. The optimized conditions identified using this approach provided the desired product in excellent yield and enantioselectivity. As the next step, a data science-driven strategy was also used to explore a diverse set of aryl and heteroaryl iodides, providing key information about the scope and limitations of the method. Furthermore, we tested a range of racemic sulfonimidamides for compatibility of this coupling partner. The developed method offers a general and efficient strategy for accessing enantioenriched sulfonimidamides, which should facilitate their application in industrial and academic settings.

Objective: Depression is a serious mental disorder which is the leading cause of suicide. This study investigated the association between incident depression and 4-year leisure-time physical activity (PA) levels and/or resistance training (RT)., Methods: This community-based Korean cohort included 3,967 participants without depression at baseline. The average PA-time (the total duration of moderate-intensity leisure-time PA) up to 4 years prior to baseline enrollment was calculated to evaluate the cumulative levels of PA. Participants were divided into four groups based on their average PA-time: "Non-PA," " <150 min/week," "150-299 min/week," and "≥300 min/week." Furthermore, based on compliance to PA guidelines (≥150 min/week of PA-time) and participation in RT, the participants were categorized into four subgroups: "Low-PA," "Low-PA+RT," "High-PA," and "High-PA+RT." A multivariate Cox proportional hazards regression model was used to assess the 4-year incidence of depression according to leisure-time PA levels and/or regularity of RT., Results: During the mean 3.72 ± 0.69 years of follow-up, 432 participants (10.89%) developed depression. In women, performing 150-299 min/week of moderate-intensity leisure-time PA was associated with a 38% risk reduction for incident depression (HR, 0.62; CI, 0.43-0.89; p < 0.05), whereas more than 300 min/week of that was related to a 44% risk reduction for incident depression (HR, 0.56; CI, 0.35-0.89; p < 0.05) as compared to that in the Non-PA group. However, in men, there was no significant relationship between the amount of leisure-time PA per week and the risk of incident depression. Moreover, in both sexes, RT had no significant effect on depression in either the Low-PA or High-PA group., Conclusions: There was an inverse dose-response association between leisure-time PA levels and incident depression only in women, whereas adding RT to high levels of PA had no significant effect on depression in either sex., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Park, Lim and Park.)

A chromatography-free asymmetric synthesis of GDC-6036 ( 1 ) was achieved via a highly atroposelective Negishi coupling of aminopyridine 5 and quinazoline 6b catalyzed by 0.5 mol % [Pd(cin)Cl] 2 and 1 mol % ( R , R )-Chiraphite to afford the key intermediate ( R a )- 3 . An alkoxylation of ( R a )- 3 with ( S )- N -methylprolinol ( 4 ) and a global deprotection generates the penultimate heterobiaryl intermediate 2 . A controlled acrylamide installation by stepwise acylation/sulfone elimination and final adipate salt formation and crystallization delivered high-purity GDC-6036 ( 1 ).

Background: This study aimed to evaluate the prevalence of dysmenorrhea and to investigate the effect of weight changes or unhealthy weight control behaviors on dysmenorrhea in young Korean women., Methods: We used large-scale data of women, aged 14 to 44 years, who participated in the Korean Study of Women's Health-Related Issues. Dysmenorrhea was measured using a visual analog scale and was categorized as none, mild, moderate, and severe according to the severity. Weight changes and unhealthy weight control behaviors (any of the behaviors, fasting/meal skipping, drugs, the use of unapproved dietary supplements, and one-food diets) over the past year were self-reported. We used multinomial logistic regression to investigate the association between weight changes or unhealthy weight control behaviors and dysmenorrhea., Results: Of the 5,829 young women participating in the study, 5,245 (90.0%) participants experienced dysmenorrhea [2,184 (37.5%) had moderate and 1,358 (23.3%) had severe]. After adjusting for confounders, the odds ratios for moderate and severe dysmenorrhea in participants with weight changes ≥ 3 kg (vs. < 3 kg) were 1.19 (95% confidence interval: 1.05-1.35) and 1.25 (95% confidence interval: 1.08-1.45), respectively. The odds ratios in participants with any unhealthy weight control behaviors were 1.22 (95% confidence interval: 1.04-1.42) and 1.41 (95% confidence interval: 1.19-1.67) for those with moderate and severe dysmenorrhea, respectively., Conclusion: Weight changes (≥ 3 kg) or unhealthy weight control behaviors are common among young women, which may adversely affect dysmenorrhea. Therefore, attention needs to be paid to excessive weight changes and unhealthy weight control behaviors to improve dysmenorrhea in young women., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2023 The Korean Academy of Medical Sciences.)

Diabetes mellitus contributes to 15-25% of all chronic foot ulcers. Peripheral vascular disease is a cause of ischemic ulcers and exacerbates diabetic foot disease. Cell-based therapies are viable options to restore damaged vessels and induce the formation of new vessels. Adipose-derived stem cells (ADSCs) have the potential for angiogenesis and regeneration because of their greater paracrine effect. Preclinical studies are currently using other forced enhancement techniques (e.g., genetic modification or biomaterials) to increase the efficacy of human ADSC (hADSC) autotransplantation. Unlike genetic modifications and biomaterials, many growth factors have been approved by the equivalent regulatory authorities. This study confirmed the effect of enhanced human ADSC (ehADSC)s with a cocktail of FGF and other pharmacological agents to promote wound healing in diabetic foot disease. In vitro, ehADSCs exhibited a long and slender spindle-shaped morphology and showed significantly increased proliferation. In addition, it was shown that ehADSCs have more functionalities in oxidative stress toleration, stem cell stemness, and mobility. In vivo, the local transplantation of 1.2 × 10 6 hADSCs or ehADSCs was performed in animals with diabetes induced by STZ. The ehADSC group showed a statistically decreased wound size and increased blood flow compared with the hADSC group and the sham group. Human Nucleus Antigen (HNA) positive cells were observed in some ADSC-transplanted animals. The ehADSC group showed a relatively higher portion of HNA-positive animals than the hADSC group. The blood glucose levels showed no significant difference among the groups. In conclusion, the ehADSCs showed a better performance in vitro, compared with conventional hADSCs. Additionally, a topical injection of ehADSCs into diabetic wounds enhanced wound healing and blood flow, while improving histological markers suggesting revascularization.

