bluuebunny/crossref_metadata_2025 huggingface dataset:
Will the New CDC Opioid Prescribing Guidelines Help Correct the Course in Pain Care?
Authors: Peachman Rachel Rabkin
Published: December 2022

This Medical News article discusses the 2022 Clinical Practice Guideline for Prescribing Opioids for Pain, an update to widely criticized recommendations released by the CDC in 2016.
Association of PCSK9 Loss-of-Function Variants With Risk of Heart Failure
Authors: Trudsø Linea C. , Ghouse Jonas , Ahlberg Gustav , Bundgaard Henning , Olesen Morten S.
Published: December 2022

Importance

An animal (mouse) study indicated that deficiency of proprotein convertase subtilisin/kexin type 9 (PCSK9) causes cardiac remodeling and heart failure (HF). Cardiac remodeling after PCSK9-inhibitor treatment is a concern for patients and for development of treatment directed against PCSK9.

Objective

To determine whether genetic variants in the PCSK9 gene are associated with altered cardiac structure, cardiac function, and HF in humans.

Design, Setting, Participants

This was a nested case-control study within the UK Biobank. Between March 13, 2006, and October 1, 2010, the UK Biobank enrolled 502 480 individuals aged 40 to 69 years. This study focused on a subset of those individuals, who completed cardiac magnetic resonance (CMR) imaging and had available genetic data. Analyses were conducted between November 2, 2021, and October 28, 2022.

Exposures

Carrier status of predicted loss-of-function (pLoF) PCSK9 variants, R46L missense variant, and a genetic risk score (GRS).

Main Outcomes and Measures

A total of 11 CMR imaging measurements, generated using a machine learning algorithm, and HF diagnosis.

Results

In up to 35 135 individuals with CMR images, 18 252 (52%) were female individuals, and mean (SD) age was 55.0 (7.4) years. No significant association between PCSK9 carrier status and CMR indices were found for left ventricular mass (pLoF: β = −1.01; 95% CI, −2.99 to 0.98; P = .32; R46L: β = −0.18; 95% CI, −0.55 to 0.19; P = .35; GRS: β = −0.19; 95% CI, −0.50 to 0.11; P = .22) and left ventricular ejection fraction (pLoF: β = 0.43; 95% CI, −1.32 to 2.18; P = .63; R46L: β = −0.19; 95% CI, −0.52 to 0.14; P = .26; GRS: β = −0.08; 95% CI, −0.35 to 0.20; P = .58) or HF (pLoF: odds ratio [OR], 1.14; 95% CI, 0.56-2.05; P = .69; R46L: OR, 0.99; 95% CI, 0.90-1.10; P = .91; GRS: OR, 1.04; 95% CI, 0.96-1.13; P = .32).

Conclusions and Relevance

Results of this case-control study suggest that there was no association between PCSK9 genetic variants and altered cardiac structure, cardiac function, or HF in humans.
High-Dose Vitamin D for the Management of Toxic Erythema of Chemotherapy in Hospitalized Patients
Authors: Nguyen Cuong V. , Zheng Lida , Zhou Xiaolong A. , Ernst Madison K. , Kye Yae , Choi Jennifer N. , Lu Kurt Q.
Published: December 2022

This case series describes the outcome of high-dose vitamin D treatment in 6 inpatients with acute skin injury.
Racial and Ethnic Disparities in Access to Minimally Invasive Mitral Valve Surgery
Authors: Glance Laurent G. , Joynt Maddox Karen E. , Mazzefi Michael , Knight Peter W. , Eaton Michael P. , Feng Changyong , Kertai Miklos D. , Albernathy James , Wu Isaac Y. , Wyrobek Julie A. , Cevasco Marisa , Desai Nimesh , Dick Andrew W.
Published: December 2022

Importance

Whether people from racial and ethnic minority groups experience disparities in access to minimally invasive mitral valve surgery (MIMVS) is not known.

Objective

To investigate racial and ethnic disparities in the utilization of MIMVS.

Design, Setting, and Participants

This cross-sectional study used data from the Society of Thoracic Surgeons Database for patients who underwent mitral valve surgery between 2014 and 2019. Statistical analysis was performed from January 24 to August 11, 2022.

Exposures

Patients were categorized as non-Hispanic White, non-Hispanic Black, and Hispanic individuals.

Main Outcomes and Measures

The association between MIMVS (vs full sternotomy) and race and ethnicity were evaluated using logistic regression.

Results

Among the 103 753 patients undergoing mitral valve surgery (mean [SD] age, 62 [13] years; 47 886 female individuals [46.2%]), 10 404 (10.0%) were non-Hispanic Black individuals, 89 013 (85.8%) were non-Hispanic White individuals, and 4336 (4.2%) were Hispanic individuals. Non-Hispanic Black individuals were more likely to have Medicaid insurance (odds ratio [OR], 2.21; 95% CI, 1.64-2.98; P < .001) and to receive care from a low-volume surgeon (OR, 4.45; 95% CI, 4.01-4.93; P < .001) compared with non-Hispanic White individuals. Non-Hispanic Black individuals were less likely to undergo MIMVS (OR, 0.65; 95% CI, 0.58-0.73; P < .001), whereas Hispanic individuals were not less likely to undergo MIMVS compared with non-Hispanic White individuals (OR, 1.08; 95% CI, 0.67-1.75; P = .74). Patients with commercial insurance had 2.35-fold higher odds of undergoing MIMVS (OR, 2.35; 95% CI, 2.06-2.68; P < .001) than those with Medicaid insurance. Patients operated by very-high volume surgeons (300 or more cases) had 20.7-fold higher odds (OR, 20.70; 95% CI, 12.7-33.9; P < .001) of undergoing MIMVS compared with patients treated by low-volume surgeons (less than 20 cases). After adjusting for patient risk, non-Hispanic Black individuals were still less likely to undergo MIMVS (adjusted OR [aOR], 0.88; 95% CI, 0.78-0.99; P = .04) and were more likely to die or experience a major complication (aOR, 1.25; 95% CI, 1.16-1.35; P < .001) compared with non-Hispanic White individuals.

