bluuebunny/crossref_metadata_2025 huggingface dataset:
A novel risk signature for predicting brain metastasis in patients with lung adenocarcinoma
Authors: Zhao Yanyan , Gu Shen , Li Lingjie , Zhao Ruping , Xie Shujun , Zhang Jingjing , Zhou Rongjing , Tu Linglan , Jiang Lei , Zhang Shirong , Ma Shenglin
Published: June 2023

Background

Brain metastasis (BM) are a devastating consequence of lung cancer. This study was aimed to screen risk factors for predicting BM.

Methods

Using an in vivo BM preclinical model, we established a series of lung adenocarcinoma (LUAD) cell subpopulations with different metastatic ability. Quantitative proteomics analysis was used to screen and identify the differential protein expressing map among subpopulation cells. Q-PCR and Western-blot were used to validate the differential proteins in vitro. The candidate proteins were measured in LUAD tissue samples (n = 81) and validated in an independent TMA cohort (n = 64). A nomogram establishment was undertaken by performing multivariate logistic regression analysis.

Results

The quantitative proteomics analysis, qPCR and Western blot assay implied a five-gene signature that might be key proteins associated with BM. In multivariate analysis, the occurrence of BM was associated with age ≤ 65 years, high expressions of NES and ALDH6A1. The nomogram showed an area under the receiver operating characteristic curve (AUC) of 0.934 (95% CI, 0.881–0.988) in the training set. The validation set showed a good discrimination with an AUC of 0.719 (95% CI, 0.595–0.843).

Conclusions

We have established a tool that is able to predict occurrence of BM in LUAD patients. Our model based on both clinical information and protein biomarkers will help to screen patient in high-risk population of BM, so as to facilitate preventive intervention in this part of the population.
The Crowding-out Effect of Tobacco Expenditure on Health Expenditure: Evidence From a Lower-Middle-Income Country
Authors: Nguyen Cuong Viet , Thi Le Thu , Nguyen Nguyen Hanh
Published: June 2023

Introduction

Poor people have remarkably lower health expenditures than rich people in Vietnam. According to the 2016 Vietnam Household Living Standard Survey (VHLSS), per capita health expenditure of the top quintile households is around 6 times higher than that of the bottom quintile households.

Aims and Methods

We analyze economic inequalities in health expenditure using the concentration index approach and data from the VHLSS 2010–2016. Next, we use the instrumental-variable regression analysis to examine the crowding-out effect of tobacco expenditure on health expenditure. Finally, we use decomposition analysis to explore whether economic inequality in tobacco expenditure is associated with an economic inequality in health expenditure.

Results

We find a crowding-out effect of tobacco expenditure on health expenditure of households. The share of health expenditure of households with tobacco spending is 0.78% lower than that of households without tobacco spending. It is estimated that a one-VND increase in tobacco expenditure results in a 0.18 Vietnamese Dong (VND) (95% CI: −0.30 to −0.06) decrease in health expenditure. There is a negative association between economic inequality in tobacco expenditure and economic inequality in health expenditure. This means that if the poor consume less tobacco, their expenditure on health can be increased, resulting in a decrease in inequality in health expenditure.

Conclusions

Findings from this study suggest that reducing tobacco expenditure could improve health care of the poor and reduce inequality in health care in Vietnam. Our study recommends that the government continuously increase the tobacco tax in order to effectively reduce tobacco consumption.

Implications

Empirical studies show mixed results on the effect of tobacco expenditure on health expenditure. We find a crowding-out effect of tobacco expenditure on health expenditure of poor households in Vietnam. It implies that if the poor reduce their expenditure on tobacco, economic inequality in health expenditure can be reduced. Our findings suggest that reducing tobacco consumption in poor households can increase their health expenditure, therefore, decreasing inequality in health expenditure. Different policies to reduce tobacco consumption such as tobacco taxation, smoke-free areas, and tobacco advertisement bans should be strengthened.
What drives overhead aversion in charity? Evidence from field-experimental variation in fundraising costs
Authors: Cagala Tobias , Rincke Johannes , Tuset Cueva Amanda
Published: June 2023

This article explores donors’ aversion to financing charities’ fundraising expenses. We hypothesize that such expenses can signal a charity’s efficiency, or affect the donors’ perception of the impact a donation has on the cause. Using data from a randomized field experiment, we disentangle both effects, differentiating between weakly and strongly committed donors. Among potential donors who are weakly committed to the cause, information on the charity’s efficiency does not affect donation behavior. Signaling an increased impact leaves unaffected the average donation among weakly committed donors, but diminishes their likelihood to give. Regarding strongly committed donors, we find that impact-related information does not affect behavior, but a signal of improved efficiency strongly increases donations along the intensive margin. We conclude that information on fundraising expenses plays little role for weakly committed donors. In contrast, strongly committed donors are averse to financing fundraising expenses mostly due to efficiency concerns.
Religion and Pluralism before the Inter-American Court of Human Rights: From Individualizing Religious Freedom to Deregulating the Religious Market
Authors: Chaibi Moncef
Published: June 2023