Hypertension is the most common preventable risk factor for the onset of cardiovascular disease and mortality. We aimed to investigate the association between incident hypertension and 4-year leisure-time physical activity (PA) levels and resistance training (RT). In this community-based Korean cohort, 5,075 participants without hypertension were included. To evaluate cumulative PA, the average PA time (the total time of moderate-intensity leisure-time PA) at baseline, 2-year follow-up, and 4-year follow-up were calculated. Based on participation in RT and compliance to PA guidelines (≥150 min/week of PA time), the participants were divided into the following four groups: Low-PA, Low-PA+RT, High-PA, and High-PA+RT. A multivariate Cox proportional hazards regression model was used to evaluate the 12-year incidence of hypertension in relation to leisure-time PA levels and RT regularity. During a mean 7.86 ± 4.20-year follow-up, 2,544 participants (1,366 women) were diagnosed with hypertension. Compared with Low-PA, High-PA, and High-PA+RT decreased the risk for hypertension by 30 and 39%, respectively. Participation in RT without compliance to PA guidelines did not affect the incidence of hypertension. The additive effect of RT on hypertension in the High-PA group was further examined. Although sex-based comparisons indicated that men had a significantly longer training period for RT than women, an additional reduction in the risk for hypertension in relation to the addition of RT was observed only in women (35%). PA may confer protective effects against hypertension, whereas the addition of RT to high levels of PA can further reduce the risk for hypertension in women., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Park, Lim and Park.)

Catastrophic incidents would necessitate the intervention of multiple specializations with plastic surgery (PS) as an indispensable area of expertise. In view of PS, prognostic assessment of trauma patients should be focused on the qualitative value rather than mortality because plastic surgeons rarely handled patients' vital signs in actual. Thus, we explored the association between the involvement of the PS department and qualitative prognoses for severe trauma patients. From November 2014 to December 2019, we enrolled total 529 trauma patients with an injury severity score (ISS) over 15 points. We set the prognostic factors that the rate of admission in intensive care unit (ICU), total or ICU duration of hospitalization, post-discharge progress and disability diagnosis which were regarded as qualitative prognoses. The analysis was performed with logistic regression analysis or regression analysis adjusted for age, sex, past medical history, cause of trauma, and frequency of operation. Among total of 529 patients, 290 patients in PS group and 239 patients in non-PS group were analyzed. In both groups, the under-65-year ages and male patients were significantly predominant. The rate of going home showed 2.082 times higher in PS group than non-PS group after adjusting for covariates, while there was no significant difference in diagnosis of disability. Meanwhile, overall prognoses were highly correlated with either higher ISS or lower Glasgow Coma Scale (GCS). In conclusion, higher severity generally affected to the severe trauma patient's prognoses, and the PS treatment only contributes to discharge disposition to home., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

An efficient asymmetric synthesis of a potent KRAS G12C covalent inhibitor, GDC-6036 ( 1 ), is reported. The synthesis features a highly atroposelective Negishi coupling to construct the key C-C bond between two highly functionalized pyridine and quinazoline moieties by employing a Pd/Walphos catalytic system. Statistical modeling by comparing computational descriptors of a range of Walphos chiral bisphosphine ligands to a training set of experimental results was used to inform the selection of the best ligand, W057-2 , which afforded the desired Negishi coupling product ( R a )-3 in excellent selectivity. A subsequent telescoped reaction sequence of alkoxylation, global deprotection, and acrylamide formation, followed by a final adipate salt formation, furnished GDC-6036 ( 1 ) in 40% overall yield from starting materials pyridine 5 and quinazoline 6 .

While plastic surgeons have been historically indispensable in the reconstruction of posttraumatic defects, their role in trauma centers worldwide has not been clearly defined. Therefore, we aimed to investigate the contribution of plastic surgeons in trauma care using machine learning from an anatomic injury viewpoint. We conducted a retrospective study reviewing the data for all trauma patients of our hospital from March 2019 to February 2021. In total, 4809 patients were classified in duplicate according to the 17 trauma-related departments while conducting the initial treatment. We evaluated several covariates, including age, sex, cause of trauma, treatment outcomes, surgical data, and severity indices, such as the Injury Severity Score and Abbreviated Injury Scale (AIS). A random forest algorithm was used to rank the relevance of 17 trauma-related departments in each category for the AIS and outcomes. Additionally, t test and chi-square test were performed to compare two groups, which were based on whether the patients had received initial treatment in the trauma bay from the plastic surgery department (PS group) or not (non-PS group), in each AIS category. The department of PS was ranked first in the face and external categories after analyzing the relevance of the 17 trauma-related departments in six categories of AIS, through the random forest algorithm. Of the 1108 patients in the face category of AIS, the PS group was not correlated with all outcomes, except for the rate of discharge to home (P < .0001). Upon re-verifying the results using random forest, we found that PS did not affect the outcomes. In the external category in AIS, there were 30 patients in the PS group and 56 patients in the non-PS group, and there was no statistically significant difference between the two groups when comparing the outcomes. PS has contributed considerably to the face and external regions among the six AIS categories; however, there was no correlation between plastic surgical treatment and the outcome of trauma patients. We investigated the plastic surgeons' role based on anatomical injury, using machine learning for the first time in the field of trauma care., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: While plastic surgeons have been historically indispensable in reconstruction of posttraumatic defects, their role in Level I trauma centers around the world has not yet been clearly approved. This study aims to assess the contribution of plastic surgeons in major trauma care by evaluating the characteristics of trauma patients underwent plastic surgery at a Level I trauma center., Method: From November 2014 to October 2020, we conducted a retrospective review of our hospital's Trauma Registry System for patients with an Injury Severity Score (ISS) of 9 or higher. Of all of 7174 patients, the plastic surgery (PS) department treated 870 patients; the 6304 patients not treated by the PS were classified as the Non-PS. Then, we performed propensity score matching to reduce the statistical bias, after the death in the emergency room and the missing value were considered exclusion criteria., Result: The mean ISS showed no significant difference between two groups (16.29 ± 7.04 in the PS vs. 16.68 ± 9.16 in the Non-PS, p = 0.3221). According to investigate the Abbreviated Injury Scale, both head and neck (65.0%) and face (46.4%) categories showed significantly higher in the PS group than the Non-PS group (p < 0.0001), and its contribution ratio was 2.151 and 21.822 times, respectively., Conclusion: This study revealed the specialty of plastic surgery was face area in trauma care. We thus argue that plastic surgical care is imperative for trauma patients, and expect to be implicated in trauma system planning., Competing Interests: The author has declared that no competing interests exist.