Conclusions and Relevance

In this cross-sectional study, non-Hispanic Black patients were less likely to undergo MIMVS and more likely to die or experience a major complication than non-Hispanic White patients. These findings suggest that efforts to reduce inequity in cardiovascular medicine may need to include increasing access to private insurance and high-volume surgeons.
Race and Ethnicity Reporting and Representation in Obstetrics and Gynecology Clinical Trials and Publications From 2007-2020
Authors: Steinberg Jecca R. , Turner Brandon E. , DiTosto Julia D. , Weeks Brannon T. , Young Anna Marie P. , Lu Connie F. , Wolgemuth Tierney , Holder Kai , Laasiri Nora , Squires Natalie , Zhang Naixin , Richardson Michael Taylor , Magnani Christopher J. , Anderson Jill N. , Roque Dario R. , Yee Lynn M.
Published: December 2022

Importance

Clinical trials guide evidence-based obstetrics and gynecology (OB-GYN) but often enroll nonrepresentative participants.

Objective

To characterize race and ethnicity reporting and representation in US OB-GYN clinical trials and their subsequent publications and to analyze the association of subspecialty and funding with diverse representation.

Design and Setting

Cross-sectional analysis of all OB-GYN studies registered on ClinicalTrials.gov (2007-2020) and publications from PubMed and Google Scholar (2007-2021). Analyses included logistic regression controlling for year, subspecialty, phase, funding, and site number. Data from 332 417 studies were downloaded. Studies with a noninterventional design, with a registration date before October 1, 2007, without relevance to OB-GYN, with no reported results, and with no US-based study site were excluded.

Exposures

OB-GYN subspecialty and funder.

Main Outcomes and Measures

Reporting of race and ethnicity data and racial and ethnic representation (the proportion of enrollees of American Indian or Alaskan Native, Asian, Black, Latinx, or White identity and odds of representation above US Census estimates by race and ethnicity).

Results

Among trials with ClinicalTrials.gov results (1287 trials with 591 196 participants) and publications (1147 trials with 821 111 participants), 662 (50.9%) and 856 (74.6%) reported race and ethnicity data, respectively. Among publications, gynecology studies were significantly less likely to report race and ethnicity than obstetrics (adjusted odds ratio [aOR], 0.54; 95% CI, 0.38-0.75). Reproductive endocrinology and infertility trials had the lowest odds of reporting race and ethnicity (aOR, 0.14; 95% CI, 0.07-0.27; reference category, obstetrics). Obstetrics and family planning demonstrated the most diverse clinical trial cohorts. Compared with obstetric trials, gynecologic oncology had the lowest odds of Black representation (ClinicalTrials.gov: aOR, 0.04; 95% CI, 0.02-0.09; publications: aOR, 0.06; 95% CI, 0.03-0.11) and Latinx representation (ClinicalTrials.gov: aOR, 0.05; 95% CI, 0.02-0.14; publications: aOR, 0.23; 95% CI, 0.10-0.48), followed by urogynecology and reproductive endocrinology and infertility. Urogynecology (ClinicalTrials.gov: aOR, 0.15; 95% CI, 0.05-0.39; publications: aOR, 0.24; 95% CI, 0.09-0.58) had the lowest odds of Asian representation.

Conclusions and Relevance

Race and ethnicity reporting and representation in OB-GYN trials are suboptimal. Obstetrics and family planning trials demonstrate improved representation is achievable. Nonetheless, all subspecialties should strive for more equitably representative research.
Comparison of Postoperative Outcomes of Laparoscopic vs Open Inguinal Hernia Repair
Authors: Meier Jennie , Stevens Audrey , Berger Miles , Makris Konstantinos I. , Bramos Athanasios , Reisch Joan , Cullum C. Munro , Lee Simon C. , Sugg Skinner Celette , Zeh Herbert , Brown Cynthia J. , Balentine Courtney J.
Published: December 2022

Importance

Advocates of laparoscopic surgery argue that all inguinal hernias, including initial and unilateral ones, should be repaired laparoscopically. Prior work suggests outcomes of open repair are improved by using local rather than general anesthesia, but no prior studies have compared laparoscopic surgery with open repair under local anesthesia.

Objective

To evaluate postoperative outcomes of open inguinal hernia repair under general or local anesthesia compared with laparoscopic repair.

Design, Setting, and Participants

This retrospective cohort study identified 107 073 patients in the Veterans Affairs Surgical Quality Improvement Program database who underwent unilateral initial inguinal hernia repair from 1998 to 2019. Data were analyzed from October 2021 to March 2022.

Exposures

Patients were divided into 3 groups for comparison: (1) open repair with local anesthesia (n = 22 333), (2) open repair with general anesthesia (n = 75 104), and (3) laparoscopic repair with general anesthesia (n = 9636).

Main Outcomes and Measures

Operative time and postoperative morbidity were compared using quantile regression and inverse probability propensity weighting. A 2-stage least-squares regression and probabilistic sensitivity analysis was used to quantify and address bias from unmeasured confounding in this observational study.

Results

Of 107 073 included patients, 106 529 (99.5%) were men, and the median (IQR) age was 63 (55-71) years. Compared with open repair with general anesthesia, laparoscopic repair was associated with a nonsignificant 0.15% (95% CI, −0.39 to 0.09; P = .22) reduction in postoperative complications. There was no significant difference in complications between laparoscopic surgery and open repair with local anesthesia (−0.05%; 95% CI, −0.34 to 0.28; P = .70). Operative time was similar for the laparoscopic and open general anesthesia groups (4.31 minutes; 95% CI, 0.45-8.57; P = .048), but operative times were significantly longer for laparoscopic compared with open repair under local anesthesia (10.42 minutes; 95% CI, 5.80-15.05; P < .001). Sensitivity analysis and 2-stage least-squares regression demonstrated that these findings were robust to bias from unmeasured confounding.

