bluuebunny/crossref_metadata_2025 huggingface dataset:
Drug sensitivity prediction from cell line-based pharmacogenomics data: guidelines for developing machine learning models
Authors: Sharifi-Noghabi Hossein , Jahangiri-Tazehkand Soheil , Smirnov Petr , Hon Casey , Mammoliti Anthony , Nair Sisira Kadambat , Mer Arvind Singh , Ester Martin , Haibe-Kains Benjamin
Published: July 2021

The goal of precision oncology is to tailor treatment for patients individually using the genomic profile of their tumors. Pharmacogenomics datasets such as cancer cell lines are among the most valuable resources for drug sensitivity prediction, a crucial task of precision oncology. Machine learning methods have been employed to predict drug sensitivity based on the multiple omics data available for large panels of cancer cell lines. However, there are no comprehensive guidelines on how to properly train and validate such machine learning models for drug sensitivity prediction. In this paper, we introduce a set of guidelines for different aspects of training gene expression-based predictors using cell line datasets. These guidelines provide extensive analysis of the generalization of drug sensitivity predictors and challenge many current practices in the community including the choice of training dataset and measure of drug sensitivity. The application of these guidelines in future studies will enable the development of more robust preclinical biomarkers.
CoSMeD: a user-friendly web server to estimate 5-year survival probability of left-sided and right-sided colorectal cancer patients using molecular data
Authors: Xin Junyi , Wu Yanling , Ben Shuai , Li Shuwei , Chu Haiyan , Wang Meilin , Wang Molin , Song Mingyang , Du Mulong , Zhang Zhengdong
Published: July 2021

Colorectal cancer is a heterogeneous disease with diverse prognoses between left-sided and right-sided patients; therefore, it is necessary to precisely evaluate the survival probability of side-specific colorectal cancer patients. Here, we collected multi-omics data from The Cancer Genome Atlas program, including gene expression, DNA methylation and microRNA expression. Specificity measure and robust likelihood-based survival analysis were used to identify 6 left-sided and 28 right-sided prognostic biomarkers. Compared to the performance of clinical prognostic models, the addition of these biomarkers could significantly improve the discriminatory ability and calibration in predicting side-specific 5-year survival for colorectal cancer. Additional dataset derived from Gene Expression Omnibus was used to validate the prognostic value of side-specific genes. Finally, we constructed colorectal cancer side-specific molecular database (CoSMeD), a user-friendly interface for estimating side-specific colorectal cancer 5-year survival probability, which can lay the basis for personalized management of left-sided and right-sided colorectal cancer patients.

Availability and implementation

CoSMeD is freely available at https://mulongdu.shinyapps.io/cosmed.

Supplementary information

Supplementary data are available at Bioinformatics online.
HDAC1: an environmental sensor regulating endothelial function
Authors: Dunaway Luke S , Pollock Jennifer S
Published: July 2021

The histone deacetylases (HDACs) are a family of enzymes that catalyse lysine deacetylation of both histone and non-histone proteins. Here, we review, summarize, and provide perspectives on the literature regarding one such HDAC, HDAC1, in endothelial biology. In the endothelium, HDAC1 mediates the effects of external and environmental stimuli by regulating major endothelial functions such as angiogenesis, inflammatory signalling, redox homeostasis, and nitric oxide signalling. Angiogenesis is most often, but not exclusively, repressed by endothelial HDAC1. The regulation of inflammatory signalling is more complex as HDAC1 promotes or suppresses inflammatory signalling depending upon the environmental stimuli. HDAC1 is protective in models of atherosclerosis where loss of HDAC1 results in increased cytokine and cell adhesion molecule (CAM) abundance. In other models, HDAC1 promotes inflammation by increasing CAMs and repressing claudin-5 expression. Consistently, from many investigations, HDAC1 decreases antioxidant enzyme expression and nitric oxide production in the endothelium. HDAC1 decreases antioxidant enzyme expression through the deacetylation of histones and transcription factors, and also regulates nitric oxide production through regulating both the expression and activity of nitric oxide synthase 3. The HDAC1-dependent regulation of endothelial function through the deacetylation of both histone and non-histone proteins ultimately impacts whole animal physiology and health.
Recent progress toward the implementation of phage therapy in Western medicine
Authors: Pirnay Jean-Paul , Ferry Tristan , Resch Grégory
Published: July 2021

Like the sword of Damocles, the threat of a post-antibiotic era is hanging over humanity's head. The scientific and medical community is thus reconsidering bacteriophage therapy (BT) as a partial but realistic solution for treatment of difficult-to-eradicate bacterial infections. Here, we summarize the latest developments in clinical BT applications, with a focus on developments in the following areas: (i) pharmacology of bacteriophages of major clinical importance and their synergy with antibiotics; (ii) production of therapeutic phages; and (iii) clinical trials, case studies and case reports in the field. We address regulatory concerns, which are of paramount importance insofar as they dictate the conduct of clinical trials, which are needed for broader BT application. The increasing amount of new available data confirms the particularities of BT as being innovative and highly personalized. The current circumstances suggest that the immediate future of BT may be advanced within the framework of national BT centers in collaboration with competent authorities, which are urged to adopt incisive initiatives originally launched by some national regulatory authorities.
The Evolutionary Origins of Extreme Halophilic Archaeal Lineages
Authors: Feng Yutian , Neri Uri , Gosselin Sophia , Louyakis Artemis S , Papke R Thane , Gophna Uri , Gogarten Johann Peter
Published: July 2021