This study investigated the associations of relative handgrip strength (rHGS) and hypertension. Individual differences in visceral adipose dysfunction (VAD) were evaluated to verify whether rHGS was associated with a reduction in the risk of hypertension, even in individuals with VAD. We included 77,991 participants (50,616 women) from nationwide cohorts in Korea. Participants were categorized into three groups based on sex-specific tertiles of rHGS (Low, Mid, and High). The visceral adiposity index (VAI) was used to evaluate VAD. The multiple logistic regression model was used to assess the risk of hypertension. High rHGS is associated with reduction of hypertension risk in 38 and 26% of men and women, respectively, although rHGS was significantly low in women compared to men. The benefit of rHGS was observed from middle-aged to older participants in both sexes. High rHGS is associated with risk reduction for hypertension in both VAD and non-VAD groups. In the VAD group, compared to Low rHGS, High rHGS was associated with 32 and 22% risk reductions in hypertension in men and women, respectively, and these associations remained significant even when classified according to age, such as in middle-aged and older subgroups. Therefore, the present study suggests that high levels of rHGS are significantly associated with a reduced risk of hypertension even in participants with VAD. Thus, maintaining a higher level of rHGS may be associated with protective benefits against hypertension., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Park, Lim and Park.)

Background: Alcohol drinking during pregnancy has been well-known to cause the detrimental effects on fetal development; however, the adverse effects of pre-pregnancy drinking are largely unknown. We investigate whether alcohol drinking status before pregnancy is associated with the risk for macrosomia, an offspring's adverse outcome, in a Korean pregnancy registry cohort (n = 4,542) enrolled between 2013 and 2017., Methods: Binge drinking was defined as consuming ≥5 drinks on one occasion and ≥2 times a week, and a total 2,886 pregnant, included in the final statistical analysis, were divided into 3 groups: never, non-binge, and binge drinking., Results: The prevalence of macrosomia was higher in binge drinking before pregnancy than those with never or non-binge drinking (7.5% vs. 3.2% or 2.9%, p = 0.002). Multivariable logistic regression analysis demonstrated an independent association between macrosomia and prepregnancy binge drinking after adjusting for other confounders (adjusted odds ratio = 2.29; 95% CI, 1.08-4.86; p = 0.031). The model added binge drinking before pregnancy led to improvement of 10.6% (95% CI, 2.03-19.07; p = 0.0006) in discrimination from traditional risk prediction models., Conclusion: Together, binge drinking before pregnancy might be an independent risk factor for developing macrosomia. Intensified intervention for drinking alcohol in women who are planning a pregnancy is important and may help prevent macrosomia., Competing Interests: The authors have declared that no competing interests exist.

The emergence of vaccines for coronavirus disease 2019 (COVID-19) raises risk of possible adverse events from interaction between the vaccines and facial aesthetic care. A 47-year-old female with no medical comorbidities visited our emergency room due to midface painful swelling after 3 hours following receiving the second dose of the messenger RNA BNT162b2 COVID-19 vaccine. About 14 years ago, she underwent nonsurgical augmentation on the nasojugal groove with a calcium hydroxylapatite dermal filler. We performed incision and drainage under general anesthesia on the next day. During operation, yellowish pus-like materials bulged out. After an operation, we performed a combination therapy with antibiotics and methylprednisolone. Her symptoms improved day by day after surgery, and then a complete recovery was achieved at 3 weeks after the treatment. In conclusion, providers of aesthetic procedures are to be aware of the potential risks of such vaccines for patients who already had or seek to receive dermal filler injections., Competing Interests: Conflict of Interest None declared., (The Korean Society of Plastic and Reconstructive Surgeons. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. ( https://creativecommons.org/licenses/by-nc-nd/4.0/ ).)

Objectives: The effect of photobiomodulation (PBM) treatment on wound healing and macrophage polarization was investigated in vivo. Animal models of oral ulcers were simulated through chemically induced oral ulcers in rats., Materials and Methods: PBM treatment using an infrared pulsed laser was used to treat oral ulcers in the animal models. Twelve Sprague-Dawley rats were randomly divided into four groups depending on set absorbed energy: Group 1 (control), Group 2 (30 J), Group 3 (60 J), and Group 4 (100 J). Laser treatment was performed every other day for 8 days after ulcer confirmation. Parameters used were as follows: wavelength 808 nm, power output 50 mW, spot size 10 mm, frequency 10 Hz, and pulse duration 1 millisecond. Ulcers were measured to determine the effect of the treatments over time. Histology, immunostaining, and real-time polymerase chain reaction analyses were performed to evaluate the effect of PBM treatment on macrophage-related (IL-6/IL-10) and wound-healing-related (TNF-α/TGF-β/MMP-2) cytokine expression., Results: Histological examinations indicate that the PBM treatment stimulated a higher level of wound recovery after 8 days of treatment at 60 J absorbed energy compared to other treatment groups. Analyses of relative gene expression of proinflammatory, anti-inflammatory, and tissue remodeling cytokines indicate that the macrophages in the tissue samples were predominantly characterized as M2 subtypes (alternatively activated), which possibly accounts for the accelerated tissue repair in the animal model of oral ulcer., Conclusion: This preliminary study stands as a proof of concept regarding the potential use of infrared laser PBM treatment for oral ulcers which have not been previously investigated upon. PBM treatment affects macrophage polarization and enhances wound healing. Further experimentation will be conducted to expand the understanding of how PBM treatment affects the healing mechanism of ulcers., (© 2021 Wiley Periodicals LLC.)