Conclusions and Relevance

In this study, laparoscopic and open repair with local anesthesia were reasonable options for patients with initial unilateral inguinal hernias, and the decision should be made considering both patient and surgeon factors.
Does the nuclear envelope retain its identity during mitosis?
Authors: Tsuda Natsumi , Fukagawa Ryohei , Sueda Shinji
Published: December 2022

During mitosis in metazoan species, the nuclear envelope (NE) undergoes breakdown, and its fragments are absorbed within the membranous network of the endoplasmic reticulum (ER). Past observations by fluorescence microscopy led researchers to think that the NE loses its identity when it is absorbed within the ER membrane. However, in our previous work, we developed a more specific labelling method and found evidence that the NE does not completely lose its identity during mitosis. In the present work, we conduct further experiments, the results of which support the idea that the NE partially retains its identity during mitosis.
White matter hyperintensity, neurofilament light chain, and cognitive decline
Authors: Dhana Anisa , DeCarli Charles , Dhana Klodian , Desai Pankaja , Wilson Robert S. , Evans Denis A. , Rajan Kumar B.
Published: December 2022

Objective

We aimed to determine whether combining white matter hyperintensity (WMH) with neurofilament light chain (NfL) could provide additional information for cognition in older adults.

Methods

Utilizing data from the population‐based Chicago Health and Aging Project, we studied 701 individuals with both biomarkers and cognitive data during the follow‐up period. NfL was measured using an ultrasensitive immunoassay, single‐molecule array technology. MRI scans of the brain were acquired using 1.5‐T systems. Global cognitive function was created as a composite measure of four neuropsychological tests, standardized and averaged to z‐scores. Multivariable linear mixed‐effects models were used to evaluate the association of WMH and NfL with the rate of cognitive decline.

Results

Higher WMH and NfL were associated with a faster rate of cognitive decline during the follow‐up; ‐coefficients (95%CIs) were −0.011 (−0.02, −0.001) and −0.010 (−0.017, −0.003), respectively. In individuals with lower concentration of NfL (i.e., bottom tertile), a higher WMH volume was associated with a faster cognitive decline (: −0.030; 95%CI −0.046, −0.014). Similarly, in individuals with lower volumes of WMH (i.e., bottom tertile), a higher concentrations of NfL was associated with a faster cognitive decline (: −0.023; 95%CI −0.042, −0.005). When we combined WMH with NfL, we noted a graded association with increasing volumes of WMH, particularly in people with lower NfL values.

Interpretation

While both biomarkers, WMH and NfL, were similarly associated with the annual rate of cognitive decline, our study suggests that they provide different underlying mechanisms affecting cognition.
Microstructures and Tensile Properties of New Mg–0.9Zn–0.2Mn–0.5RE Alloys via Different Al Additions
Authors: Fu Li , Zhang Zhiqian , Li Xiaoqiang , Jia Zheng , Lu Lin , Le Qichi
Published: December 2022

Effects of Al content on the microstructure and tensile properties of Mg–0.9Zn–0.2Mn–0.5RE (0.2Sm + 0.3La) alloy have been systematically investigated. In the as‐cast Mg–0.9Zn–0.2Mn–0.5RE alloy, intermetallic compounds are identified as Mg41Sm5, Mg12La, and Mg12(La, Sm) phases, while when Al is added, new Mg17Al12 and Al11(La, Sm)3 phase is formed instead of Mg12(La, Sm) phase. As Al content increases, Al11(La, Sm)3 phase increases and the morphology changes from a bright needle to a short rod in the as‐cast alloys. Al11(La, Sm)3 phase is broken and characterized as polygonal and rod shapes in as‐extruded alloys, and gradually increases in size and segregation as Al content increases, resulting in an increase in the ultimate strength and fluctuation of the average grain size, yield strength, and elongation. It should be noted that the as‐extruded alloy has good elongation (A ≈ 25.3%) with 3% Al content and good tensile strength (280 MPa ≤ Rm ≤ 300 MPa) with 6% and 9% Al content. Besides, the as‐extruded Mg–0.9Zn–0.2Mn–0.5RE–3Al alloy shows outstanding ductility due to the weakened texture of DRXed and sub‐structured grains and the high SF value in pyramidal  slip and basal  slip.
Defects Passivation via Potassium Iodide Post‐Treatment for Antimony Selenosulfide Solar Cells with Improved Performance
Authors: Li Jiashuai , Gao Zheng , Hu Xuzhi , Wang Shuxin , Liu Yongjie , Wang Chen , Dong Kailian , Zeng Zhaofeng , Tao Chen , Fang Guojia
Published: December 2022

Antimony selenosulfide (Sb2(S,Se)3) has been emerging as a promising light absorber in the past few years owing to tunable bandgap (1.1–1.7 eV), high absorption coefficient (>105 cm−1) and excellent phase and environmental stability. However, the efficiency of Sb2(S,Se)3 solar cells lags far behind the Shockley–Queisser limit. One of the critical obstacles originates from various extrinsic and intrinsic defects. They mostly locate in the deep energy levels and are prone to form recombination centers, inhibiting the improvement of device performance. Herein, surface post‐treatment via potassium iodide is introduced to fabricate high‐quality Sb2(S,Se)3 films and solar cells. The surface post‐treatment not only manipulates the crystal growth process to form compact films with larger grain size but also forms better band alignment and inhibits the formation of deep‐level defects antimony antisite (SbSe), thus improving the quality of heterojunction. Consequently, the resultant Sb2(S,Se)3 solar cells achieve a champion power conversion efficiency of 9.22%. This study provides a new strategy of passivating deep‐level intrinsic defects via surface post‐treatment for high‐efficiency Sb2(S,Se)3 solar cells.
Origin of Fast Capacity Decay in Fe‐Mn Based Sodium Layered Oxides
Authors: Gao Xu , Fang Liang , Wang HaoJi , Lee Suwon , Liu Huanqing , Zhang Shu , Gao Jinqiang , Mei Yu , Park Mihui , Zhang Jing , Chen Mingzhe , Zhou Limin , Deng Wentao , Zou Guoqiang , Hou Hongshuai , Kang Yong‐Mook , Ji Xiaobo
Published: December 2022

