bluuebunny/crossref_metadata_2025_split huggingface dataset:
Computational structure‐based approach to study chimeric antigens using a new protein scaffold displaying foreign epitopes
Authors: Cappelli Luigia , Cinelli Paolo , Perrotta Andrea , Veggi Daniele , Audagnotto Martina , Tuscano Giovanna , Pansegrau Werner , Bartolini Erika , Rinaudo Daniela , Cozzi Roberta 
Published: November 2023

AbstractThe identification and recombinant production of functional antigens and/or epitopes of pathogens represent a crucial step for the development of an effective protein‐based vaccine. Many vaccine targets are outer membrane proteins anchored into the lipidic bilayer through an extended hydrophobic portion making their recombinant production challenging. Moreover, only the extracellular loops, and not the hydrophobic regions, are naturally exposed to the immune system. In this work, the Domain 3 (D3) from Group B Streptococcus (GBS) pilus 2a backbone protein has been identified and engineered to be used as a scaffold for the display of extracellular loops of two Neisseria gonorrhoeae membrane proteins (PorB.1b and OpaB). A computational structure‐based approach has been applied to the design of both the scaffold and the model antigens. Once identified the best D3 engineerable site, several different chimeric D3 displaying PorB.1b and OpaB extracellular loops were produced as soluble proteins. Each molecule has been characterized in terms of solubility, stability, and ability to correctly display the foreign epitope. This antigen dissection strategy allowed the identification of most immunogenic extracellular loops of both PorB.1b and OpaB gonococcal antigens. The crystal structure of chimeric D3 displaying PorB.1b immunodominant loop has been obtained confirming that the engineerization did not alter the predicted native structure of this epitope. Taken together, the reported data suggest that D3 is a novel protein scaffold for epitope insertion and display, and a valid alternative to the production of whole membrane protein antigens. Finally, this work describes a generalized computational structure‐based approach for the identification, design, and dissection of epitopes in target antigens through chimeric proteins.
Recruitment of large peritoneal macrophages to capsular fibrosis developed on the liver surface
Authors: Balog Steven , Jeong Soi , Asahina Kinji 
Published: November 2023

AbstractUpon injury to Glisson's capsule, mesothelial cells covering the liver surface differentiate into myofibroblasts and participate in capsular fibrosis. In the fibrotic area, infiltrating macrophages are present, but their origin and role in capsular fibrosis remain elusive. In the present study, we examined whether macrophages in the peritoneal cavity migrate to the liver and participate in capsular fibrosis. Capsular fibrosis was induced by intraperitoneal injection of chlorhexidine gluconate. Chlorhexidine gluconate treatment induced disappearance of CD11bHigh F4/80High large peritoneal macrophages from the peritoneal cavity. Transplantation of TIMD4+ large peritoneal macrophages to the mouse peritoneal cavity resulted in their recruitment to the fibrotic area of the liver. Bone marrow‐derived monocytes were also recruited to the chlorhexidine gluconate‐induced fibrotic area upon their transplantation to the peritoneal cavity. However, bone marrow‐derived macrophages, Kupffer cells, peritoneal B cells, and small peritoneal macrophages prepared from chlorhexidine gluconate‐treated mice did not exhibit such potential. In the hepatic fibrotic area, peritoneal macrophages lost expression of unique markers (Gata6, Timd4) and increased expression of genes involved in inflammation (Il1b, Il6, Tnf) and extracellular matrix remodeling (Mmp13, Timp1). Depletion of peritoneal macrophages by clodronate liposomes reduced capsular fibrosis. Our data indicate that large peritoneal macrophages are recruited to the injured liver surface and promote capsular fibrosis by inducing inflammation and extracellular matrix remodeling. Modulating the function of peritoneal macrophages might be a new approach for suppressing capsular fibrosis.
LPCAT3/LPLAT12 deficiency in the liver ameliorates acetaminophen‐induced acute liver injury
Authors: Inagaki Natsuko F. , Nakanishi Hiroki , Ohto Takayo , Shindou Hideo , Shimizu Takao 
Published: November 2023