Interest and controversy surrounding the evolutionary origins of extremely halophilic Archaea has increased in recent years, due to the discovery and characterization of the Nanohaloarchaea and the Methanonatronarchaeia. Initial attempts in explaining the evolutionary placement of the two new lineages in relation to the classical Halobacteria (also referred to as Haloarchaea) resulted in hypotheses that imply the new groups share a common ancestor with the Haloarchaea. However, more recent analyses have led to a shift: the Nanohaloarchaea have been largely accepted as being a member of the DPANN superphylum, outside of the euryarchaeota; whereas the Methanonatronarchaeia have been placed near the base of the Methanotecta (composed of the class II methanogens, the Halobacteriales, and Archaeoglobales). These opposing hypotheses have far-reaching implications on the concepts of convergent evolution (distantly related groups evolve similar strategies for survival), genome reduction, and gene transfer. In this work, we attempt to resolve these conflicts with phylogenetic and phylogenomic data. We provide a robust taxonomic sampling of Archaeal genomes that spans the Asgardarchaea, TACK Group, euryarchaeota, and the DPANN superphylum. In addition, we assembled draft genomes from seven new representatives of the Nanohaloarchaea from distinct geographic locations. Phylogenies derived from these data imply that the highly conserved ATP synthase catalytic/noncatalytic subunits of Nanohaloarchaea share a sisterhood relationship with the Haloarchaea. We also employ a novel gene family distance clustering strategy which shows this sisterhood relationship is not likely the result of a recent gene transfer. In addition, we present and evaluate data that argue for and against the monophyly of the DPANN superphylum, in particular, the inclusion of the Nanohaloarchaea in DPANN.
Associations Between Recently Diagnosed Conditions and Hospitalization due to COVID-19 in Patients Aged 50 Years and Older—A SHARE-Based Analysis
Authors: López-Bueno Rubén , Torres-Castro Rodrigo , Koyanagi Ai , Smith Lee , Soysal Pinar , Calatayud Joaquín
Published: July 2021

Background

Only a few studies have been carried out with a large sample size on the relationship between chronic conditions and hospitalization for coronavirus disease 2019 (COVID-19), and there is no research examining recently diagnosed conditions. Our purpose was to evaluate this association in a large sample including the older population from Europe and Israel.

Method

Data from the Survey of Health, Ageing and Retirement in Europe COVID-19 Survey, a representative survey of individuals aged 50 or older residing in 27 European countries and Israel, were retrieved. Associations between recently diagnosed chronic conditions (ie, conditions detected over the last 3 years) (exposure) and hospitalization due to COVID-19 (outcome) were assessed using multivariable logistic regression.

Results

A total of 51 514 participants on average 71.0 (SD = 9.2) years old were included. Participants with multimorbidity (ie, 2 or more recently diagnosed conditions) had significantly higher odds for COVID-19 hospitalization (adjusted odds ratio [AOR] = 3.91 [95% CI = 2.14–7.12]). Independent conditions such as lung disease (AOR = 16.94 [95% CI = 9.27–30.95]), heart disease (AOR = 3.29 [95% CI = 1.50–7.21]), or cancer (AOR = 3.45 [95% CI = 1.26–9.48]) showed particularly high odds for hospitalization due to COVID-19.

Conclusions

People with recently diagnosed diseases, and in particular those having lung disease, heart disease, or cancer, were significantly more likely to be hospitalized for COVID-19.
Postoperative complications and perioperative management of lung resection in patients with a history of oesophagectomy for oesophageal carcinoma
Authors: Watanabe Yukio , Hattori Aritoshi , Nojiri Shuko , Fukui Mariko , Matsunaga Takeshi , Takamochi Kazuya , Oh Shiaki , Suzuki Kenji
Published: July 2021

OBJECTIVES

Advances in chemoradiation have improved the long-term prognosis of oesophageal cancer, although perioperative management for lung resection postoesophagectomy is unknown. The purpose of this study was to investigate postoperative complications and perioperative management for lung resection postoesophagectomy.

METHODS

Between 2002 and 2017, a total of 4694 patients underwent lung resections; of these, 79 were performed postoesophagectomy. Using propensity score matching, we analysed postoperative complications between groups with and without postoesophagectomy lung resection. We also investigated the risk factors of Clavien–Dindo classification grade ≥2 complications by logistic regression analysis.

RESULTS

Sixty-nine of the patients were men with a median age of 67 years. The types of lung resections were as follows: lobectomy in 34, segmentectomy in 12 and wedge resection in 33 patients. Postoperative complications were detected in 35 patients, including grade ≥2 complications in 24. After matching, aspiration pneumonia (P = 0.09) tended to be common in the postoesophagectomy group. Until 2008, non-fasting management before lung resection was performed in all 31, and intraoperative aspiration pneumonia was detected in 2 patients. After switching to fasting management before lung resection, there were no cases of intraoperative aspiration pneumonia. Multivariable analysis revealed that lung resection ipsilateral to oesophagectomy (P = 0.04) and lobectomy (P = 0.03) were predictors of grade ≥2 morbidity.