Background: Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease. The present study aimed to investigate the association of NAFLD with leisure-time physical activity (PA) levels and resistance training (RT)., Methods: We used data from large nationwide cohorts in Korea. NAFLD was defined based on the Framingham steatosis index. Participants were categorized into four groups based on RT frequency and adherence to PA guidelines (≥150 min/week of moderate-intensity PA): Low-PA, Low-PA+RT, High-PA, and High-PA+RT. Multiple logistic regression models were used to assess the risk of NAFLD according to leisure-time PA levels and regularity of RT., Results: When compared with Low-PA, High-PA decreased the risk of NAFLD by 17%, and High-PA+RT further decreased the risk by 30%. However, the additional reduction in risk associated with the addition of RT was observed in men (19%), but not in women. In the High-PA group, men had a significantly higher training frequency and period for RT than women., Conclusions: Following the PA guideline may confer protective effects against NAFLD, while adding RT to High-PA can further decrease the risk of NAFLD. Sex-based differences in NAFLD risk in the High-PA+RT group may be due to the differences in the frequency and period of RT.

Background/objective: Healthy weight maintenance before and during pregnancy has a significant effect on pregnancy outcomes; however, there are no specific guidelines for gestational weight gain in pregnant Korean women. Therefore, we investigated the impact of pre-pregnancy body mass index (BMI) and gestational weight gain on the risk of maternal and infant pregnancy complications in pregnant Korean women., Methods: Study participants comprised 3454 singleton pregnant women from the Korean Pregnancy Outcome Study who had baseline examination and pregnancy outcome data. Maternal pre-pregnancy BMI and gestational weight gain were categorized according to the Asia-pacific regional guidelines and the Institute of Medicine recommendations, respectively. The primary outcome was any adverse outcomes, defined as the presence of one or more of the following: hypertensive disorders of pregnancy, gestational diabetes mellitus, peripartum depressive symptom, cesarean delivery, delivery complications, preterm birth, small or large weight infant, neonatal intensive care unit admission, or a congenital anomaly. Multiple logistic regression models were applied to examine the independent and combined impact of pre-pregnancy BMI and gestational weight gain on the risk of maternal and infant outcomes., Results: Obesity before pregnancy significantly increased the risk of perinatal adverse outcomes by more than 2.5 times [odds ratio (OR): 2.512, 95% confidence interval (CI): 1.817-3.473]. Compared to that in women with appropriate gestational weight gain, women with excessive weight gain had a 36.4% incremental increase in the risk of any adverse outcomes [OR: 1.364, 95% CI: 1.115-1.670]. Moreover, women who were overweight or obese before pregnancy and had excessive gestational weight gain had a three-fold increase in the risk of adverse outcomes [OR: 3.460, 95% CI: 2.210-5.417]., Conclusion: This study highlights the need for appropriate weight recommendations before and during pregnancy to prevent perinatal complications in Korean women of childbearing age., (© 2021. The Author(s).)

Objectives: The use of menstrual hygiene products and its effect on women's health remains under studied. Patterns of menstrual hygiene product use and the rationale behind choices among Korean women aged 18-45 years were examined., Methods: This cross-sectional study was a part of the Korea Nurses' Health Study. A total of 20,613 nurses participated, and 8,658 nurses participated in Module 7 which included a menstrual hygiene products-related survey. The data were collected through the mobile survey using a self-reported questionnaire. Participants' use of menstrual hygiene products and related characteristics were analyzed using frequency (percentage) or mean (SD)., Results: The most common types of menstrual hygiene products across all age groups were disposable menstrual pads (89.0%), followed by cloth menstrual pads (4.5%), tampons (4.2%), and only 1.6% used a menstrual cup. Disposable menstrual pads were the most common across all age groups, but in those aged under 30 years this was followed by tampon use (6%). The most important criteria when choosing a menstrual hygiene product was comfort for disposable menstrual pads (31.3%) and tampons (41.5%), natural ingredients or organic products for cloth menstrual pads (51.4%), and custom fit for the menstrual cup (50.7%). However, for all menstrual hygiene products (except cloth menstrual pads), there was a higher proportion of anxiety than perception of safety, and low awareness of toxic shock syndrome., Conclusion: It is important for women to use menstrual hygiene products with confidence. More research is needed to better understand potential health effects of menstrual hygiene products., Competing Interests: Conflicts of Interest The authors have no conflicts of interest to declare., (©2021 Korea Disease Control and Prevention Agency.)