AbstractAcetaminophen (APAP) is a double‐edged sword, mainly depending on the dosage. A moderate dose of APAP is effective for fever and pain relief; however, an overdose induces acute liver injury. The mechanism underlying APAP‐induced acute liver failure is unclear, and its treatment is limited. A recent report has shown that several oxidized phospholipids are associated with APAP‐induced acute liver failure. Lysophosphatidylcholine acyltransferase 3 (Lpcat3, Lplat12), which is highly expressed in the liver, preferentially catalyzes the incorporation of arachidonate into lysophospholipids (PLs). In the present study, we investigated the roles of Lpcat3 on APAP‐induced acute liver injury using liver‐specific Lpcat3‐knockout mice. Hepatic Lpcat3 deficiency reduced the degree of APAP‐induced necrosis of hepatocytes around Zone 3 and ameliorated the elevation of hepatic injury serum marker levels, and prolonged survival. Lipidomic analysis showed that the accumulation of oxidized and hydroperoxidized phospholipids was suppressed in Lpcat3‐knockout mice. The amelioration of APAP‐induced acute liver injury was due not only to the reduction in the lipid synthesis of arachidonic acid PLs because of Lpcat3 deficiency, but also to the promotion of the APAP detoxification pathway by facilitating the conjugation of glutathione and N‐acetyl‐p‐benzoquinone imine. Our findings suggest that Lpcat3 is a potential therapeutic target for treating APAP‐induced acute liver injury.
Xylazine-associated Wounds: Clinical Experience From a Low-barrier Wound Care Clinic in Philadelphia
Authors: McFadden Rachel , Wallace-Keeshen Sara , Petrillo Straub Kristi , Hosey Rebecca A. , Neuschatz Rachel , McNulty Keara , Thakrar Ashish P. 
Published: November 2023

Abstract
The veterinary sedative xylazine is spreading in unregulated opioid supplies across North America. Among people who use drugs with repeated exposure to xylazine, a distinct wound type has emerged. Here, we describe these wounds and share our experience treating them in a nurse-led, low-barrier wound care clinic in Philadelphia, PA. We propose a reimagining of wound treatment across settings to better serve people who use drugs, and we advocate for stronger protections against the harms of an increasingly adulterated drug supply. Our perspective from the epicenter of the xylazine crisis can inform the response of communities across the country who are starting to face harms associated with xylazine.
Intraoperative Fluorescence Imaging During Robotic Pancreatoduodenectomy to Detect Suture-Induced Hypoperfusion of the Pancreatic Stump as a Predictor of Postoperative Pancreatic Fistula (FLUOPAN): Prospective Proof-of-concept Study
Authors: Chen Jeffrey W. , Lof Sanne , Zwart Maurice J. W. , Busch Olivier R. , Daams Freek , Festen Sebastiaan , Fong Zhi Ven , Hogg Melissa E. , Slooter Maxime D. , Nieveen van Dijkum Els J.M. , Besselink Marc G. ,   for HPB-Amsterdam
Published: November 2023

Background:
A potential downside of robotic pancreatoduodenectomy (RPD) is the lack of tactile feedback when tying sutures, which could be especially perilous during pancreatic anastomosis. Near-infrared fluorescence imaging with indocyanine green (NIRF-ICG) could detect transpancreatic-suture-induced hypoperfusion of the pancreatic stump during RPD, which may be related to postoperative pancreatic fistula (POPF) grade B/C, but studies are lacking.

Methods:
This prospective study included 37 patients undergoing RPD to assess the relation between pancreatic stump hypoperfusion as objectified with NIRF-ICG using Firefly and the rate of POPF grade B/C. In 27 patients, NIRF-ICG was performed after tying down the transpancreatic U-sutures. In 10 ‘negative control’ patients, NIRF-ICG was performed before tying these sutures.

Results:
Pancreatic stump hypoperfusion was detected using NIRF-ICG in 9/27 patients (33%) during RPD. Hypoperfusion was associated with POPF grade B/C (67% [6/9 patients] versus 17% [3/18 patients], P = 0.026). No hypoperfusion was objectified in 10 ‘negative controls’.