With the rise of religious diversity within domestic societies, religion and religious pluralism have become increasingly important issues around the world. Therefore, it is important to examine the legal regulations governing religion and religious freedom, particularly in light of international human rights—the ultimate guarantee of individual rights. This article examines the regulation of religion, religious freedom, and religious pluralism by the Inter-American Court of Human Rights (the Court). Despite the central role religion plays in the social dynamics of the Americas, it has been largely absent from the Court’s jurisprudence. The latter discussed religion in a few cases only, thus making sporadic—but nevertheless key—findings regarding the regulation of religious freedom within its jurisdiction. Analysing these findings, as exposed in the corresponding judgments and advisory opinions, reveals the creative and progressive approach that the Court takes on religion, religious freedom, and religious pluralism.
Pathological Outcomes of Patients With Advanced Renal Cell Carcinoma Who Receive Nephrectomy Following Immunotherapy
Authors: Panian Justine , Saidian Ava , Hakimi Kevin , Ajmera Archana , Anderson William J , Barata Pedro , Berg Stephanie , Signoretti Sabina , Lee Chang Steven , D’Andrea Vincent , George Daniel , Dzimitrowicz Hannah , El Zarif Talal , Emamekhoo Hamid , Gross Evan , Kilari Deepak , Lam Elaine , Lashgari Isabel , Psutka Sarah , Rauterkus Grant P , Shabaik Ahmed , Thapa Bicky , Wang Luke , Weise Nicole , Yim Kendrick , Zhang Tian , Derweesh Ithaar , McKay Rana R
Published: June 2023

Background

Even though cytoreductive nephrectomy (CN) was once the standard of care for patients with advanced renal cell carcinoma (RCC), its role in treatment has not been well analyzed or defined in the era of immunotherapy (IO).

Materials and Methods

This study analyzed pathological outcomes in patients with advanced or metastatic RCC who received IO prior to CN. This was a multi-institutional, retrospective study of patients with advanced or metastatic RCC. Patients were required to receive IO monotherapy or combination therapy prior to radical or partial CN. The primary endpoint assessed surgical pathologic outcomes, including American Joint Committee on Cancer (AJCC) staging and frequency of downstaging, at the time of surgery. Pathologic outcomes were correlated to clinical variables using a Wald-chi squared test from Cox regression in a multi-variable analysis. Secondary outcomes included objective response rate (ORR) defined by response evaluation criteria in solid tumors (RECIST) version 1.1 and progression-free survival (PFS), which were estimated using the Kaplan-Meier method with reported 95% CIs.

Results

Fifty-two patients from 9 sites were included. Most patients were male (65%), 81% had clear cell histology, 11% had sarcomatoid differentiation. Overall, 44% of patients experienced pathologic downstaging, and 13% had a complete pathologic response. The ORR immediately prior to nephrectomy was stable disease in 29% of patients, partial response in 63%, progressive disease in 4%, and 4% unknown. Median follow-up for the entire cohort was 25.3 months and median PFS was 3.5 years (95% CI, 2.1-4.9).

Conclusions

IO-based interventions prior to CN in patients with advanced or metastatic RCC demonstrates efficacy, with a small fraction of patients showing a complete response. Additional prospective studies are warranted to investigate the role of CN in the modern IO-era.
The COVID-19 lockdown: a unique perspective into heterogeneous impacts of transboundary pollution on snow and ice darkening across the Himalayas
Authors: Hou Zhengyang , Li Yang , Zhang Liqiang , Song Changqing , Lin Jintai , Zhou Chenghu , Wang Yuebin , Qu Ying , Yao Xin , Gao Peichao
Published: June 2023

The Tibetan Plateau holds the largest mass of snow and ice outside of the polar regions. The deposition of light-absorbing particles (LAPs) including mineral dust, black carbon and organic carbon and the resulting positive radiative forcing on snow (RFSLAPs) substantially contributes to glacier retreat. Yet how anthropogenic pollutant emissions affect Himalayan RFSLAPs through transboundary transport is currently not well known. The COVID-19 lockdown, resulting in a dramatic decline in human activities, offers a unique test to understand the transboundary mechanisms of RFSLAPs. This study employs multiple satellite data from the moderate resolution imaging spectroradiometer and ozone monitoring instrument, as well as a coupled atmosphere–chemistry–snow model, to reveal the high spatial heterogeneities in anthropogenic emissions-induced RFSLAPs across the Himalaya during the Indian lockdown in 2020. Our results show that the reduced anthropogenic pollutant emissions during the Indian lockdown were responsible for 71.6% of the reduction in RFSLAPs on the Himalaya in April 2020 compared to the same period in 2019. The contributions of the Indian lockdown-induced human emission reduction to the RFSLAPs decrease in the western, central, and eastern Himalayas were 46.8%, 81.1%, and 110.5%, respectively. The reduced RFSLAPs might have led to 27 Mt reduction in ice and snow melt over the Himalaya in April 2020. Our findings allude to the potential for mitigating rapid glacial threats by reducing anthropogenic pollutant emissions from economic activities.
Wild orangutans can simultaneously use two independent vocal sound sources similarly to songbirds and human beatboxers
Authors: Lameira Adriano R , Hardus Madeleine E
Published: June 2023