Fe‐Mn based layered oxides are recognized as promising cathode materials for sodium‐ion batteries (SIBs) with high capacities and earth‐abundant ingredients. However, their real‐world applications are still constrained by fast capacity decay accompanied with the requirements of deeper insights into the principles behind. Herein, taking O3‐NaxFe1/2Mn1/2O2 as a classic sample, the capacity fading mechanism of Fe‐Mn based layered oxides is comprehensively investigated through combined techniques. For the first time, it is revealed that Fe migration is merely triggered after the oxidation of ≈0.3 mol Fe3+ based on solid proofs from ex situ X‐ray absorption spectroscopy and Mössbauer spectroscopy, which implies the crucial role of the accumulated structural distortion induced by Jahn–Teller active Fe4+. O3‐P3 phase transition during cycling is obviously constrained along with Fe migration as evidenced by in situ/ex situ X‐ray diffraction, well interpreting the intensified polarization and the resulting large capacity loss. More importantly, within the desodiation depth (≈80% of sodium extraction) where Fe migration is almost absent, the capacity fading is dominantly rooted in the Fe4+ activated and Mn‐dissolution aggravated surface passivation as confirmed by mass/X‐ray spectroscopies and electrochemical analysis. These renewed understandings of the fast capacity decay in Fe‐Mn based layered oxides offer clearer clues for designing desirable cathodes for SIBs.
Profiling of Tumor Cell‐Delivered Exosome by Surface Enhanced Raman Spectroscopy‐Based Biosensor for Evaluation of Nasopharyngeal Cancer Radioresistance
Authors: Wu Qiong , Ding Qin , Lin Wanzun , Weng Youliang , Feng Shangyuan , Chen Rong , Chen Chuanben , Qiu Sufang , Lin Duo
Published: December 2022

Although the advancement of radiotherapy significantly improves the survival of nasopharyngeal cancer (NPC), radioresistance associated with recurrence and poor outcomes still remains a daunting challenge in the clinical scenario. Currently, effective biomarkers and convenient detection methods for predicting radioresistance have not been well established. Here, the surface‐enhanced Raman spectroscopy combined with proteomics is used to firstly profile the characteristic spectral patterns of exosomes secreted from self‐established NPC radioresistance cells, and reveals specific variations of proteins expression during radioresistance formation, including collagen alpha‐2 (I) chain (COL1A2) that is associated with a favorable prognosis in NPC and is negatively associated with DNA repair scores and DNA repair‐related genes via bioinformatic analysis. Furthermore, deep learning model‐based diagnostic model is generated to accurately identify the exosomes from radioresistance group. This work demonstrates the promising potential of exosomes as a novel biomarker for predicting the radioresistance and develops a rapid and sensitive liquid biopsy method that will provide a personalized and precise strategy for clinical NPC treatment.
Calcium–Zinc Phosphate Chemical Conversion Coating Facilitates the Osteointegration of Biodegradable Zinc Alloy Implants by Orchestrating Macrophage Phenotype
Authors: Zhao Da‐Wang , Du Chun‐Miao , Zuo Kang‐Qing , Zhao Yi‐Xiang , Xu Xiao‐Qian , Li Yi‐Bo , Tian Shuai , Yang Hong‐Ru , Lu Yu‐Peng , Cheng Lei , Xiao Gui‐Yong
Published: December 2022

Zinc (Zn) alloys provide a new generation for orthopedic applications due to their essential physiological effects and promising degradation properties. However, excessive release of Zn ions (Zn2+) during degradation and the severe inflammatory microenvironment are not conducive to osseointegration, which is determined by the characteristics of the implant surface. Therefore, it is essential to modulate the release rate of Zn alloys by surface modification technology and endow them with anti‐inflammatory and osteogenic effects. In this study, two kinds of phosphate chemical conversion (PCC) coatings with different compositions and morphological structures are prepared, namely Zn–P (with disk‐like crystals) and Ca–Zn–P (with lamellar crystals). Although all the PCC‐coated Zn implants have low cytotoxicity, Ca–Zn–P show better osteoimmunomodulation effects in several aspects: the induction of the M2‐phenotype macrophage polarization and thus promotion of osteogenesis in vitro; the regulation of the bone immune microenvironment which is conducive to tissue regeneration and osseointegration in vivo; and the release of ions (through PI3K/AKT and Wnt signaling pathways) and the morphological structures (through RhoGTPase signaling pathways) act as possible mechanisms of M2 polarization. The Ca–Zn–P coating can be considered to provide new insights into bone immunomodulation and osseointegration.
Biohybrid 3D Printing of a Tissue‐Sensor Platform for Wireless, Real‐Time, and Continuous Monitoring of Drug‐Induced Cardiotoxicity
Authors: Yong Uijung , Kim Donghwan , Kim Hojoong , Hwang Dong Gyu , Cho Sungkeon , Nam Hyoryung , Kim Sejin , Kim Taeyeong , Jeong Unyong , Kim Keehoon , Chung Wan Kyun , Yeo Woon‐Hong , Jang Jinah
Published: December 2022