Conclusions:
Transpancreatic-suture-induced pancreatic stump hypoperfusion can be detected using NIRF-ICG during RPD and was associated with POPF grade B/C. Surgeons could use NIRF-ICG to adapt their suturing approach during robotic pancreatico-jejunostomy. Further larger prospective studies are needed to validate the association between transpancreatic-suture-induced hypoperfusion and POPF.
Investigation of Age and Gender Effects on the Middle Ear With Wideband Tympanometry in Adults
Authors: Kavruk Hatice , Öztürk Burak 
Published: November 2023

Objectives:
Several studies have reported the effects of age and gender on the middle ear of adults using wideband acoustic immittance (WAI) that measures middle ear function over a range of frequencies rather than the traditional measures with a single probe tone. Although these results are often based on WAI measurements under ambient pressure, using WAI under varying ear-canal pressures (wideband tympanometry [WBT]) may be able to provide more information about age and gender effects on the middle ear. The aim of this study is to examine the effects of age and gender on the middle ear with WBT in three different age groups consisting of young, middle-aged, and older adults.

Design:
A total of 95 adults with normal middle ear function were assessed, including 32 young adults (16 men, 16 women, aged 20 to 39 years), 31 middle-aged adults (15 men, 16 women, aged 41 to 60 years), and 32 older adults (16 men, 16 women, aged 65 to 82 years). WBT measurements were performed from 226 to 8000 Hz using Interacoustics Titan. Energy absorbance data at tympanometric peak pressure (EATPP) and ambient pressure (EAAP) at 1/3 octave frequencies, and resonance frequency (RF) data were analyzed according to age and gender variables.

Results:
Analysis results showed that the mean EATPP was significantly higher from 500 to 794 Hz and at 5040 and 6350 Hz, and significantly lower from 1587 to 3175 Hz in older adults compared with young adults. The mean EAAP was significantly lower from 1587 to 3175 Hz, and significantly higher at 5040 and 6350 Hz in older adults compared with young adults. There was no significant difference in the mean EATPP and mean EAAP at any frequency between young and middle-aged adults, and middle-aged and older adults. RF was significantly lower in older adults compared with young adults. In all age groups, men had higher mean EATPP and mean EAAP at lower frequencies and lower mean EATPP and mean EAAP at higher frequencies than women. Men had slightly lower RF than women in young and older adults, while men had significantly lower RF than women in middle-aged adults.

Conclusions:
This study demonstrated that there are possible age and gender effects on the middle ear that may affect the mechanical transmission of sound. It may be useful to consider this finding in clinical evaluation in adults of different ages and genders, and to establish age- and gender-specific WBT norms in the adult population.
Durable natural killer cell response after three doses of SARS-CoV-2 inactivated vaccine in HIV-infected individuals
Authors: Yang Xiaodong , Wang Xiuwen , Zhang Xin , Ding Haifeng , Wang Hu , Huang Tao , Zhang Guanghui , Duan Junyi , Xia Wei , Su Bin , Jin Cong , Wu Hao , Zhang Tong 
Published: November 2023

Abstract

Background:
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine can induce a potent cellular and humoral immune response to protect against SARS-CoV-2 infection. However, it was unknown whether SARS-CoV-2 vaccination can induce effective natural killer (NK) cell response in people living with human immunodeficiency virus (PLWH) and healthy individuals.

Methods:
Forty-seven PLWH and thirty healthy controls (HCs) inoculated with SARS-CoV-2 inactivated vaccine were enrolled from Beijing Youan Hospital in this study. The effect of SARS-CoV-2 vaccine on NK cell frequency, phenotype, and function in PLWH and HCs was evaluated by flow cytometry, and the response of NK cells to SARS-CoV-2 Omicron Spike (SARS-2-OS) protein stimulation was also evaluated.

Results:
SARS-CoV-2 vaccine inoculation elicited activation and degranulation of NK cells in PLWH, which peaked at 2 weeks and then decreased to a minimum at 12 weeks after the third dose of vaccine. However, in vitro stimulation of the corresponding peripheral blood monocular cells from PLWH with SARS-2-OS protein did not upregulate the expression of the aforementioned markers. Additionally, the frequencies of NK cells expressing the activation markers CD25 and CD69 in PLWH were significantly lower than those in HCs at 0, 4 and 12 weeks, but the percentage of CD16+ NK cells in PLWH was significantly higher than that in HCs at 2, 4 and 12 weeks after the third dose of vaccine. Interestingly, the frequency of CD16+ NK cells was significantly negatively correlated with the proportion of CD107a+ NK cells in PLWH at each time point after the third dose. Similarly, this phenomenon was also observed in HCs at 0, 2, and 4 weeks after the third dose. Finally, regardless of whether NK cells were stimulated with SARS-2-OS or not, we did not observe any differences in the expression of NK cell degranulation markers between PLWH and HCs.