Speech is among the most complex motoric tasks humans ever perform. Songbirds match this achievement during song production through the precise and simultaneous motor control of two sound sources in the syrinx. Integrated and intricate motor control has made songbirds comparative models par excellence for the evolution of speech, however, phylogenetic distance with humans prevents an improved understanding of the precursors that, within the human lineage, drove the emergence of advanced vocal motor control and speech. Here, we report two types of biphonic call combination in wild orangutans that articulatorily resemble human beatboxing and that result from the simultaneous exercise of two vocal sound sources: one unvoiced source achieved through articulatory maneuvering of the lips, tongue, and jaw as typically used for consonant-like call production, plus one voiced source achieved through laryngeal action and voice activation as typically used for vowel-like call production. Orangutan biphonic call combinations showcase unappreciated levels of, and distinct neuromotor channels for, vocal motor control in a wild great ape, providing a direct vocal motor analogy with birdsong based on the precise and simultaneous co-control of two sound sources. Findings suggest that speech and human vocal fluency likely built upon complex call combination, coordination and coarticulation capacities that involved vowel-like and consonant-like calls in an ancestral hominid.
Coproduction and Usability of a Smartphone App for Falls Reporting in Parkinson Disease
Authors: Wales Jill , Moore Jason , Naisby Jenni , Ratcliffe Natasha , Barry Gill , Amjad Annee , Godfrey Alan , Standerline Gerry , Webster Elaine , Morris Rosie
Published: June 2023

Objective

The purpose of this study was to coproduce a smart-phone application for digital falls reporting in people with Parkinson disease (PD) and to determine usability using an explanatory mixed-methods approach.

Methods

This study was undertaken in 3 phases. Phase 1 was the development phase, in which people with PD were recruited as co-researchers to the project. The researchers, alongside a project advisory group, coproduced the app over 6 months. Phase 2 was the implementation phase, in which 15 people with PD were invited to test the usability of the app. Phase 3 was the evaluation phase, in which usability was assessed using the systems usability scale by 2 focus groups with 10 people with PD from phase 2.

Results

A prototype was successfully developed by researchers and the project advisory group. The usability of the app was determined as good (75.8%) by people with PD when rating using the systems usability scale. Two focus groups (n = 5 per group) identified themes of 1) usability, 2) enhancing and understanding management of falls, and 3) recommendations and future developments.

Conclusions

A successful prototype of the iFall app was developed and deemed easy to use by people with PD. The iFall app has potential use as a self-management tool for people with PD alongside integration into clinical care and research studies.

Impact

This is the first digital outcome tool to offer reporting of falls and near-miss fall events. The app may benefit people with PD by supporting self-management, aiding clinical decisions in practice, and providing an accurate and reliable outcome measure for future research.

Lay Summary

A smartphone application designed in collaboration with people who have PD to record their falls was acceptable and easy to use by people with PD.
Approaches to Studying and Improving Social Motivation in Schizophrenia
Authors: Catalano Lauren T , Green Michael F
Published: June 2023

Social motivation impairments, or “asociality,” have long been considered a core clinical feature of schizophrenia. Although the prevalence and pervasive negative impact of poor social motivation is well-documented, our understanding is limited regarding causal mechanisms. Advances in definition, conceptualization, and characterization are needed to inform research aimed at understanding these mechanisms and developing effective interventions. This theme issue is intended to accelerate efforts to study and treat social motivation in schizophrenia by synthesizing the current knowledge and providing new frameworks to guide future research in this area.
Thinking Outside the West: Religious Change from the Nation-State to the Global-Market Regime
Authors: Gauthier François
Published: June 2023

This article proposes to question the sociology of religion’s Western-centrism by taking a sidestep and looking at key religious changes in the non-Western world. It does so by examining religious change in Indonesia and China over the course of the last century. This exercise shows with some clarity that religion in these countries has gone through two radically different historical phases: a first in which religion (as all other social dimensions) was shaped by the nation-state (differentiated and “churched”) and a second in which consumerism and marketization appear as major forces behind bottom-up religious booms. The article argues that this shift in religious regimes can be generalized to global societies, including in the West, thereby significantly refreshing many ongoing debates and diagnoses and enabling a new appraisal of the limits of the “secularization” and “Rational Choice” narratives for understanding religion in the world today.
Functional response and resistance to drought in seedlings of six shrub species with contrasting leaf traits from the Mediterranean Basin and California
Authors: Parra Antonio , Pratt R Brandon , Jacobsen Anna L , Chamorro Daniel , Torres Iván , Moreno José M
Published: June 2023