Background: More than 13,000 cases were reported to be infected with COVID-19 by RT-PCR in South Korea. Most studies report clinical characteristics of hospitalized patients with COVID-19; the full spectrum of disease severity has thus not yet been well described., Methods: Using retrospective observational methods, this study analyzed factors affecting early clinical symptoms, clinical progress, and severity of disease for COVID-19 positive patients released from quarantine to provide information on establishing optimized care for new patients. The medical data of 7803 laboratory-confirmed patients who had been discharged or died by April 30, 2020 were analyzed using multivariate logistic regression analysis., Findings: On admission, 7383 (94•5%) patients were asymptomatic or showed mild illness, and 372 (4•8%) patients were severe illness. Also, 48 (0 0•6%) were hospitalized with critically ill when diagnosed. Most patients with asymptomatic or mild illness on admission remained mild until discharge, 253 (3•4%) progressed to severe illness, and 83 (1•1%) died in hospital. However, the case fatality were 29•8% and 62•5% in severe and critically ill patients, respectively. At admission, 73•0% of hospitalized patients had symptoms; most common were cough (42•5%), sputum (28•8%), and fever (20•1%). Only 35•2% of laboratory confirmed patients admitted to the temporary care facility complained of symptoms. Increasing odds of being critically ill was associated with older age (OR 28•93, 95% CI 13•34-62•75 for age >70y, vs. age <50 y; p <0•0001), being male (OR 2•15, 95% CI1•59-2•89; p <0•0001), fever (OR 2•52, 95% CI 1.84-3•45; p <0•0001), and shortness of breath (OR 7•40, 95% CI 5•37-10•19; p <0•0001). Comorbid illness significantly increased risk of critical illness or death., Interpretation: Most cases were discharged as asymptomatic or recovered from mild illness, and only 9•7% developed severe disease requiring oxygen therapy or more. Case fatality rate was 2•9%, and markedly increased in those over age 50. Risk factors such as age, sex, fever, shortness of breath, and underlying disease can be useful in predicting future clinical severity. Additionally, the number of confirmed asymptomatic COVID-19 patients significantly contribute to continued spread., Funding: none., Competing Interests: None., (© 2020 The Authors. Published by Elsevier Ltd.)

Purpose: This study evaluated the shear bond strength between 3D printed provisional resin and conventional provisional resin depending on type of conventional provisional resin and different surface treatments of 3D printed resin., Materials and Methods: Ninety-six disc-shaped specimens (Ø14 mm × 20 mm thickness) were printed with resin for 3D printing (Nextdent C&B, Vertex-Dental B. V., Soesterberg, Netherlands). After post-processing, the specimens were randomly divided into 8 groups (n=12) according to two types of conventional repair resin (methylmethacrylate and bis-acryl composite) and four different surface treatments: no additional treatment, air abrasion, soaking in methylmethacrylate (MMA) monomer, and soaking in MMA monomer after air abrasion. After surface treatment, each repair resin was bonded in cylindrical shape using a silicone mold. Specimens were stored in 37℃ distilled water for 24 hours. The shear bond strength was measured using a universal testing machine at a crosshead speed of 0.5 mm/min. Failure modes were analyzed by scanning electron microscope. Statistical analysis was done using one-way ANOVA test and Kruskal-Wallis test (α=.05)., Results: The group repaired with bis-acryl composite without additional surface treatment showed the highest mean shear bond strength. It was significantly higher than all four groups repaired with methylmethacrylate ( P <.05). Additional surface treatments, neither mechanical nor chemical, increased the shear bond strength within methylmethacrylate groups and bis-acryl composite groups ( P >.05). Failure mode analysis showed that cohesive failure was most frequent in both methylmethacrylate and bis-acryl composite groups., Conclusion: Our results suggest that when repairing 3D printed provisional restoration with conventional provisional resin, repair with bis-acryl composite without additional surface treatment is recommended., (© 2020 The Korean Academy of Prosthodontics.)

Objective: To determine the prognostic value of atrial fibrillation (AF) in patients with heart failure (HF) and preserved, mid-range or reduced ejection fraction (EF)., Methods: Patients hospitalised for acute HF were enrolled in the Korean Acute Heart Failure registry, a prospective, observational, multicentre cohort study, between March 2011 and February 2014. HF types were defined as reduced EF (HFrEF, LVEF <40%), mid-range EF (HFmrEF, LVEF 40%-49%) or preserved EF (HFpEF, LVEF ≥50%)., Results: Of 5414 patients enrolled, HFrEF, HFmrEF and HFpEF were seen in 3182 (58.8%), 875 (16.2%) and 1357 (25.1%) patients, respectively. The prevalence of AF significantly increased with increasing EF (HFrEF 28.9%, HFmrEF 39.8%, HFpEF 45.2%; p for trend <0.001). During follow-up (median, 4.03 years; IQR, 1.39-5.58 years), 2806 (51.8%) patients died. The adjusted HR of AF for all-cause death was 1.06 (0.93-1.21) in the HFrEF, 1.10 (0.87-1.39) in the HFmrEF and 1.22 (1.02-1.46) in the HFpEF groups. The HR for the composite of all-cause death or readmission was 0.97 (0.87-1.07), 1.14 (0.93-1.38) and 1.03 (0.88-1.19) in the HFrEF, HFmrEF and HFpEF groups, respectively, and the HR for stroke was 1.53 (1.03-2.29), 1.04 (0.57-1.91) and 1.90 (1.13-3.20), respectively. Similar results were observed after propensity score matching analysis., Conclusions: AF was more common with increasing EF. AF was seen to be associated with increased mortality only in patients with HFpEF and was associated with an increased risk of stroke in patients with HFrEF or HFpEF., Trial Registration Number: NCT01389843., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: The main objective is to assess the appropriate level of achieved SBP and DBP to prevent cardiovascular events., Methods: We used the National Sample Cohort from the National Health Insurance Service in Korea and analyzed data of 44 462 hypertensive patients aged 20--84 years. Achieved SBP and DBP were categorized according to average achieved SBP (<120, 120-129, 130-139, 140-149, and ≥150 mmHg) and DBP (<70, 70-79, 80-89, 90-99, and ≥100 mmHg). We examined the association between achieved BP and composite outcome including cardiovascular death, admission of stroke, myocardial infarction, or heart failure, and all-caused death in elderly aged more than 65 years and in younger patients., Results: After a median follow-up of 6.8 years, achieved SBP less than 120 mmHg and at least 150 mmHg in elderly and younger patients, respectively, were significantly associated with a higher risk of composite outcome than achieved SBP of 120-129 mmHg. Cox's proportional hazard analysis showed that the association between achieved SBP and risk of composite outcome and all-cause death had U-shaped relationships and identified a nadir of SBP of 135.6 and 128.9 mmHg, respectively, for composite outcome and 135.1 and 131.4 mmHg, respectively, for all-cause death in elderly and younger patients., Conclusion: Compared with SBP of 120-129 mmHg, not only low achieved SBP of less than 120 mmHg but also high BP are associated with risk of adverse cardiovascular event and all-cause death in both elderly and younger patients with a distinct U-shaped relationship.