Drug‐induced cardiotoxicity is regarded as a major hurdle in the early stages of drug development. Although there are various methods for preclinical cardiotoxicity tests, they cannot completely predict the cardiotoxic potential of a compound due to the lack of physiological relevance. Recently, 3D engineered heart tissue (EHT) has been used to investigate cardiac muscle functions as well as pharmacological effects by exhibiting physiological auxotonic contractions. However, there is still no adequate platform for continuous monitoring to test acute and chronic pharmacological effects in vitro. Here, a biohybrid 3D printing method for fabricating a tissue‐sensor platform, composed of a bipillar‐grafted strain gauge sensor and EHT, is first introduced. Two pillars are three‐dimensionally printed as grafts onto a strain gauge‐embedded substrate to promote the EHT contractility and guide the self‐assembly of the EHTs along with the strain gauge. In addition, the integration of a wireless multi‐channel electronic system allows for continuous monitoring of the EHT contractile force by the tissue‐sensor platform and, ultimately, for the observation of the acute and chronic drug effects of cardiotoxicants. In summary, biohybrid 3D printing technology is expected to be a potential fabrication method to provide a next‐generation tissue‐sensor platform for an effective drug development process.
Dissolvable Self‐Locking Microneedle Patches Integrated with Immunomodulators for Cancer Immunotherapy
Authors: Joo Seung‐Hwan , Kim Jaehyun , Hong Juhyeong , Fakhraei Lahiji Shayan , Kim Yong‐Hee
Published: December 2022

Advancements in micro‐resolution 3D printers have significantly facilitated the development of highly complex mass‐producible drug delivery platforms. Conventionally, due to the limitations of micro‐milling machineries, dissolvable microneedles (MNs) are mainly fabricated in cone‐shaped geometry with limited drug delivery accuracy. Herein, to overcome the limitations of conventional MNs, a novel projection micro‐stereolithography 3D printer‐based self‐locking MN for precise skin insertion, adhesion, and transcutaneous microdose drug delivery is presented. The geometry of self‐locking MN consists of a sharp skin‐penetrating tip, a wide skin interlocking body, and a narrow base with mechanical supports fabricated over a flexible hydrocolloid patch to improve the accuracy of skin penetration into irregular surfaces. Melanoma, a type of skin cancer, is selected as the model for the investigation of self‐locking MNs due to its irregular and uneven surface. In vivo immunotherapy efficacy is evaluated by integrating SD‐208, a novel transforming growth factor‐β (TGF‐β) inhibitor that suppresses the proliferation and metastasis of tumors, and anti‐PD‐L1 (aPD‐L1 Ab), an immune checkpoint inhibitor that induces T cell‐mediated tumor cell death, into self‐locking MNs and comparing them with intratumoral injection. Evaluation of (aPD‐L1 Ab)/SD‐208 delivery effectiveness in B16F10 melanoma‐bearing mice model confirms significantly improved dose efficacy of self‐locking MNs compared with intratumoral injection.
Microenvironmentally Responsive Chemotherapeutic Prodrugs and CHEK2 Inhibitors Self‐Assembled Micelles: Protecting Fertility and Enhancing Chemotherapy
Authors: Wu Meng , Xue Liru , Guo Yican , Dong Xiaoqi , Chen Zhaojun , Wei Simin , Yi Xiaoqing , Li Yinuo , Zhang Jinjin , Zhou Su , Wu Mingfu , Lou Xiaoding , Dai Jun , Xia Fan , Wang Shixuan
Published: December 2022

Chemotherapy is a widely used and effective adjuvant treatment for cancer, and it has unavoidable damage to female fertility, with statistics showing 38% of women who have received chemotherapy are infertile. How to reduce fertility toxicity while enhancing the oncologic chemotherapy is a clinical challenge. Herein, co‐delivery micelles (BML@PMP) are developed, which are composed of a reduction‐sensitive paclitaxel prodrug (PMP) for chemotherapy and a CHEK2 inhibitor (BML277) for both fertility protection and chemotherapy enhancement. BML@PMP achieves fertility protection through three actions: (1) Due to the enhanced permeability and retention (EPR) effect, BML@PMP is more enriched in the tumor, while very little in the ovary (about 1/10th of the tumor). (2) Glutathione (GSH) triggers the release of PTX, and with low levels of GSH in the ovary, the amount of PTX released in the ovary is correspondingly reduced. (3) BML277 inhibits oocyte apoptosis by inhibiting the CHEK2‐TAp63α pathway. Because of the different downstream targets of CHEK2 in tumor cells and oocytes, BML277 also enhances chemotherapeutic efficacy by reducing DNA damage repair which is activated through the CHEK2 pathway. This bidirectional effect of CHEK2 inhibitor‐based co‐delivery system represents a promising strategy for improving oncology treatment indices and preventing chemotherapy‐associated fertility damage.
Anion‐Vacancy‐Defect Passivation of a 2D‐Layered Tin‐Based Perovskite Thin‐Film Transistor with Sulfur Doping
Authors: Cho Jae‐Hyeok , Go Ji‐Young , Bui Tan Tan , Mun Seunguk , Kim Yunseok , Ahn Kyunghan , Noh Yong‐Young , Kim Myung‐Gil
Published: December 2022