CONCLUSIONS

Patients having a lung resection postoesophagectomy tended to have a higher risk of aspiration pneumonia. Fasting management before lung resection is important in preventing intraoperative aspiration pneumonia. Lung resection ipsilateral to oesophagectomy and lobectomy may result in complications requiring therapeutic intervention.
Between Martyrdom and Silence: Dissent, Duress, and Persecution as the Suppression of Human Rights under the Refugee Convention
Authors: Wilsher Daniel
Published: July 2021

A real risk of death, torture, violence, or arbitrary detention is generally sufficient to satisfy ‘persecution’ under the Refugee Convention. Where, however, physical harm will only arise if a claimant were to exercise certain human rights upon return, jurisprudential uncertainty reigns. Only a few individuals are impelled to become ‘martyrs’ through open dissent. Courts strongly endorse these dissenters’ entitlement to international protection even if they could avoid retribution through self-censorship. A second group – ‘a silent minority’ – are those who would actually refrain from exercising their rights to avoid physical harm. Most jurisprudence appears to accept that such a situation may sometimes amount to persecution. Unlike martyrs, however, these claimants are required to meet control devices based upon the severity of the human rights restriction, and/or the mental effects of self-censorship on the claimant. These are, however, both arbitrary and unprincipled. This article argues the real harm felt by martyrs and the silent minority is the same: the forcible suppression of their enjoyment of human rights. Importantly, the United Nations High Commissioner for Refugees’ approach to military service, religious, and sexuality cases already embodies this principle. To generalize, this ‘suppressive’ persecution arises when (a) claimants sincerely wish to engage in actions which (b) are international human rights entitlements and (c) they face objective conditions of sufficient duress such that they cannot reasonably assert their rights through civil disobedience. When States or private actors suppress the exercise of rights by duress in this way, those affected suffer a denial of rights amounting to persecution. This analysis should apply whether a claimant would be a martyr or would be intimidated into self-censorship.
Asian American Jews, Race, and Religious Identity
Authors: Mehta Samira K
Published: July 2021

This article is an exploration of marriages between white American Jews and non-Christian or Jewish Asian Americans in order to illustrate how Christian roots and biases inherent in the term religion delineate these families’ boundaries around family practice such that such Jewish-Asian American families produce a broader range of cultural mixture than their Jewish-Christian counterparts. It argues that this blending occurs because of the different relationships to the notion of “religion” held by American Jews and non-Christian/Jewish Asian Americans, and their histories in the United States, due to 1) the reality that American Jews have been deeply involved in shaping contemporary understandings of religion in the United States and have spent several generations being formed by those understandings, whereas many Asian Americans have not; 2) the tendency among non-Christian and Jewish Asian Americans to use broader terminology like “tradition” and “culture” to describe various practices because religion is not understood as a separate system, and 3) Jewish involvement in white American appropriation of Asian practices.
Cancer-related FGFR2 overexpression and gene amplification in Japanese patients with gastric cancer
Authors: Minashi Keiko , Yamada Takeshi , Hosaka Hisashi , Amagai Kenji , Shimizu Yoshiaki , Kiyozaki Hirokazu , Sato Mikio , Soeda Atsuko , Endo Shinji , Ishida Hiroyasu , Kamoshida Toshiro , Sakai Yoshinori , Shitara Kohei
Published: July 2021

Objective

Fibroblast growth factor receptor 2 (FGFR2) has been proposed as a novel druggable target in unresectable gastric cancer. FGFR2 alteration has been reported as associated with poor prognosis even in patients with gastric cancer who received systemic chemotherapy. This study aimed to evaluate the frequency of FGFR2 overexpression and gene amplification in clinical specimens from Japanese patients with recurrent or unresectable gastric cancer.

Methods

This observational study enrolled patients who were histologically or cytologically confirmed with unresectable HER2-negative or unknown gastric or gastroesophageal junctional adenocarcinoma treated with at least one previous chemotherapy. FGFR2 overexpression and gene amplification in the specimens were evaluated by immunohistochemical staining and fluorescence in situ hybridization methods, respectively.

Results

In a total of 173 eligible cases, FGFR2 immunohistochemistry score was evaluated as 0, 1, 2, 3 and 4 for 20, 80, 35, 28 and 10 cases, respectively. In 151 evaluable cases with FGFR2 immunohistochemistry scores of 1–4, FGFR2 copy number expressed as fluorescence in situ hybridization signals were detected as <4, ≥4 < 10 and ≥10 copies for 123, 16 and 12 cases, respectively. FGFR2 copy number showed an increasing tendency along with higher FGFR2 immunohistochemistry scores in the corresponding specimen. The response rate and time to treatment failure for first line chemotherapy did not have any obvious relationship to FGFR2 immunohistochemistry score and FGFR2 copy number.

Conclusions

Although FGFR2 overexpression and gene amplification were shown in Japanese patients with unresectable gastric cancer, these alterations did not impact the effects of cytotoxic agents as first line chemotherapy.
Oncological and prognostic analysis of soft tissue sarcoma of the elbow: report using the bone and soft tissue tumor registry in Japan
Authors: Emori Makoto , Iba Kousuke , Murahashi Yasutaka , Shimizu Junya , Sonoda Tomoko , Wada Takuro , Yamashita Toshihiko , Kawai Akira
Published: July 2021

Objective

Soft tissue sarcomas in the elbow are extremely rare, and they have primarily been described in case series. Definitive concerning the prevalence and prognostic factors of elbow soft tissue sarcomas remain unknown. We examined the outcome of patients with elbow soft tissue sarcomas and identified the relevant prognostic factors.