Besides degradation, lysosomes can also carry molecules for secretion out of the cell, such as ATP and cytokines, during unconventional secretion. Phosphatidylinositols and their metabolizing enzymes play important roles in the sorting and trafficking of lysosomal materials through the trans-Golgi network. The present study reveals a new function of phosphatidylinositol kinase-III alpha in the 'kiss-and-run' fusion of lysosomes at the plasma membrane to release ATP from microglia.

Alcohol consumption before or during pregnancy poses serious health risks to the fetus; however, the underlying mechanisms involved remain obscure. Here, we investigated whether ethanol consumption before pregnancy affects maternal or fetal health and whether pharmacological inhibition of CYP2E1, a major ethanol oxidation enzyme, by 4-methylpyrazole (4-MP) has therapeutic effects. We found that ethanol consumption (5%) 2 weeks before pregnancy resulted in a decrease in the number of viable fetuses and abnormal fetal development, and these effects were accompanied by impaired maternal glucose homeostasis and hepatic steatosis during pregnancy. Neonates of ethanol-fed mice had postnatal macrosomia and significantly decreased growth rates during the lactation period. However, treatment with 4-MP, a CYP2E1 inhibitor, markedly ameliorated the reduction in insulin action and glucose disposal responsiveness in the livers of ethanol-fed mice. Blockage of CYP2E1 significantly reduced the alteration in hepatic lipid deposition, fatty acid oxidation, mitochondrial energy status, and macrophage infiltration observed in ethanol-fed mice. Finally, there was a positive correlation between postnatal macrosomia or growth retardation and increased inflammatory responses. Collectively, our study suggests that even moderate ethanol intake may be detrimental to fetal development and may cause growth retardation through maternal metabolic disorders.

Background: We have reported orbital wall restoration surgery with primary orbital wall fragment in pure blowout fractures using a combination of transorbital and transnasal approach in pure blow out fractures. However, this method was thought to be difficult to use for complex orbital wall fractures, since the sharp screw tip that fixate the maxillary wall increases the risk of balloon ruptures. In this study, we reviewed 23 cases of complex orbital fractures that underwent orbital wall restoration surgery with primary orbital wall fragment and evaluated the result., Methods: A retrospective review was conducted of 23 patients with complex orbital fracture who underwent orbital restoration surgery with primary orbital wall fragments between 2012 and 2019. The patients underwent orbital wall restoration surgery with primary orbital wall fragment with temporary balloon support. The surgical results were evaluated by the Naugle scale and a comparison of preoperative and postoperative orbital volume ratio. Complex fracture type, type of screw used for fixation and complications such as balloon rupture were also investigated., Results: There were 23 patients with complex orbital fracture that used transnasal balloon technique for restoration. 17 cases had a successful outcome with no complications, three patients had postoperative balloon rupture, two patients had soft-tissue infection, and one patient had balloon malposition., Conclusion: The orbital wall restoration technique with temporary balloon support can produce favorable results when done correctly even in complex orbital wall fracture. Seventeen cases had favorable results, six cases had postoperative complications thus additional procedure seems necessary to complement this method.

Background: After the laws regulating emergency medicine were amended in 2012, regional trauma centers were established in South Korea. Plastic surgeons specialize in the simultaneous surgical care of patients with facial trauma, burns, and complicated wounds. The objective of this study was to evaluate the role of the plastic surgery department in treating severe trauma patients., Methods: From January 2012 to December 2018, we enrolled 366 severe trauma patients with an Injury Severity Score (ISS) over 15 who received treatment by specialists in the plastic surgery department. Of these patients, 298 (81.4%) were male, and their mean age was 51.35 years (range, 6-91 years). The average ISS was 22.01 points (range, 16-75 points)., Results: The most common diagnosis was facial trauma (95.1%), and facial bone fracture (65.9%) was most common injury within this subgroup. Patients were referred to 1.8 departments on average, with the neurosurgery department accounting for a high proportion of collaborations (37.0%). The most common cause of trauma was traffic accidents (62.3%), and the average length of stay in the general ward and intensive care unit was 36.90 and 8.01 days, respectively. Most patients were discharged home (62.0%) without additional transfer or readmission., Conclusions: Through this study, we scoped out the role of the specialty of plastic surgery in the multidisciplinary team at regional trauma centers. These results may have implications for trauma system planning.

We report herein an efficient, stereocontrolled, and chromatography-free synthesis of the novel broad spectrum antibiotic GDC-5338 . The route features the construction of a functionalized tripeptide backbone, a high-yielding macrocyclization via a Pd-catalyzed Suzuki-Miyaura reaction, and the late-stage elaboration of key amide bonds with minimal stereochemical erosion. Through extensive reaction development and analytical understanding, these key advancements allowed the preparation of GDC-5338 in 17 steps, 15% overall yield, >99 A % HPLC, and >99:1 dr.