Metal halide perovskites have attracted a considerable amount of research attention with significant progress made in the field of optoelectronics. Despite their outstanding electrical characteristics, structural defects impede their potential performance due to the polycrystalline nature of solution‐processed perovskite films. Herein, the effective p‐type doping and defect passivation of phenethylammonium tin iodide ((PEA)2SnI4) perovskite films using xanthate additives as a sulfur source is reported. Sulfur can be introduced to the iodine vacancies mainly at the grain boundaries of the perovskite film, passivating the electrical defects originating from the iodine vacancy and increasing the hole concentration. The Fermi‐level shift toward the valence band maximum of the sulfur‐doped perovskite film is confirmed using ultraviolet photoemission spectroscopy, resulting in p‐type doping. Finally, the electrical performance improvement for the 0.2% sulfur‐doped (PEA)2SnI4 thin‐film transistor with a mobility of 1.45 cm2 V−1 s−1, an on/off ratio of 2.9 × 105 is demonstrated, and hysteresis of 10 V is reduced.
Unravelling plant diversification: Intraspecific genetic differentiation in hybridizingAnacyclusspecies in the western Mediterranean Basin
Authors: Bruno Agudo A. , Xavier Picó F. , Mateo Rubén G. , Marcer Arnald , Torices Rubén , Álvarez Inés
Published: December 2022

Premise

The interfertile speciesAnacyclus clavatus,A. homogamos, andA. valentinusrepresent a plant complex coexisting in large anthropic areas of the western Mediterranean Basin with phenotypically mixed populations exhibiting a great floral variation. The goal of this study was to estimate the genetic identity of each species, to infer the role of hybridization in the observed phenotypic diversity, and to explore the effect of climate on the geographic distribution of species and genetic clusters.

Methods

We used eight nuclear microsatellites to genotype 585 individuals from 31 populations of threeAnacyclusspecies for population genetic analyses by using clustering algorithms based on Bayesian models and ordination methods. In addition, we used ecological niche models and niche overlap analyses for both the species and genetic clusters. We used an expanded data set, including 721 individuals from 129 populations for ecological niche models of the genetic clusters.

Results

We found a clear correspondence between species and genetic clusters, except forA. clavatusthat included up to three genetic clusters. We detected individuals with admixed genetic ancestry inA. clavatusand in mixed populations. Ecological niche models predicted similar distributions for species and genetic clusters. For the two specific genetic clusters ofA. clavatus, ecological niche models predicted remarkably different areas.

Conclusions

Gene flow betweenAnacyclusspecies likely explains phenotypic diversity in contact areas. In addition, we suggest that introgression could be involved in the origin of one of the twoA. clavatusgenetic clusters, which also showed ecological differentiation.
A de novo hexokinase 1 (HK1) variant presenting as Boucher–Neuhäuser syndrome
Authors: Peretz Ryan H. , Zein Wadih M. , Hufnagel Robert B. , Ku Christine , Godfrey Rena , Wolfe Lynne , Adams David , Gahl William , Toro Camilo
Published: December 2022

Boucher–Neuhäuser syndrome (BNHS) is characterized by chorioretinal dystrophy, hypogonadotropic hypogonadism, and cerebellar dysfunction and atrophy. The disorder has been associated with biallelic pathogenic variants in the patatin‐like phospholipase domain‐containing protein 6 (PNPLA6) gene. We present an individual with a clinical diagnosis consistent with BNHS who lacked any PNPLA6 variants but on quartet family exome sequencing had a de novo variant in the hexokinase 1 (HK1) gene (NM_000188.2 [GRCh37/hg19]: g.71139826G>A, c.1240G>A, p.Gly414Arg), suggesting genetic heterogeneity for BNHS. Longitudinal follow‐up indicated neurological deterioration, neuropsychiatric symptoms, and progressive cerebellar atrophy. The BNHS phenotype overlaps and expands the known HK1 genotypic and phenotypic spectrum. Individuals with variants in HK1 should undergo evaluation for hypogonadotropic hypogonadism, potentially amenable to treatment.
Dermatological manifestations, management, and care in RASopathies
Authors: Kavamura Maria Ines , Leoni Chiara , Neri Giovanni
Published: December 2022

RASopathies are rare genetic disorders caused by germline pathogenic variants in genes belonging to the RAS/MAPK pathway, which signals cell proliferation, differentiation, survival and death. The dysfunction of such signaling pathway causes syndromes with overlapping clinical manifestations. Skin and adnexal lesions are the cardinal clinical signs of RASopathies, such as cardiofaciocutaneous syndrome, Noonan syndrome with multiple lentigines, formerly known as LEOPARD syndrome, Costello syndrome, neurofibromatosis (NF1), Legius syndrome, Noonan‐like syndrome with loose anagen hair (NSLH) and Noonan syndrome. As NF1, one of the most common RASopathies, described in 1882, has its clinical features well delineated, we will focus on the dermatological diagnosis, management and care of non‐NF1 RASopathies, which are less known and more recently described. Dermatological manifestations are important clinical diagnostic elements that can aid differential diagnosis among RASopathies. They can affect dermis and epidermis, causing pigmented lesions (melanocytic nevi, café‐au‐lait spots, and lentigines), hyperkeratosis (keratosis pilaris, ulerythema ophryogenes, and palmoplantar keratosis) or hyperplasia. To date there are rare known links to malignancy, but oftentimes skin lesions require close attention because they can highly affect quality of life.
Optic nerve sheath diameter correlates to intracranial pressure in spontaneous CSF leak patients
Authors: Tilak Ashwini M. , Yang Lydia C. , Morgan Jake , Peña‐Garcia Jaime , Thompson Maxwell , Burleson Samuel , Atkins Amanda , Sheehan Delaney , Cho Do‐Yeon , Woodworth Bradford A. , Grayson Jessica W.
Published: December 2022

Background

Spontaneous cerebrospinal fluid (sCSF) leaks develop from pressure erosion due to idiopathic intracranial hypertension, treatment of which is paramount to preventing recurrence. Direct measurements of intracranial pressure (ICP) for monitoring response to treatment via lumbar drain (LD) or ventriculostomy are invasive and have risks. The objectives of this study are to determine whether ultrasonographic measurements of optic nerve sheath diameter (ONSD) correlate with LD ICP in patients with sCSF leaks undergoing treatment, and whether ONSDs are larger in patients with sCSF leaks than controls.