Methods

In total, 219 patients with elbow soft tissue sarcomas were identified using data from the bone and soft tissue tumor registry in Japan. Differences in demographics, disease characteristics, treatment and survival were compared among the patients. Survival analyses including local recurrence-free survival, distant metastasis-free survival, and overall survival were performed using the Kaplan–Meier method with log-rank tests and the Cox proportional hazards model.

Results

Two hundred nineteen patients with elbow soft tissue sarcomas were identified, including 119 males (54.3%) and 100 females (45.7%). In total, 189 patients (86.3%) underwent surgery including re-excision. Of the surgically treated patients, 180 (95.2%) underwent limb salvage surgery, and nine patients (4.8%) underwent amputation. The 5-year overall survival, local recurrence-free survival, and distant metastasis-free survival rates for the entire patient cohort were 76.3, 70.1, and 69.3%, respectively. After adjusting for clinically relevant factors, overall survival was significantly worse among patients with tumors: >10 cm (hazard ratio = 4.34; 95% confidence interval = 1.03–18.2) and metastatic disease (hazard ratio = 6.94; 95% confidence interval = 1.55–31.0).

Conclusions

Tumor size was identified as an independent risk factor for poor prognosis.
Community-Associated Clostridioides difficile Infection in Children: A Review of Recent Literature
Authors: Adams Daniel J , Barone Josephine B , Nylund Cade M
Published: July 2021

Clostridioides difficile infection (CDI) in children is more often acquired in the community than in the hospital. Community-associated Clostridioides difficile infection (CA-CDI) cases seem to be rising, although this is confounded by the unclear role of C. difficile in children 1 and 3 years of age and overreliance on nucleic acid amplification tests for diagnosis. Exposure to antibiotics, acid suppression medications, health care settings, and close contacts with CDI are associated with CA-CDI in children. These infections are more common in children with chronic medical conditions, especially those involving the gastrointestinal tract and immune suppression. Most CA-CDI in children are mild and managed in the outpatient setting, but a small subset requires hospitalization and can be quite severe. Approximately 10% of children with CA-CDI experience a recurrence. Infection control guidance focuses on the hospital setting and future studies on the best methods for preventing community spread of C. difficile are needed.
Cross-Dressing in the City: Olive Malvery’s The Speculator
Authors: Colella Silvana
Published: July 2021

Despite a growing body of scholarship on finance and fiction, Malvery’s The Speculator has not yet received the critical attention it deserves. In this article, I undertake the first detailed analysis of Malvery’s fictional foray into the world of finance, centred on the story of a female stockbroker operating in disguise in the City of London. The first section of the article focuses on late nineteenth-century and early Edwardian novels of finance, chiefly concerned with deploring the cunning ruses of company promoters, and provides a brief overview of their representations of the ‘popular investor’. I then analyse how the cross-dressing masquerade is orchestrated and tested in The Speculator, culminating in a scene of violence that takes place at the Stock Exchange and exposes the threat of physical force underpinning discriminatory regulation. The final section argues that the swerve towards the spy thriller, a popular genre in Edwardian England, allows Malvery to contain and disperse the fear of violence, the crude underside of the cross-dressing act, and to go on envisioning for her intrepid heroine ever more incredible adventures with geopolitical implications. By attending closely to the novel’s hybrid formal structure, my reading suggests that a good deal of fictionalizing was necessary to imagine the protagonism of women in the money market, at a time when their role as investors was no longer exceptional, but their inclusion into the circle of active financial players was still a matter of dispute.
L2, a chloroplast metalloproteinase, regulates fruit ripening by participating in ethylene autocatalysis under the control of ethylene response factors
Authors: Li Guobin , Wang Jiafa , Zhang Chunli , Ai Guo , Zhang Dedi , Wei Jing , Cai Liangyu , Li Changbao , Zhu Wenzhao , Larkin Robert M , Zhang Junhong
Published: July 2021

Although autocatalytic ethylene biosynthesis plays an important role in the ripening of climacteric fruits, our knowledge of the network that promotes it remains limited. We identified white fruit (wf), a tomato mutant that produces immature fruit that are white and that ripen slowly. We found that an inversion on chromosome 10 disrupts the LUTESCENT2 (L2) gene, and that white fruit is allelic to lutescent2. Using CRISPR/Cas9 technology we knocked out L2 in wild type tomato and found that the l2-cr mutants produced phenotypes that were very similar to white fruit (lutescent2). In the l2-cr fruit, chloroplast development was impaired and the accumulation of carotenoids and lycopene occurred more slowly than in wild type. During fruit ripening in l2-cr mutants, the peak of ethylene release was delayed, less ethylene was produced, and the expression of ACO genes was significantly suppressed. We also found that exogenous ethylene induces the expression of L2 and that ERF.B3, an ethylene response factor, binds to the promoter of the L2 gene and activates its transcription. Thus, the expression of L2 is regulated by exogenous ethylene. Taken together, our results indicate that ethylene may affect the expression of L2 gene and that L2 participates in autocatalytic ethylene biosynthesis during tomato fruit ripening.
A fast and precise methodology to search for and analyse strongly lensed gravitational-wave events
Authors: Janquart Justin , Hannuksela Otto A , Haris K , Van Den Broeck Chris
Published: July 2021