Conclusion:
s:SARS-CoV-2 vaccine elicited activation and degranulation of NK cells, indicating that the inoculation of SARS-CoV-2 vaccine enhances NK cell immune response.
Anticipated Versus Unanticipated Incomplete Mohs Micrographic Surgery for Keratinocyte Carcinomas: Impact on Treatment Delays and Final Margin Status
Authors: Lin Stephanie K. , Deitermann Annika M. , Lubeck Marissa , Veerabagu Surya , Cheng Brian , Miller Christopher J. , Etzkorn Jeremy , Sobanko Joseph F. , Shin Thuzar M. , Higgins H. William , Giordano Cerrene N. , Walker Joanna L. , Zhang Junqian , Nguyen Harrison P. , McMurray Stacy L. 
Published: November 2023

BACKGROUND
Mohs micrographic surgery may be discontinued with positive margins as an anticipated strategy for multidisciplinary care or as an unanticipated occurrence. Management of primary tumors has not been compared after anticipated versus unanticipated incomplete Mohs micrographic surgery (iMMS).

OBJECTIVE
To compare rates and timing of adjuvant surgery after iMMS and final margin status when iMMS is anticipated versus unanticipated. Secondary outcomes were preoperative and intraoperative clinicopathologic factors associated with iMMS.

METHODS
Cases of iMMS of keratinocyte carcinomas at a tertiary academic center between 2005 and 2022 were classified as anticipated (preoperative assembly of multidisciplinary teams) or unanticipated (ad hoc management of positive margins). Rate, timing, and final margin status of adjuvant surgery was compared between anticipated and unanticipated iMMS cohorts using χ2/Fisher exact test for categorical variables and t-test for continuous variables.

RESULTS
Of 127 iMMS cases, 51.2% (65/127) were anticipated. Anticipated iMMS cases were more likely to undergo additional resection (98.5% vs 72.6%, p < .001), with fewer delays (3.9 vs 13.2 days, p < .001) and higher rates of final margin clearance (84.6% vs 59.7%, p < .001).

CONCLUSION
When iMMS is anticipated as part of multidisciplinary care, patients are more likely to undergo additional resection, with fewer delays to next surgery and higher final margin clearance rates.
Therapeutic outcomes arising from adverse drug reactions
Authors: Heerfordt Ida M. , Rix Iben , Horwitz Henrik 
Published: November 2023

Summary
This article examines five cases where unintended adverse reactions have led to new therapeutic outcomes. The cases cover subsequent applications of acetylsalicylic acid, sildenafil, thalidomide, domperidone, and disulfiram. These examples demonstrate the versatility of drugs in addressing diverse medical challenges. The discussion highlights the importance of analyzing adverse drug reactions to identify therapeutic opportunities arising from adverse reactions.
Update Lessons from Positron Emission Tomography Imaging Part I: A Systematic Critical Review on Therapeutic Plasma Concentrations of Antipsychotics
Authors: Hart Xenia M. , Spangemacher Moritz , Uchida Hiroyuki , Gründer Gerhard 
Published: November 2023

Background:
Positron emission tomography (PET) and single photon emission tomography (SPECT) of molecular drug targets (neuroreceptors and transporters) provide essential information for therapeutic drug monitoring–guided antipsychotic drug therapy. The optimal therapeutic windows for D2 antagonists and partial agonists, as well as their proposed target ranges, are discussed based on an up-to-date literature search.

Methods:
This part I of II presents an overview of molecular neuroimaging studies in humans and primates involving the target engagement of amisulpride, haloperidol, clozapine, aripiprazole, olanzapine, quetiapine, risperidone, cariprazine, and ziprasidone. The systemic review particularly focused on dopamine D2-like and 5-HT2A receptors. Target concentration ranges were estimated based on receptor occupancy ranges that relate to clinical effects or side effects (ie, extrapyramidal side effects). In addition, findings for other relevant receptor systems were included to further enrich the discussion.

Results:
The reported reference ranges for aripiprazole and clozapine align closely with findings from PET studies. Conversely, for haloperidol, risperidone, and olanzapine, the PET studies indicate that a lowering of the previously published upper limits would be necessary to decrease the risk of extrapyramidal side effect.