Methods

Subjects with sCSF leaks and controls were prospectively recruited. ONSD, sex, and body mass index (BMI) were analyzed. For sCSF leak subjects, ultrasonography was performed at the time of LD opening and each pressure check postoperatively, including the acetazolamide response. In control patients, measurements were obtained at the time of surgery. Pearson's correlation between ONSD and ICP was performed.

Results

Subjects with sCSF leaks (n = 9, age 52.4 ± 9.5, all female) and controls (n = 8, age 60.1 ± 14.8, two females) had significantly different BMIs, 38.4 ± 8.1 vs. 29.2 ± 4.8, t(15) = 2.793, p = 0.014. ONSD was strongly correlated with ICP measurements (r = 0.583, p = 0.002). However, percentage change in ONSD and ICP measurements were more strongly correlated (r = 0.733, p < 0.001). Patients with sCSF leaks had significantly higher ONSDs than controls, 0.63 cm ± 0.044 vs. 0.56 cm ± 0.074, t(15) = 2.329, p = 0.034.

Conclusion

ONSD significantly correlated with ICP in sCSF leak patients and was wider in sCSF leak subjects than controls. Ultrasonography has utility in monitoring the ICP response to acetazolamide.
The First Synthesis of Subporphyrins
Authors: Shimizu Soji
Published: December 2022

Because of the rich coordination chemistry and unique optical and electrochemical properties, porphyrin analogues have been intensively investigated. Among them, subporphyrins have been long‐awaited molecules, with only their boron complexes known to date because of the crucial role of the central boron atom as a template in synthesis. The challenges related to the synthesis of a genuine subporphyrin (boron‐free) have finally been met and reported in a recent article from Kim, Osuka, and Song. A key strategy of their synthesis lies in the introduction of an exocyclic double bond at themeso‐position and subsequent reduction to obtain macrocyclic conjugation. Considering the fact that the development of porphyrin chemistry is ultimately linked to the availability of free base porphyrins, this seminal work will facilitate studies on coordination chemistry and applications in materials science.
Na2Ba[Na2Sn2S7]: Structural Tolerance Factor‐Guided NLO Performance Improvement
Authors: Li Rui‐An , Liu Qian‐Qian , Liu Xin , Liu Youquan , Jiang Xingxing , Lin Zheshuai , Jia Fei , Xiong Lin , Chen Ling , Wu Li‐Ming
Published: December 2022

The strong mutual coupling of and even the opposite change in the key parameters, such as the band gap (Eg) and second‐order harmonic generation (SHG), leads to the extreme scarcity in high‐performance IR nonlinear optical (NLO) chalcogenides. Herein, we report 8 new sulfides, Na2Ba[(AgxNa1−x)2Sn2S7] (1, x=0; 1 series, x=0.1–0.6; Na2Ba[(Li0.58Na0.42)2Sn2S7], 1‐0.6Li); Na2Sr[Cu2Sn2S7] (2); and Na2Ba[Cu2Sn2S7] (3). We use the structural tolerance factor (
) to connect the chemical composition, crystal structure, and NLO properties. Guided by these correlations, a better balance between Eg and SHG is realized in 1, which exhibits a large Eg of 3.42 eV and excellent NLO properties (SHG: 1.5×AGS; laser‐induced damage threshold: 12×AGS), representing the best performance among the known Hg‐ or As‐free sulfides to date.
Simple plant‐based production and purification of the assembled human ferritin heavy chain as a nanocarrier for tumor‐targeted drug delivery and bioimaging in cancer therapy
Authors: Knödler Matthias , Opdensteinen Patrick , Sankaranarayanan Ramya Ambur , Morgenroth Agnieszka , Buhl Eva Miriam , Mottaghy Felix M. , Buyel Johannes Felix
Published: December 2022

Nanoparticles are used as carriers for the delivery of drugs and imaging agents. Proteins are safer than synthetic nanocarriers due to their greater biocompatibility and the absence of toxic degradation products. In this context, ferritin has the additional benefit of inherently targeting the membrane receptor transferrin 1, which is overexpressed by most cancer cells. Furthermore, this self‐assembling multimeric protein can be loaded with more than 2000 iron atoms, as well as drugs, contrast agents, and other cargos. However, recombinant ferritin currently costs ~3.5 million € g−1, presumably because the limited number of producers cannot meet demand, making it generally unaffordable as a nanocarrier. Because plants can produce proteins at very‐large‐scale, we developed a simple, proof‐of‐concept process for the production of the human ferritin heavy chain by transient expression in Nicotiana benthamiana. We optimized the protein yields by screening different compartments and 5′‐untranslated regions in PCPs, and selected the best‐performing construct for production in differentiated plants. We then established a rapid and scalable purification protocol by combining pH and heat treatment before extraction, followed by an ultrafiltration/diafiltration size‐based separation process. The optimized process achieved ferritin levels of ~40 mg kg−1 fresh biomass although depth filtration limited product recovery to ~7%. The purity of the recombinant product was >90% at costs ~3% of the current sales price. Our method therefore allows the production of affordable ferritin heavy chain as a carrier for therapeutic and diagnostic agents, which is suitable for further stability and functionality testing in vitro and in vivo.
Chromosome evolution of Escherichia coli Nissle 1917 for high‐level production of heparosan
Authors: Yu Yanying , Gong Bingxue , Wang Huili , Yang Guixia , Zhou Xianxuan
Published: December 2022