Gravitational waves, like light, can be gravitationally lensed by massive astrophysical objects such as galaxies and galaxy clusters. Strong gravitational-wave lensing, forecasted at a reasonable rate in ground-based gravitational-wave detectors such as Advanced LIGO, Advanced Virgo, and KAGRA, produces multiple images separated in time by minutes to months. These images appear as repeated events in the detectors: gravitational-wave pairs, triplets, or quadruplets with identical frequency evolution originating from the same sky location. To search for these images, we need to, in principle, analyse all viable combinations of individual events present in the gravitational-wave catalogues. An increasingly pressing problem is that the number of candidate pairs that we need to analyse grows rapidly with the increasing number of single-event detections. At design sensitivity, one may have as many as $\mathcal {O}(10^5)$ event pairs to consider. To meet the ever-increasing computational requirements, we develop a fast and precise Bayesian methodology to analyse strongly lensed event pairs, enabling future searches. The methodology works by replacing the prior used in the analysis of one strongly lensed gravitational-wave image by the posterior of another image; the computation is then further sped up by a pre-computed lookup table. We demonstrate how the methodology can be applied to any number of lensed images, enabling fast studies of strongly lensed quadruplets.
The radio loudness of SDSS quasars from the LOFAR Two-metre Sky Survey: ubiquitous jet activity and constraints on star formation
Authors: Macfarlane C , Best P N , Sabater J , Gürkan G , Jarvis M J , Röttgering H J A , Baldi R D , Calistro Rivera G , Duncan K J , Morabito L K , Prandoni I , Retana-Montenegro E
Published: July 2021

We examine the distribution of radio emission from ∼42 000 quasars from the Sloan Digital Sky Survey, as measured in the LOFAR Two-metre Sky Survey (LoTSS). We present a model of the radio luminosity distribution of the quasars that assumes that every quasar displays a superposition of two sources of radio emission: active galactic nuclei (jets) and star formation. Our two-component model provides an excellent match to the observed radio flux density distributions across a wide range of redshifts and quasar optical luminosities; this suggests that the jet-launching mechanism operates in all quasars but with different powering efficiency. The wide distribution of jet powers allows for a smooth transition between the ‘radio-quiet’ and ‘radio-loud’ quasar regimes, without need for any explicit bimodality. The best-fitting model parameters indicate that the star formation rate of quasar host galaxies correlates strongly with quasar luminosity and also increases with redshift at least out to z ∼ 2. For a model where star formation rate scales as $L_{\rm bol}^{\alpha } (1+z)^{\beta }$, we find α = 0.47 ± 0.01 and β = 1.61 ± 0.05, in agreement with far-infrared studies. Quasars contribute ≈0.15 per cent of the cosmic star formation rate density at z = 0.5, rising to 0.4 per cent by z ∼ 2. The typical radio jet power is seen to increase with both increasing optical luminosity and black hole mass independently, but does not vary with redshift, suggesting intrinsic properties govern the production of the radio jets. We discuss the implications of these results for the triggering of quasar activity and the launching of jets.
EEG findings in CAR T-cell-associated neurotoxicity: Clinical and radiological correlations
Authors: Beuchat Isabelle , Danish Husain H , Rubin Daniel B , Jacobson Caron , Robertson Matthew , Vaitkevicius Henrikas , Lee Jong Woo
Published: July 2021

Background

While EEG is frequently reported as abnormal after chimeric antigen receptor (CAR) T-cell therapy, its clinical significance remains unclear. We aim to systematically describe EEG features in a large single-center cohort and correlate them with clinical and radiological findings.

Methods

We retrospectively identified patients undergoing CAR T-cell therapy who had continuous EEG. Neurotoxicity grades, detailed neurological symptoms, and brain MRI or FDG-PET were obtained. Correlation between clinical and radiological findings and EEG features was assessed.

Results

In 81 patients with median neurotoxicity grade 3 (IQR 2–3), diffuse EEG background slowing was the most common finding and correlated with neurotoxicity severity (P <.001). A total of 42 patients had rhythmic or periodic patterns, 16 of them within the ictal-interictal-continuum (IIC), 5 with clinical seizures, and 3 with only electrographic seizures. Focal EEG abnormalities, consisting of lateralized periodic discharges (LPD, n = 1), lateralized rhythmic delta activity (LRDA, n = 6), or focal slowing (n = 19), were found in 22 patients. All patients with LRDA, LPD, and 10/19 patients with focal slowing had focal clinical symptoms concordant with these EEG abnormalities. In addition, these focal EEG changes are often correlated with PET hypometabolism or MRI hypoperfusion, in absence of a structural lesion.

Conclusion

In adult patients experiencing neurotoxicity after CAR T-cell infusion, EEG degree of background disorganization correlated with neurotoxicity severity. IIC patterns and focal EEG abnormalities are frequent and often correlate with focal clinical symptoms and with PET-hypometabolism/MRI-hypoperfusion, without structural lesion. The etiology of these findings remains to be elucidated.
Crimmigration and the ‘Paradox of Exclusion’
Authors: Rosenberg Rubins Rottem
Published: July 2021