Conclusions:
Molecular neuroimaging studies serve as a strong tool for defining target ranges for antipsychotic drug treatment and directing therapeutic drug monitoring.
Evaluation for Blood Concentration and Efficacy/Safety of Continuous Administration of Thiamylal in Children
Authors: Hirata Kenshiro , Obara Takafumi , Ikeda Tokunori , Watanabe Hiroshi , Fujita Issei , Furusho Hirokazu , Ishiguro Takako , Jingami Sachiko , Maruyama Toru , Hirai Katsuki , Miyamura Shigeyuki 
Published: November 2023

Background:
Thiamylal exerts excellent sedative effects. However, it is not routinely used because of its serious adverse effects. This study aimed to clarify the target blood concentration range and infusion rate of thiamylal in children by measuring its blood concentration and evaluating its relationship with efficacy and adverse effects.

Methods:
This study was approved by the Ethics Committee of Japanese Red Cross Kumamoto Hospital. The authors included 10 children aged between 1 and 7 years who had received continuous intravenous (IV) infusion of thiamylal for the management of refractory status epilepticus, excluding those who met the exclusion criteria. After a 2 mg/kg bolus injection of thiamylal, continuous IV infusion was initiated at a rate of 2–3 mg/kg/h. Thiamylal concentration in the blood was measured using high-performance liquid chromatography. The State Behavioral Scale and the frequency of bolus injections were used to evaluate efficacy. Blood pressure and heart rate were measured to evaluate adverse effects. Statistical analyses of the time to awakening and the factors affecting it were also conducted.

Results:
The State Behavioral Scale score during thiamylal administration was −2 or lower in all cases, suggesting that the depth of sedation was sufficient. The frequency of bolus injections decreased in a blood concentration-dependent manner, suggesting that the frequency tended to decrease, especially at thiamylal blood concentrations of 20 mcg/mL or higher. An increase of the infusion rate to 3 mg/kg/h was recommended, because the blood concentration may not reach 20 mcg/mL at an infusion rate of 2 mg/kg/h. There was also a case in which a rapid increase in blood concentration accompanied by a decrease in blood pressure and heart rate was observed when the infusion rate was increased to 4 mg/kg/h. Furthermore, the time to awakening after the end of administration correlated with the highest blood concentration during administration; therefore, delayed awakening was noted when using a high dose of thiamylal.

Conclusions:
The target blood concentration of thiamylal in children should be 20–30 mcg/mL, and the infusion rate should be based on 3 mg/kg/h.
A Systematic Review of Clozapine Concentration–Dose Ratio from Therapeutic Drug Monitoring Studies in Children and Adolescents Treated with Clozapine for Mental Disorders
Authors: Jiménez-Fernández Sara , Gurpegui Manuel , Correll Christoph U. , de Leon Jose , Schoretsanitis Georgios 
Published: November 2023

Background:
Therapeutic drug monitoring of clozapine in children and adolescents has received insufficient attention. Calculation of concentration-to-dose (C/D) ratios from trough steady-state concentrations estimate drug clearance.

Methods:
A systematic electronic literature search was conducted in 3 article databases from inception until January 10, 2023, and articles reporting clozapine concentrations in children and adolescents were retrieved. The pharmacokinetic quality of the studies was assessed, and clozapine C/D ratios were calculated using the sample mean clozapine dose and concentration.

Results:
Of the 37 articles of potential interest, only 7 reported clozapine trough and steady-state concentrations. After excluding case reports and a study confounded by fluvoxamine, 4 studies on psychosis from Europe and the United States were included. The clozapine C/D ratios were similar to published adult values and ranged from 0.82 to 1.24 with a weighted mean of 1.08 ng/mL per mg/d. The weighted means were 334 mg/d for the dose and 380 ng/mL for the concentration. The stratified analysis of the weighted mean clozapine C/D ratios from 2 studies showed lower values in 52 male (1.05 ng/mL per mg/d) than in 46 female (1.46 ng/mL per mg/d) children and adolescents, with values similar to those reported for European adult nonsmokers. Two female adolescents had high clozapine C/D ratios (2.54 ng/mL per mg/d), an Asian American patient with borderline obesity and a patient with intellectual disability with low dosage (mean = 102 mg/d) and concentration (mean = 55 ng/mL).

Conclusions:
Reports on clozapine therapeutic drug monitoring in children and adolescents are limited in number and quality. Future studies should focus on basic pharmacokinetic issues, such as stratification by sex, smoking, and relevant comedications with inductive or inhibitory properties.