Heparosan is a crucial‐polysaccharide precursor for the chemoenzymatic synthesis of heparin, a widely used anticoagulant drug. Presently, heparosan is mainly extracted with the potential risk of contamination from Escherichia coli strain K5, a pathogenic bacterium causing urinary tract infection. Here, a nonpathogenic probiotic, E. coli strain Nissle 1917 (EcN), was metabolically engineered to carry multiple copies of the 19‐kb kps locus and produce heparosan to 9.1 g/L in fed‐batch fermentation. Chromosome evolution driven by antibiotics was employed to amplify the kps locus, which governed the synthesis and export of heparosan from EcN at 21 mg L−1 OD−1. The average copy number of kps locus increased from 1 to 24 copies per cell, which produced up to 104 mg L‐1 OD−1 of heparosan in the shaking flask cultures of engineered strains. The following in‐frame deletion of recA stabilized the recombinant duplicates of chromosomal kps locus and the productivity of heparosan in continuous culture for at least 56 generations. Fed‐batch fermentation of the engineered strain EcN8 was carried out to bring the yield of heparosan up to 9.1 g/L. Heparosan from the fermentation culture was further purified at a 75% overall recovery. The structure of purified heparosan was characterized and further modified by N‐sulfotransferase with 3′‐phosphoadenosine‐5′‐phosphosulfate as the sulfo‐donor. The analysis of element composition showed that heparosan was N‐sulfated by over 80%. These results indicated that duplicating large DNA cassettes up to 19‐kb, followed by high‐cell‐density fermentation, was promising in the large‐scale preparation of chemicals and could be adapted to engineer other industrial‐interest bacteria metabolically.
Trace‐level determination of potential genotoxic impurities in quetiapine fumarate using LC–MS
Authors: Kavitapu DasameswaraRao , Gopireddy Ramana Reddy , Maruthapillai Arthanareeswari , Murty Jayanti Naga Sri Rama Chandra , Katari Naresh Kumar
Published: December 2022

A novel LC–MS method was developed and validated to determine three potential genotoxic impurities, namely 2‐(2‐aminophenylthio)benzoic acid hydrochloride, 2‐aminothiophenol, and 2‐(2‐aminophenylthio)benzonitrile, at trace level (~1.6 ppm) in quetiapine fumarate drug substance, an antipsychotic drug. These impurities are potentially genotoxic and therefore should be controlled at or below specific acceptance limits. An InertSustain AQ‐C18 column (250 × 4.6 mm, 5 μm) in reversed‐phase mode with the column temperature at 45°C was used. The mobile phase was 0.1% trifluoroacetic acid in water and acetonitrile with gradient elution mode, and the run time was 45 min. The flow rate was 0.8 ml/min. A mass spectrometer was used to quantify the amount of impurities using electrospray ionization mode at specific m/z 245.9, 126.0, and 226.9 for 2‐(2‐aminophenylthio)benzoic acid hydrochloride, 2‐aminothiophenol, and 2‐(2‐aminophenylthio) benzonitrile, respectively. The method was found to be sensitive and possessed excellent linearity in the concentration ranges from the limit of quantification to 150% of the permitted level (0.47–2.36 μg/ml) with correlation coefficients above 0.999. The results showed that the method was specific, precise, linear, and accurate for the estimation of these three impurities in quetiapine fumarate.
Government eco‐innovation incentives in a recycling system: A Stackelberg‐type model
Authors: Bimonte Giovanna , Ioppolo Giuseppe , Senatore Luigi , Trincone Barbara
Published: December 2022

As past economic progress has come at the expense of diminishing natural resources, increasing pollution and widespread damage to ecosystems around the world, an imperative we must respond to is to seek ways in which to achieve economic, social, and environmental sustainability, including actions aimed at a circular economy and eco‐innovation. Recycling has numerous implications for the environment, economic and production performance, employment, and production of wealth. The environmental regulator must therefore consider all the aspects of the waste cycle when deciding the right policies to maximize social welfare. We consider three types of agents involved in a Stackelberg game: manufacturers, importers and sellers (MIS), recyclers, and the government acting as an Environmental Protection Agency (EPA). In our model, we introduce the cost to adopt new technology for eco‐innovation per unit produced by the MIS, resulting in the possibility to reduce the weight of the advanced recycling fees if they invest more in the aptitude to be recycled of their products. The results give interesting prompts to investigate the relationship between environmental taxation and ecological incentives.
Photobiomodulation augments the effects of mitochondrial transplantation in the treatment of spinal cord injury in rats by facilitating mitochondrial transfer to neurons via Connexin 36
Authors: Zhu Zhijie , Li Xin , Wang Xuankang , Zuo Xiaoshuang , Ma Yangguang , Gao Xue , Liang Zhuowen , Zhang Zhihao , Song Zhiwen , Ding Tan , Ju Cheng , Li Penghui , Li Kun , Zhang Jiawei , Quan Huilin , Wang Zhe , Hu Xueyu
Published: December 2022

Mitochondrial transplantation is a promising treatment for spinal cord injury (SCI), but it has the disadvantage of low efficiency of mitochondrial transfer to targeted cells. Here, we demonstrated that Photobiomodulation (PBM) could promote the transfer process, thus augmenting the therapeutic effect of mitochondrial transplantation. In vivo experiments, motor function recovery, tissue repair, and neuronal apoptosis were evaluated in different treatment groups. Under the premise of mitochondrial transplantation, the expression of Connex36 (Cx36), the trend of mitochondria transferred to neurons, and its downstream effects, such as ATP production and antioxidant capacity, were evaluated after PBM intervention. In in vitro experiments, dorsal root ganglia (DRG) were cotreated with PBM and 18β‐GA (a Cx36 inhibitor). In vivo experiments showed that PBM combined with mitochondrial transplantation could increase ATP production and reduce oxidative stress and neuronal apoptosis levels, thereby promoting tissue repair and motor function recovery. In vitro experiments further verified that Cx36 mediated the transfer of mitochondria into neurons. PBM could facilitate this progress via Cx36 both in vivo and in vitro. The present study reports a potential method of using PBM to facilitate the transfer of mitochondria to neurons for the treatment of SCI.