Much scholarship underscores the exclusionary nature of crimmigration (the policy of criminalising infringements of immigration rules and imposing adverse immigration consequences as sanctions for criminal conduct), viewing it as a system of social marginalisation designed to prevent integration. This article, conversely, demonstrates crimmigration’s potential to contribute to the partial and symbolic acceptance of migrants. The article argues that crimmigration is characterised by a ‘paradox of exclusion’—a contradictory attempt to exclude undesirable migrants via the field of criminal law, which is designed primarily for citizens. Consequently, crimmigration regimes extend to migrants certain rights associated with membership and provide irregular migrants with various opportunities to gain admittance into the community. Two main processes contribute to this dynamic: the extension of principles typical of ‘citizen criminal law’ to migrants and the equation of law abidance with ‘good citizenship’, which informally confirms the right of certain migrants to remain in the country or their suitability for membership. The article discusses crimmigration’s consequent contribution to the process of civic stratification.
Sticky Stigma: The Impact of Incarceration on Perceptions of Personality Traits and Deservingness
Authors: Brew Bridget , Alani Frances , Li Anita , Wildeman Christopher
Published: July 2021

Stigma is often cited as a mechanism driving the consequences of incarceration for formerly incarcerated people and their families. Few studies, however, provide quantitative evidence of the nature and strength of stigma stemming from direct and indirect interaction with jails. In this article, we use an experimental vignette design to make two contributions. First, we use two nonincarceration control groups that allow us to differentiate the stigma attached to incarceration relative to one condition that is not stigmatized (colorblindness) from another that is (drug addiction). Second, we test whether having a partner or family member who has been incarcerated in jail generates stigma. We find that having a formerly incarcerated relative negatively impacts perceptions of personality traits, financial deservingness, and parenting quality. We also show that the stigmatized control condition is comparable with the prior incarceration of a male relative, but more favorable than one’s own prior incarceration, indicating unique incarceration stigma. These findings have implications for our understanding of social inequality because they demonstrate how members of marginalized groups who are most likely to experience incarceration or have an incarcerated loved one continue to face informal social exclusion and the attendant consequences long after the formal punishment.
Theoretical Performance of Nonlinear Mixed-Effect Models Incorporating Saliva as an Alternative Sampling Matrix for Therapeutic Drug Monitoring in Pediatrics: A Simulation Study
Authors: Kruizinga Matthijs D. , Stuurman Frederik E. , Driessen Gertjan J.A. , Cohen Adam F. , Bergmann Kirsten R. , van Esdonk Michiel J.
Published: July 2021

Background:

Historically, pharmacokinetic (PK) studies and therapeutic drug monitoring (TDM) have relied on plasma as a sampling matrix. Noninvasive sampling matrices, such as saliva, can reduce the burden on pediatric patients. The variable plasma–saliva relationship can be quantified using population PK models (nonlinear mixed-effect models). However, criteria regarding acceptable levels of variability in such models remain unclear. In this simulation study, the authors aimed to propose a saliva TDM evaluation framework and evaluate model requirements in the context of TDM, with gentamicin and lamotrigine as model compounds.

Methods:

Two population pharmacokinetic models for gentamicin in neonates and lamotrigine in pediatrics were extended with a saliva compartment including a delay constant (kSALIVA), a saliva:plasma ratio, and between-subject variability (BSV) on both parameters. Subjects were simulated using a realistic covariate distribution. Bayesian maximum a posteriori TDM was applied to assess the performance of an increasing number of TDM saliva samples and varying levels of BSV and residual variability. Saliva TDM performance was compared with plasma TDM performance. The framework was applied to a known voriconazole saliva model as a case study.

Results:

TDM performed using saliva resulted in higher target attainment than no TDM, and a residual proportional error <25% on saliva observations led to saliva TDM performance comparable with plasma TDM. BSV on kSALIVA did not affect performance, whereas increasing BSV on saliva:plasma ratios by >25% for gentamicin and >50% for lamotrigine reduced performance. The simulated target attainment for voriconazole saliva TDM was >90%.

Conclusions:

Saliva as an alternative matrix for noninvasive TDM is possible using nonlinear mixed-effect models combined with Bayesian optimization. This article provides a workflow to explore TDM performance for compounds measured in saliva and can be used for evaluation during model building.
Population Pharmacokinetics of Teicoplanin and Its Dosing Recommendations for Neutropenic Patients With Augmented Renal Clearance for Hematological Malignancies
Authors: Sako Ken-ichi , Nakamaru Yuta , Ikawa Kazuro , Maeda Tomoji , Goto Sotaro , Ishihara Yoko , Kato Yukio , Matsuda Yoshikazu
Published: July 2021

Background:

Plasma teicoplanin concentrations do not reach the therapeutic range in several patients with hematological malignancies. Nevertheless, the characteristics of the population pharmacokinetic (PPK) models have not been clarified for malignancy. The decrease in the teicoplanin concentration in patients with cancer has been attributed to augmented renal clearance (ARC). It is essential to identify the causative factors of ARC to construct a PPK model to optimize the administration method. The authors aimed to establish a PPK model and develop an appropriate dosing regimen for teicoplanin in patients with hematological malignancies.

Methods:

PPK analysis was performed using therapeutic drug monitoring (TDM) data from 119 patients with hematological malignancies. The developed model was verified by predictive performance.

Results:

The covariates affecting systemic clearance were serum creatinine, presence or absence of neutropenia (<500/μL), and body size descriptor. Patients with hematologic malignancies and neutropenia showed a 25% increase in clearance compared with those with a normal neutrophil count. The PPK model was constructed based on the presence or absence of neutropenia. This model allowed the selection of the most appropriate dosage regimen out of those recommended by the TDM guidelines for patients with eGFR of >60 mL/min/1.73 m2. The PPK model predicted a dosing regimen for achieving a 10% improvement in the coverage probability of the target concentration range during the loading and maintenance phases.