Extreme drought events during post-fire regeneration are becoming increasingly frequent in Mediterranean-type ecosystems. Understanding how plants with different traits and origins respond to such conditions during early life stages is therefore critical for assessing the effect of climate change. Here, seedlings of three Cistus (semi-deciduous malacophylls from the Mediterranean Basin) and three Ceanothus (evergreen sclerophylls from California) species, two post-fire seeder genera with contrasting leaf traits, were subjected to complete water deprivation for 3 months in a common garden experiment. The leaf and plant structure and plant tissue water relations were characterized before the drought, and the functional responses (water availability, gas exchange and fluorescence) were monitored during the drought. Both genera exhibited contrasting leaf structure and tissue water relations traits, with higher leaf area and specific leaf area as well as higher osmotic potential at maximum turgor and turgor loss point in Cistus than Ceanothus. During drought, Ceanothus showed a more conservative use of water than Cistus, with a water potential less sensitive to decreasing soil moisture and a strong decline in photosynthesis and stomatal conductance in response to water deficit, but also a level of fluorescence more responsive to drought than Cistus. However, we could not find a different degree of drought resistance between the genera. This was particularly clear between Cistus ladanifer L. and Ceanothus pauciflorus DC., the two most functionally contrasting species, but at the same time, the two most drought-resistant. Our findings demonstrate that species with different leaf traits and functional responses to water stress may not differ in their degree of drought resistance, at least during the seedling stage. This underlines the need to take general categorizations by genus or functional types with caution and to deepen our knowledge about the Mediterranean-type species ecophysiology, especially during early life stages, in order to anticipate their vulnerability to climate change.
Occurrence of Ascospores and White Mold Caused by Sclerotinia sclerotiorum in Dry Bean Fields in Alberta, Canada
Authors: Reich Jonathan , McLaren Debra , Kim Yong Min , Wally Owen , Yevtushenko Dmytro , Hamelin Richard , Balasubramanian Parthiba , Chatterton Syama
Published: June 2023

White mold caused by the fungal pathogen Sclerotinia sclerotiorum (Lib.) de Bary is one of the most important biological constraints to dry bean (Phaseolus vulgaris L.) production in Canada. Disease forecasting is one tool that could help growers manage the disease while reducing fungicide use. However, predicting white mold epidemics has remained difficult due to their sporadic occurrence. In this study, over the course of four growing seasons (2018 to 2021), we surveyed dry bean fields in Alberta and collected daily in-field weather data and daily in-field ascospore counts. White mold levels were variable and generally high in all years, confirming that the disease is ubiquitous and a constant threat to dry bean production. Ascospores were present throughout the growing season, and mean ascospore levels varied by field, month, and year. Models based on in-field weather and ascospore levels were not highly predictive of final disease incidence in a field, suggesting that environment and pathogen presence were not limiting factors to disease development. Rather, significant effects of market class on disease were found, with pinto beans, on average, having the highest disease incidence (33%) followed by great northern (15%), black (10%), red (6%), and yellow (5%). When incidence of these market classes was modeled separately, different environmental variables were important in each model; however, average wind speed was a significant variable in all models. Taken together, these findings suggest that white mold management in dry bean should focus on fungicide use, plant genetics, irrigation management, and other agronomic factors.
Mitochondrial reactive oxygen species modify extracellular vesicles secretion rate
Authors: Nørgård Mikkel Ø. , Lund Philip M. , Kalisi Nazmie , Andresen Thomas L. , Larsen Jannik B. , Vogel Stefan , Svenningsen Per
Published: June 2023

Extracellular vesicle (EV) secretion rate is stimulated by hypoxia that causes increased reactive oxygen species (ROS) production by the mitochondrial electron transport chain (ETC) and hypoxia‐induced factor (HIF)‐1 signaling; however, their contribution to the increased EV secretion rate is unknown. We found that the EV marker secretion rate in our EV reporter cell line CD9truc‐EGFP was unaffected by the HIF‐1α stabilizer roxadustat; yet, ETC stimulation by dichloroacetic acid (DCA) significantly increased EV secretion. The DCA‐induced EV secretion was blocked by the antioxidant TEMPO and rotenone, an inhibitor of the ETC's Complex I. Under hypoxic conditions, the limited oxygen reduction impedes the ETC's Complex III. To mimic this, we inhibited Complex III with antimycin A, which increased ROS‐dependent EV secretion. The electron transport between Complex I and III is accomplished by coenzyme Q created by the mevalonate pathway and tyrosine metabolites. Blocking an early step in the mevalonate pathway using pitavastatin augmented the DCA‐induced EV secretion, and 4‐nitrobenzoate—an inhibitor of the condensation of the mevalonate pathway with tyrosine metabolites—increased ROS‐dependent EV secretion. Our findings indicate that hypoxia‐mimetics targeting the ETC modify EV secretion and that ROS produced by the ETC is a potent stimulus for EV secretion.
Verteporfin attenuates trauma‐induced heterotopic ossification of Achilles tendon by inhibiting osteogenesis and angiogenesis involvingYAP/β‐catenin signaling
Authors: Luo Gang , Sun Ziyang , Liu Hang , Yuan Zhengqiang , Wang Wei , Tu Bing , Li Juehong , Fan Cunyi
Published: June 2023