Purpose: Anatomical variation in supraorbital transcranial exits, which can be divided into the lateral supraorbital exit and the medial frontal exit, has been investigated in several studies during the past few decades. However, in previous studies, inconsistent criteria were used for classifying those exits. The authors analyzed variations in supraorbital transcranial exits using 3 dimensional multidetector computed tomography (3D MDCT), and present a consistent classification of the types of those exits with precise location measurements., Methods: In 1181 patients (2362 orbits) who underwent facial 3D MDCT, the authors measured a set of qualitative and quantitative parameters. The qualitative parameters included an assessment of the location and type of the exit, and the number of accessory foramina. The quantitative parameters included various distance measurements., Results: A frontal exit was present in 2071 orbits and a supraorbital exit in 953. Neither a frontal exit nor a supraorbital exit was found in 11 orbits. The most common type of frontal exit was the notch type, followed by the foramen type and none. The mean distance from the nasion to the frontal exit was 24.70 ± 3.50 mm on the right side and 23.69 ± 3.42 mm on the left side., Conclusion: In conclusion, various types of supraorbital transcranial exits were observed, of which the frontal notch was the most common. This is the first study to conduct a consistent analysis of a large sample of skulls to characterize the distribution of supraorbital transcranial exit types using a comprehensive and clear set of criteria.

CDK4 and CDK6 are kinases with similar sequences that regulate cell cycle progression and are validated targets in the treatment of cancer. Glioblastoma is characterized by a high frequency of CDKN2A/CCND2/CDK4/CDK6 pathway dysregulation, making dual inhibition of CDK4 and CDK6 an attractive therapeutic approach for this disease. Abemaciclib, ribociclib, and palbociclib are approved CDK4/6 inhibitors for the treatment of HR+/HER2- breast cancer, but these drugs are not expected to show strong activity in brain tumors due to poor blood brain barrier penetration. Herein, we report the identification of a brain-penetrant CDK4/6 inhibitor derived from a literature molecule with low molecular weight and topological polar surface area (MW = 285 and TPSA = 66 Å 2 ), but lacking the CDK2/1 selectivity profile due to the absence of a basic amine. Removal of a hydrogen bond donor via cyclization of the pyrazole allowed for the introduction of basic and semi-basic amines, while maintaining in many cases efflux ratios reasonable for a CNS program. Ultimately, a basic spiroazetidine (cpK a  = 8.8) was identified that afforded acceptable selectivity over anti-target CDK1 while maintaining brain-penetration in vivo (mouse K p,uu  = 0.20-0.59). To probe the potency and selectivity, our lead compound was evaluated in a panel of glioblastoma cell lines. Potency comparable to abemaciclib was observed in Rb-wild type lines U87MG, DBTRG-05MG, A172, and T98G, while Rb-deficient cell lines SF539 and M059J exhibited a lack of sensitivity., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: The CHA 2 DS 2 -VASc score is used to assess risk of mortality as well as to stratify risk of stroke in patients with atrial fibrillation (AF). This study evaluated whether CHA 2 DS 2 -VASc score was predictive of 1 and 2 year risks of stroke and death in Asian patients with heart failure (HF)., Methods: Patients hospitalized for HF were enrolled in the Korean Acute Heart Failure (KorAHF) registry, a prospective observational multicenter cohort study, between March 2011 and February 2014. Patients with a history of cancer before hospitalization for HF were excluded. The discriminatory properties of the CHA 2 DS 2 -VASc score were quantified using C-statistics., Results: The study included 5158 patients with HF, 2091 with and 3067 without AF. Rates of stroke in these two groups were 4.5 and 2.8%, respectively, after 1 year, and 5.5 and 3.4%, respectively, after 2 years. Each 1-point increase in CHA 2 DS 2 -VASc score was associated with significantly increased risks of stroke and all-cause death in HF patients with and without AF (p-value < 0.05). The C-statistics of the CHA 2 DS 2 -VASc score for all-cause death in patients with and without AF were 0.600 and 0.630, respectively, at 1 year and 0.626 and 0.635, respectively, at 2 years. The C-statistics for stroke ranged from 0.593 to 0.639., Conclusions: Among patients with incident HF with and without AF, CHA 2 DS 2 -VASc score was significantly associated with the risks of stroke and death. However, CHA 2 DS 2 -VASc score was only a modest predictor of stroke and death, indicating the need for studies evaluating modified CHA 2 DS 2 -VASc scores. The majority of strokes occurred relatively shortly after hospitalization for HF and that mortality rates in patients with HF remain high. Thus, early treatment after HF to prevent stroke is essential.

Purpose: The global trend of resident work-hour restrictions requires a more time efficient way of resident training. Among many training programs for learning the facial anatomy, the cadaver is the most similar to live patients. A cadaver should be used as efficiently as possible due to human dignity as well as the consideration of cost. The authors designed an effective cadaver dissection method in learning facial anatomy using the plastic surgery approach., Method: A 51-year-old male cadaver was used for dissection. The program was proceeded 6 times over 6 weeks, and 4 to 8 hours each day. We used standard surgical instruments with magnifying loupes. The results were analyzed through a numerical scale survey., Result: We planned to dissect the face from medial to lateral, cephalic to caudal, and superficial to deep portion. The overall knowledge and confidence level of the face were increased in all 7 participants. The mean knowledge level before and after the seminar was 3.00 and 4.03, respectively. Confidence level also increased through the seminar from 1.86 to 2.86., Conclusion: The authors believe this cadaver dissection program could optimize learning anatomical knowledge and improve resident's surgical confidence through a wide range of procedures.

The lipid scramblase TMEM16F initiates blood coagulation by catalyzing the exposure of phosphatidylserine in platelets. The protein is part of a family of membrane proteins, which encompasses calcium-activated channels for ions and lipids. Here, we reveal features of murine TMEM16F (mTMEM16F) that underlie its function as a lipid scramblase and an ion channel. The cryo-EM data of mTMEM16F in absence and presence of Ca 2+ define the ligand-free closed conformation of the protein and the structure of a Ca 2+ -bound intermediate. Both conformations resemble their counterparts of the scrambling-incompetent anion channel mTMEM16A, yet with distinct differences in the region of ion and lipid permeation. In conjunction with functional data, we demonstrate the relationship between ion conduction and lipid scrambling. Although activated by a common mechanism, both functions appear to be mediated by alternate protein conformations that are at equilibrium in the ligand-bound state., Competing Interests: CA, NL, VC, GO, RD, CP No competing interests declared, (© 2019, Alvadia et al.)