Conclusions:

The PPK model may help optimize dose regimens and evaluate dosing methods, using comparative simulations, in patients with hematological malignancies.
Waist Narrowing without Removal of Ribs
Authors: Kudzaev Kazbek U. , Kraiushkin Igor A.
Published: July 2021

A narrow waist is considered one of the most attractive female body features. We have developed a minimally invasive surgical method of waist narrowing without rib removal. An access to XI and XII ribs is made through small incisions at the scapular line on both sides. The dorsal cortical plates are osteotomized using a sagittal oscillator saw with a 10 mm wide blade or a piezotome. The osteoclasy is performed, “green stick” type fracture is obtained, and wounds are closed. We put a tight chest corset on a patient for 2 months until the ribs’ fractures consolidate in new position. The number of our clinical cases is 93, and 14 of them were available for follow up at 6 months or more. The average waistline reduction is about 8.0 cm. We indicated period of time, number of cases, and selection criteria. This method is atraumatic, has a short rehabilitation period, and provides for obvious clinical effect.
Consumer Awareness and Comfort with Resident-run Cosmetic Clinics: A Crowdsourcing Study
Authors: Hemal Kshipra , Cignetti Natalie E. , Newsom Megan R. , David Lisa R.
Published: July 2021

Background:

Resident cosmetic clinics (RCCs) are the training modality of choice among both residents and faculty and are a mainstay at most residency programs.
1–4
Despite this, knowledge of RCCs among plastic surgery consumers remains untested. We hypothesize that the public would be aware of and receptive to RCCs.

Methods:

Participants with prior cosmetic procedures or interest in future cosmetic procedures were recruited using Amazon Mechanical Turk and asked to complete a survey in September 2020. First, prior awareness of RCCs was assessed. After a brief description of RCCs, perceptions of safety and preferences for care were assessed.

Results:

After screening for quality, 815 responses were included. Forty-five percent of consumers were aware of RCCs. Seventy-six percent of consumers believed that RCCs were just as safe as attending clinics and 65% were comfortable receiving care from fourth-year residents or higher. Belief in RCC safety was associated with 4.8 times higher odds of feeling comfortable receiving care at an RCC [95% confidence interval (3.3–7.1), P < 0.001]. When given a hypothetical choice between residents and attendings in two scenarios, 46% of consumers chose residents for abdominoplasty and 60% chose residents for Botox injections. Belief in RCC safety was associated with choosing a resident or being indifferent in both scenarios.

Conclusions:

Consumer preference regarding RCCs has largely been untested. This study shows that belief in RCC safety influences consumers’ perceived comfort with receiving care at an RCC. This knowledge can help guide RCC practice and maximize learning opportunities for surgeons-in-training.
Comparison of Complication Risk for Open Carpal Tunnel Release: In-office versus Operating Room Settings
Authors: Randall Dustin J. , Peacock Kate , Nickel Katelin B. , Olsen Margaret , Tyser Andrew R. , Kazmers Nikolas H.
Published: July 2021

Background:

Performing open carpal tunnel release (oCTR) in an office-based procedure room setting (PR) decreases surgical costs when compared with the operating room (OR). However, it is unclear if the risk of major medical, wound, and iatrogenic complications differ between settings. Our purpose was to compare the risk of major medical complications associated with oCTR between PR and OR settings.

Methods:

Utilizing the MarketScan Database, we identified adults undergoing isolated oCTR between 2006 and 2015 performed in PR and OR settings. ICD-9-CM and/or CPT codes were used to identify major medical complications, surgical site complications, and iatrogenic complications within 90 days of oCTR. Multivariable logistic regression was used to compare complication risk between groups.

Results:

Of the 2134 PR and 76,216 OR cases, the risk of major medical complications was 0.89% (19/2134) and 1.20% (914/76,216), respectively, with no difference observed in the multivariable analysis (adjusted odds ratio [OR] 0.84; 95% CI 0.53–1.33; P = 0.45). Risk of surgical site complications was 0.56% (12/2134) and 0.81% (616/76,216) for the PR and OR, respectively, with no difference in the multivariable analysis (OR 0.68; 95% C.I. 0.38–1.22; P = 0.19). Iatrogenic complications were rarely observed (PR 1/2134 [0.05%], OR 71/76,216 [0.09%]), which precluded multivariable modeling.

Conclusion:

These results support a similar safety profile for both the PR and OR surgical settings following oCTR with similar pooled major medical complications, pooled wound/surgical site complications, and iatrogenic complications.
Antagonism of the mu-delta opioid receptor heterodimer enhances opioid antinociception by activating Src and calcium/calmodulin-dependent protein kinase II signaling
Authors: Keresztes Attila , Olson Keith , Nguyen Paul , Lopez-Pier Marissa A. , Hecksel Ryan , Barker Natalie K. , Liu Zekun , Hruby Victor , Konhilas John , Langlais Paul R. , Streicher John M.
Published: July 2021