Heterotopic ossification occurs as a pathological ossification condition characterized by ectopic bone formation within soft tissues following trauma. Vascularization has long been established to fuel skeletal ossification during tissue development and regeneration. However, the feasibility of vascularization as a target of heterotopic ossification prevention remained to be further clarified. Here, we aimed to identify whether verteporfin as a widely used FDA‐approved anti‐vascularization drug could effectively inhibit trauma‐induced heterotopic ossification formation. In the current study, we found that verteporfin not only dose dependently inhibited the angiogenic activity of human umbilical vein endothelial cells (HUVECs) but also the osteogenic differentiation of tendon stem cells (TDSCs). Moreover, YAP/β‐catenin signaling axis was downregulated by the verteporfin. Application of lithium chloride, an agonist of β‐catenin, recovered TDSCs osteogenesis and HUVECs angiogenesis that was inhibited by verteporfin. In vivo, verteporfin attenuated heterotopic ossification formation by decelerating osteogenesis and the vessels densely associated with osteoprogenitors formation, which could also be readily reversed by lithium chloride, as revealed by histological analysis and Micro‐CT scan in a murine burn/tenotomy model. Collectively, this study confirmed the therapeutic effect of verteporfin on angiogenesis and osteogenesis in trauma‐induced heterotopic ossification. Our study sheds light on the anti‐vascularization strategy with verteporfin as a candidate treatment for heterotopic ossification prevention.
A patient with rapidly growing axillary masses
Authors: Marshall Jurga , Bhave Priya , Bruza-Augatis Mirela , Fernandez Christine
Published: June 2023

About 85,000 melanomas are diagnosed every year in the United States, but only about 3.2% are diagnosed without a primary site. This article describes a patient who presented with two rapidly growing axillary masses and was found to have metastatic melanoma of the lymph nodes with no known primary site. Melanoma of unknown primary (MUP) site is staged either III or IV level. Management is determined in the same manner as stage-matched melanoma of known primary site.
Should direct oral anticoagulants be used to treat protein C or S deficiency?
Authors: Bennett Kiya K. , Schwier Nicholas C.
Published: June 2023

Few studies have evaluated the use of direct oral anticoagulants (DOACs) in patients with major thrombophilias, such as protein C or S deficiency. The data related to use of DOACs in treating protein C or S deficiency are heterogeneous, consisting of various DOACs, inconsistent ranges of dosing, dissimilar patient demographics, and inconsistent clinical endpoints. Vitamin K antagonists and low-molecular-weight heparins are preferred until more robust data are available about using DOACs in patients with protein C or S deficiency.
Minimum 5-Year Results of Elongation Derotation Flexion Casting for Early Onset Scoliosis: The Story Is Not Over Until Skeletal Maturity
Authors: Regan Christina M. , Milbrandt Todd A. , Stans Anthony A. , Grigoriou Emmanouil , Larson A. Noelle
Published: June 2023

Background:

Early conservative treatment for patients with idiopathic infantile scoliosis (IIS) with elongation derotation flexion (EDF) casting and subsequent serial bracing has become widely utilized. However, the long-term outcomes of patients treated with EDF casting are limited.

Methods:

We performed a retrospective chart review of all patients who had undergone serial elongation derotation flexion casting and subsequent bracing for scoliosis presenting at a single large tertiary center. All patients were followed for a minimum of 5 years or until surgical intervention.

Results:

Our study included 21 patients diagnosed with IIS and treated with EDF casting. At a mean 7-year follow-up, 13 of the 21 patients were considered successfully treated with a mean final major coronal curvature of 9 degrees compared to a pretreatment coronal curve of 36 degrees. These patients, on average, began casting at 1.3 years old and spent 1 year in a cast. Patients that did not have substantial improvement began casting at mean 4 years old and remained in a cast for 0.8 years. Three patients initially had substantial improvement with the correction to <20 degrees at a mean age of 7; however, their curves worsened in adolescence with poor brace compliance. All 3 patients will require surgical intervention. Of the patients not successfully treated with casting, 7 required surgery at a mean 8.2 years of age, 4.3 years after initiation of casting. A significant predictor of treatment failure was older age of cast initiation (P<0.001).