Background: Identifying patients with acute heart failure (HF) at high risk for readmission or death after hospital discharge will enable the optimization of treatment and management. The objective of this study was to develop a risk score for 30-day HF-specific readmission or death in Korea., Methods: We analyzed the data from the Korean Acute Heart Failure (KorAHF) registry to develop a risk score. The model was derived from a multiple logistic regression analysis using a stepwise variable selection method. We also proposed a point-based risk score to predict the risk of 30-day HF-specific readmission or death by simply summing the scores assigned to each risk variable. Model performance was assessed using an area under the receiver operating characteristic curve (AUC), the Hosmer-Lemeshow goodness-of-fit test, the net reclassification improvement (NRI), and the integrated discrimination improvement (IDI) index to evaluate discrimination, calibration, and reclassification, respectively., Results: Data from 4566 patients aged ≥40 years were included in the analysis. Among them, 446 (9.8%) had 30-day HF-specific readmission or death. The final model included 12 independent variables (age, New York Heart Association functional class, clinical history of hypertension, HF admission, chronic obstructive pulmonary disease, etiology of cardiomyopathy, systolic blood pressure, left ventricular ejection fraction, serum sodium, brain natriuretic peptide, N-terminal prohormone of brain natriuretic peptide at discharge, and prescription of β-blockers and angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists at discharge). The point risk score showed moderate discrimination (AUC of 0.710; 95% confidence interval, 0.685-0.735) and good calibration (χ 2 =8.540, p=0.3826)., Conclusions: The risk score for the prediction of the risk of 30-day HF-specific readmission or death after hospital discharge was developed using 12 predictors. It can be utilized to guide appropriate interventions or care strategies for patients with HF., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Two practical entries to arylomycin antibiotics core structures are investigated. In route A, the activation of l-Hpg for the key macrolactamization step is achieved in 89% yield in the presence of unprotected phenol and amine functionalities. Alternatively, a propanephosphonic acid anhydride (T3P)-promoted coupling between thel-Tyr and l-Ala moieties in route B led to a facile macrolactamization in 68% yield with a marked reduction in competing oligomerization.

We report an efficient synthesis of GDC-0810 on the basis of a sequence involving a highly stereoselective lithium tert-butoxide-mediated enolization-tosylation (≥95:5 E: Z) and a Pd-catalyzed Suzuki-Miyaura cross-coupling as key steps. Global deprotection, pyrrolidine salt formation, and final active pharmaceutical ingredient (API) form control/isolation produced GDC-0810 free acid in a 40% overall yield with >99.0% purity as ascertained by HPLC analysis.

Background: Screening for risk of type 2 diabetes mellitus (T2DM) is an important public health issue. Previous studies report that fasting plasma glucose (FPG) and triglyceride (TG)-related indices, such as lipid accumulation product (LAP) and the product of fasting glucose and triglyceride (TyG index), are associated with incident T2DM. We aimed to evaluate whether FPG or TG-related indices can improve the predictive ability of a diabetes risk model for middle-aged Koreans., Methods: 7708 Koreans aged 40-69 years without diabetes at baseline were eligible from the Korean Genome and Epidemiology Study. The overall cumulative incidence of T2DM was 21.1% (766 cases) in men and 19.6% (797 cases) in women. Therefore, the overall cumulative incidence of T2DM was 20.3% (1563 cases). Multiple logistic regression analysis was conducted to compare the odds ratios (ORs) for incident T2DM for each index. The area under the receiver operating characteristic curve (AROC), continuous net reclassification improvement (cNRI), and integrated discrimination improvement (IDI) were calculated when each measure was added to the basic risk model for diabetes., Results: All the TG-related indices and FPG were more strongly associated with incident T2DM than WC in our study population. The adjusted ORs for the highest quartiles of WC, TG, FPG, LAP, and TyG index compared to the lowest, were 1.64 (95% CI, 1.13-2.38), 2.03 (1.59-2.61), 3.85 (2.99-4.97), 2.47 (1.82-3.34), and 2.79 (2.16-3.60) in men, and 1.17 (0.83-1.65), 2.42 (1.90-3.08), 2.15 (1.71-2.71), 2.44 (1.82-3.26), and 2.85 (2.22-3.66) in women, respectively. The addition of TG-related parameters or FPG, but not WC, to the basic risk model for T2DM (including age, body mass index, family history of diabetes, hypertension, current smoking, current drinking, and regular exercise) significantly increased cNRI, IDI, and AROC in both sexes., Conclusions: Adding either TyG index or FPG into the basic risk model for T2DM increases its prediction and reclassification ability. Compared to FPG, TyG index was a more robust T2DM predictor in the stratified sex and fasting glucose level. Therefore, TyG index should be considered as a screening tool for identification of people at high risk for T2DM in practice.

The cerebrospinal fluid (CSF) is a valuable body fluid for analysis in neuroscience research. It is one of the fluids in closest contact with the central nervous system and thus, can be used to analyze the diseased state of the brain or spinal cord without directly accessing these tissues. However, in mice it is difficult to obtain from the cisterna magna due to its closeness to blood vessels, which often contaminate samples. The area for CSF collection in mice is also difficult to dissect to and often only small samples are obtained (maximum of 5-7 µL or less). This protocol describes in detail a technique that improves on current methods of collection to minimize contamination from blood and allow for the abundant collection of CSF (on average 10-15 µL can be collected). This technique can be used with other dissection methods for tissue collection from mice, as it does not impact any tissues during CSF extraction. Thus, the brain and spinal cord are not affected with this technique and remain intact. With greater CSF sample collection and purity, more analyses can be used with this fluid to further aid neuroscience research and better understand diseases affecting the brain and spinal cord.