The opioid receptors are important regulators of pain, reward, and addiction. Limited evidence suggests the mu and delta opioid receptors form a heterodimer (MDOR), which may act as a negative feedback brake on opioid-induced analgesia. However, evidence for the MDOR in vivo is indirect and limited, and there are few selective tools available. We recently published the first MDOR-selective antagonist, D24M, allowing us to test the role of the MDOR in mice. We thus cotreated CD-1 mice with D24M and opioids in tail flick, paw incision, and chemotherapy-induced peripheral neuropathy pain models. D24M treatment enhanced oxymorphone antinociception in all models by 54.7% to 628%. This enhancement could not be replicated with the mu and delta selective antagonists CTAP, naltrindole, and naloxonazine, and D24M had a mild transient effect in the rotarod test, suggesting this increase is selective to the MDOR. However, D24M had no effect on morphine or buprenorphine, suggesting that only specific opioids interact with the MDOR. To find a mechanism, we performed phosphoproteomic analysis on brainstems of mice. We found that the kinases Src and CaMKII were repressed by oxymorphone, which was restored by D24M. We were able to confirm the role of Src and CaMKII in D24M-enhanced antinociception using small molecule inhibitors (KN93 and Src-I1). Together, these results provide direct in vivo evidence that the MDOR acts as an opioid negative feedback brake, which occurs through the repression of Src and CaMKII signal transduction. These results further suggest that MDOR antagonism could be a means to improve clinical opioid therapy.
Orai1 is a crucial downstream partner of group I metabotropic glutamate receptor signaling in dorsal horn neurons
Authors: Xia Jingsheng , Dou Yannong , Mei Yixiao , Munoz Frances M. , Gao Ruby , Gao Xinghua , Li Daling , Osei-Owusu Patrick , Schiffenhaus James , Bekker Alex , Tao Yuan-Xiang , Hu Huijuan
Published: July 2021

Group I metabotropic glutamate receptors (group I mGluRs) have been implicated in several central nervous system diseases including chronic pain. It is known that activation of group I mGluRs results in the production of inositol triphosphate (IP3) and diacylglycerol that leads to activation of extracellular signal-regulated kinases (ERKs) and an increase in neuronal excitability, but how group I mGluRs mediate this process remains unclear. We previously reported that Orai1 is responsible for store-operated calcium entry and plays a key role in central sensitization. However, how Orai1 is activated under physiological conditions is unknown. Here, we tested the hypothesis that group I mGluRs recruit Orai1 as part of its downstream signaling pathway in dorsal horn neurons. We demonstrate that neurotransmitter glutamate induces STIM1 puncta formation, which is not mediated by N-Methyl-D-aspartate (NMDA) or α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Glutamate-induced Ca2+ entry in the presence of NMDA or AMPA receptor antagonists is eliminated in Orai1-deficient neurons. Dihydroxyphenylglycine (DHPG) (an agonist of group I mGluRs)-induced Ca2+ entry is abolished by Orai1 deficiency, but not affected by knocking down of transient receptor potential cation channel 1 (TRPC1) or TRPC3. Dihydroxyphenylglycine-induced activation of ERKs and modulation of neuronal excitability are abolished in cultured Orai1-deficient neurons. Moreover, DHPG-induced nociceptive behavior is markedly reduced in Orai1-deficient mice. Our findings reveal previously unknown functional coupling between Orai1 and group I mGluRs and shed light on the mechanism underlying group I mGluRs-mediated neuronal plasticity.
A Buthus martensii Karsch scorpion sting targets Nav1.7 in mice and mimics a phenotype of human chronic pain
Authors: Lu Wuguang , Cheng Xiaoyang , Chen Jiao , Wang Mingyuan , Chen Yonggen , Liu Jinman , Sang Ming , Zhao Ningwei , Yan Huaijiang , Cheng Xiaolan , Zhou Qian , Ye Juan , Wang Jin , Xu Erjin , Tang Zongxiang , Zhou Xi , Rong Mingqiang , Nilsen Erik A. , Dib-Hajj Sulayman D. , Waxman Stephen G. , Yu Ye , Cao Peng
Published: July 2021

Gain-of-function and loss-of-function mutations in Nav1.7 cause chronic pain and pain insensitivity, respectively. The preferential expression of Nav1.7 in the peripheral nervous system and its role in human pain signaling make Nav1.7 a promising target for next-generation pain therapeutics. However, pharmacological agents have not fully recapitulated these pain phenotypes, and because of the lack of subtype-selective molecular modulators, the role of Nav1.7 in the perception of pain remains poorly understood. Scorpion venom is an excellent source of bioactive peptides that modulate various ion channels, including voltage-gated sodium (Nav) channels. Here, we demonstrate that Buthus martensii Karsch scorpion venom (BV) elicits pain responses in mice through direct enhancement of Nav1.7 activity and have identified Makatoxin-3, an α-like toxin, as a critical component for BV-mediated effects on Nav1.7. Blocking other Nav subtypes did not eliminate BV-evoked pain responses, supporting the pivotal role of Nav1.7 in BV-induced pain. Makatoxin-3 acts on the S3–S4 loop of voltage sensor domain IV (VSD4) of Nav1.7, which causes a hyperpolarizing shift in the steady-state fast inactivation and impairs inactivation kinetics. We also determined the key residues and structure–function relationships for the toxin–channel interactions, which are distinct from those of other well-studied α toxins. This study not only reveals a new mechanism underlying BV-evoked pain but also enriches our knowledge of key structural elements of scorpion toxins that are pivotal for toxin–Nav1.7 interactions, which facilitates the design of novel Nav1.7 selective modulators.