Conclusions:

EDF casting can be an effective cure for IIS patients if initiated at a young age with 15 of 21 patients successfully treated (76%). However, 3 patients had a recurrence in adolescence resulting in an overall success rate of only 62%. Casting should be initiated early to maximize the likelihood of treatment success and periodic monitoring should be continued through skeletal maturity as recurrence during adolescence can occur.
Organoids: approaches and utility in cancer research
Authors: Zhou Bingrui , Feng Zhiwei , Xu Jun , Xie Jun
Published: June 2023

Organoids are three-dimensional cellular structures with self-organizing and self-differentiation capacities. They faithfully recapitulate structures and functions of in vivo organs as represented by functionality and microstructural definitions. Heterogeneity in in vitro disease modeling is one of the main reasons for anti-cancer therapy failures. Establishing a powerful model to represent tumor heterogeneity is crucial for elucidating tumor biology and developing effective therapeutic strategies. Tumor organoids can retain the original tumor heterogeneity and are commonly used to mimic the cancer microenvironment when co-cultured with fibroblasts and immune cells; therefore, considerable effort has been made recently to promote the use of this new technology from basic research to clinical studies in tumors. In combination with gene editing technology and microfluidic chip systems, engineered tumor organoids show promising abilities to recapitulate tumorigenesis and metastasis. In many studies, the responses of tumor organoids to various drugs have shown a positive correlation with patient responses. Owing to these consistent responses and personalized characteristics with patient data, tumor organoids show excellent potential for preclinical research. Here, we summarize the properties of different tumor models and review their current state and progress in tumor organoids. We further discuss the substantial challenges and prospects in the rapidly developing tumor organoid field.
Proficiency score as a predictor of early trifecta achievement during the learning curve of robot-assisted radical prostatectomy for high-risk prostate cancer: Results of a multicentric series
Authors: Anceschi Umberto , Flammia Rocco Simone , Tufano Antonio , Morelli Michele , Galfano Antonio , Luciani Lorenzo Giuseppe , Misuraca Leonardo , Dell’Oglio Paolo , Tuderti Gabriele , Brassetti Aldo , Ferriero Maria Consiglia , Bove Alfredo Maria , Mastroianni Riccardo , Prata Francesco , Sperduti Isabella , Petralia Giovanni , Secco Silvia , Di Trapani Ettore , Mattevi Daniele , Cai Tommaso , Bocciardi Aldo Massimo , Simone Giuseppe
Published: June 2023

Background

Recently, an innovative tool called “proficiency score” was introduced to assess the learning curve for robot-assisted radical prostatectomy (RARP). However, the initial study only focused on patients with low-risk prostate cancer for whom pelvic lymph node dissection (PLND) was not required. To address this issue, we aimed to validate proficiency scores of a contemporary multicenter cohort of patients with high-risk prostate cancer treated with RARP plus extended PLND by trainee surgeons.

Material and methods

Between 2010 and 2020, 4 Italian institutional prostate-cancer datasets were merged and queried for “RARP” and “high-risk prostate cancer.” High-risk prostate cancer was defined according to the most recent European Association of Urology guidelines as follows: prostate-specific antigen >20 ng/mL, International Society of Urological Pathology ≥4, and/or clinical stage (cT) ≥ 2c on preoperative imaging. The selected cohort (n = 144) included clinical cases performed by trainee surgeons (n = 4) after completing their RARP learning curve (50 procedures for low-risk prostate cancer). The outcome of interest, the proficiency score, was defined as the coexistence of all the following criteria: a comparable operation time to the interquartile range of the mentor surgeon at each center, absence of any significant perioperative complications Clavien-Dindo Grade 3–5, no perioperative blood transfusions, and negative surgical margins. A logistic binary regression model was built to identify the predictors of 1-year trifecta achievement in the trainee cohort. For all statistical analyses, a 2-sided p < 0.05 was considered significant.

Results

A proficiency score was achieved in 42.3% patients. At univariable level, proficiency score was associated with 1-year trifecta achievement (odds ratio, 8.77; 95% confidence interval, 2.42–31.7; p = 0.001). After multivariable adjustments for age, nerve-sparing, and surgical technique, the proficiency score independently predicted 1-year trifecta achievement (odds ratio, 9.58; 95% confidence interval, 1.83–50.1; p = 0.007).

Conclusions

Our findings support the use of proficiency scores in patients and require extended PLND in addition to RARP.
Twelve Steps to Financial Freedom for Plastic Surgeons
Authors: Zelenova Kateryna , Raine Brielle , Chen Ricki , Williams Rachel E. , Davis Anna E. , Loree Thom , Burke Mark , Nagai Michael , Frey Jordan
Published: June 2023

Background:

Financial stress and lack of financial well-being are significant contributors to physician burnout. Many trainees believe little can contribute to developing financial freedom during their training years. However, residency is a pivotal moment in a young attending’s life; strategic financial steps taken during this time can lead to a path of financial freedom and well-being for years to come.

Methods:

We introduce 12 effective financial steps physicians can take at the start of their careers. These essential steps were compiled both anecdotally and from published financial resources such as White Coat Investigator and the Millionaire Next Door. Steps include building your “why,” becoming financially educated, eliminating debt, attaining insurance, optimizing contracts, awareness of self-net worth, budgeting, maximizing investment strategies, smart investing, wise spending, K.I.S.S, and creating a personal financial plan.

Results:

As an example, an IRA is a retirement account set up by you, and to take advantage of the tax benefits, you must have a modified adjusted gross income of less than $124,000 as a single tax filer for 2022. Most physicians are compensated at a rate higher than this; however, there is a legal loophole to take advantage of to allow earners to still contribute to a Roth IRA that is discussed.

Conclusions:

Financial education is the first step toward a path to financial success in a young physician’s life. Implementation of these 12 financial steps early in a physician’s career will enrich one’s financial freedom and well-being.
Autologous Skin Grafts, versus Tissue-engineered Skin Constructs: A Systematic Review and Meta-analysis
Authors: Kianian Sara , Zhao Kelley , Kaur Jasleen , Lu Kimberly W. , Rathi Sourish , Ghosh Kanad , Rogoff Hunter , Hays Thomas R. , Park Jason , Rafailovich Miriam , Simon Marcia , Bui Duc T. , Khan Sami U. , Dagum Alexander B. , Singh Gurtej
Published: June 2023

Background:

For over 100 years, autologous skin grafts have remained the gold standard for the reconstruction of wounds but are limited in availability. Acellular tissue-engineered skin constructs (acellular TCs) and cellular tissue-engineered skin constructs (cellular TCs) may address these limitations. This systematic review and meta-analysis compare outcomes between them.

Methods:

A systematic review was conducted using PRISMA guidelines, querying MEDLINE, Embase, Web of Science, and Cochrane to assess graft incorporation, failure, and wound healing. Case reports/series, reviews, in vitro/in vivo work, non-English articles or articles without full text were excluded.

Results:

Sixty-six articles encompassing 4076 patients were included. No significant differences were found between graft failure rates (P = 0.07) and mean difference of percent reepithelialization (p = 0.92) when split-thickness skin grafts were applied alone versus co-grafted with acellular TCs. Similar mean Vancouver Scar Scale was found for these two groups (p = 0.09). Twenty-one studies used at least one cellular TC. Weighted averages from pooled results did not reveal statistically significant differences in mean reepithelialization or failure rates for epidermal cellular TCs compared with split-thickness skin grafts (p = 0.55).

Conclusions:

This systematic review is the first to illustrate comparable functional and wound healing outcomes between split-thickness skin grafts alone and those co-grafted with acellular TCs. The use of cellular TCs seems promising from preliminary findings. However, these results are limited in clinical applicability due to the heterogeneity of study data, and further level 1 evidence is required to determine the safety and efficacy of these constructs.
Single-cell RNA sequencing reveals the immunoregulatory roles of PegIFN-α in patients with chronic hepatitis B
Authors: Jiang Penglei , Jia Hongyu , Qian Xinyue , Tang Tian , Han Yingli , Zhang Zhaoru , Jiang Lingli , Yu Zebin , Zheng Lin , Yu Guodong , Cai Huan , Zhang Shanyan , Zhang Xiaoli , Gu Jueqing , Ye Chanyuan , Yang Lisha , Lu Yingfeng , Liu Heng , Lu Xiaoqing , Jin Ciliang , Ren Yue , Lu Miaomiao , Xu Lingling , Yu Jiong , Jin Xi , Yang Yida , Qian Pengxu
Published: June 2023

Background and Aims:

Chronic hepatitis B (CHB) is caused by HBV infection and affects the lives of millions of people worldwide by causing liver inflammation, cirrhosis, and liver cancer. Interferon-alpha (IFN-α) therapy is a conventional immunotherapy that has been widely used in CHB treatment and achieved promising therapeutic outcomes by activating viral sensors and interferon-stimulated genes (ISGs) suppressed by HBV. However, the longitudinal landscape of immune cells of CHB patients and the effect of IFN-α on the immune system are not fully understood.

Approach and Results:

Here, we applied single-cell RNA sequencing (scRNA-seq) to delineate the transcriptomic landscape of peripheral immune cells in CHB patients before and after PegIFN-α therapy. Notably, we identified three CHB-specific cell subsets, pro-inflammatory (Pro-infla) CD14+ monocytes, Pro-infla CD16+ monocytes and IFNG+ CX3CR1− NK cells, which highly expressed proinflammatory genes and positively correlated with HBsAg. Furthermore, PegIFN-α treatment attenuated percentages of hyperactivated monocytes, increased ratios of long-lived naive/memory T cells and enhanced effector T cell cytotoxicity. Finally, PegIFN-α treatment switched the transcriptional profiles of entire immune cells from TNF-driven to IFN-α-driven pattern and enhanced innate antiviral response, including virus sensing and antigen presentation.

Conclusions:

Collectively, our study expands the understanding of the pathological characteristics of CHB and the immunoregulatory roles of PegIFN-α, which provides a new powerful reference for the clinical diagnosis and treatment of CHB.
Significance of Degree of HLA Disparity Using T-cell Replete Peripheral Blood Stem Cells From Haploidentical Donors With Posttransplantation Cyclophosphamide in AML in First Complete Hematologic Remission: A Study of the Acute Leukemia Working Party of the EBMT
Authors: Kharfan-Dabaja Mohamed A. , Labopin Myriam , Ayala Ernesto , Bazarbachi Ali , Blaise Didier , Vydra Jan , Bramanti Stefania , Itälä-Remes Maija , Schmid Christoph , Busca Alessandro , Forcade Edouard , Rabitsch Werner , Zecca Marco , Kröger Nicolaus , Bulabois Claude-Eric , Grillo Giovanni , Rambaldi Alessandro , Fanin Renato , Zallio Francesco , Di Renzo Nicola , Koc Yener , Novis Yana , McDonald Andrew , Herrera Arroyo Concepcion , Sanz Jaime , Nagler Arnon , Ciceri Fabio , Mohty Mohamad
Published: June 2023

Availability of haploidentical donors has broadened utilization of allogeneic hematopoietic cell transplantation (allo-HCT). Peripheral blood stem cells (PBSC) are being used with increased frequency in haploidentical allo-HCT. We evaluated extent of HLA disparity (2–3/8 versus 4/8 HLA antigen mismatches) on post-allograft outcomes when using T-cell replete PBSC from haploidentical donors for acute myeloid leukemia in first complete remission. Primary objectives entailed assessing cumulative incidence of grade 2–4 acute graft-versus-host disease (GVHD) and chronic GVHD (any grade). A total of 645 patients received a haploidentical allo-HCT from a donor with either 2–3 of 8 HLA antigen mismatches (n = 180) or with 4 of 8 HLA antigen mismatches (n = 465). Presence of 2–3 of 8 versus 4 of 8 HLA mismatches did not affect the incidence of acute GVHD (grade 2–4) and chronic GVHD (any grade). Overall survival (OS), leukemia-free survival (LFS) relapse incidence (RI), nonrelapse mortality and the composite endpoint of GVHD-free relapse-free survival were also similar among the groups. Pertaining to HLA-B leader matching effect, our analysis did not discern any difference in aforementioned post-allograft outcomes for this variable. However, in univariate analysis, absence of an antigen mismatch in HLA-DPB1 showed a trend for better OS. Notwithstanding inherent limitations associated with registry data, our results did not show an advantage of selecting a haploidentical donor with 2–3 of 8 HLA antigen mismatches over one with 4 of 8 HLA antigen mismatches when using PBSC as the cell source. Adverse cytogenetics remains a major adverse determinant of inferior OS and LFS and a higher RI. Using reduced-intensity conditioning yielded worse OS and LFS.
Biomolecular Condensates in Myeloid Leukemia: What Do They Tell Us?
Authors: Jevtic Zivojin , Allram Melanie , Grebien Florian , Schwaller Juerg
Published: June 2023

Recent studies have suggested that several oncogenic and tumor-suppressive proteins carry out their functions in the context of specific membrane-less cellular compartments. As these compartments, generally referred to as onco-condensates, are specific to tumor cells and are tightly linked to disease development, the mechanisms of their formation and maintenance have been intensively studied. Here we review the proposed leukemogenic and tumor-suppressive activities of nuclear biomolecular condensates in acute myeloid leukemia (AML). We focus on condensates formed by oncogenic fusion proteins including nucleoporin 98 (NUP98), mixed-lineage leukemia 1 (MLL1, also known as KMT2A), mutated nucleophosmin (NPM1c) and others. We also discuss how altered condensate formation contributes to malignant transformation of hematopoietic cells, as described for promyelocytic leukemia protein (PML) in PML::RARA-driven acute promyelocytic leukemia (APL) and other myeloid malignancies. Finally, we discuss potential strategies for interfering with the molecular mechanisms related to AML-associated biomolecular condensates, as well as current limitations of the field.
Healthcare-associated Infections Drive Antimicrobial Prescribing in Pediatric Departments at Three Academic Hospitals in South Africa
Authors: Chetty Terusha , Pillay Ashendri , Balakrishna Yusentha , Reddy Tarylee , Goga Ameena , Moore David P. , Karsas Maria , Cloete Jeané , Archary Moherndran , Kwawegen Alison van , Thomas Reenu , Nakwa Firdose Lambey , Waggie Zainab , Magrath Stephanie , Jeena Prakash
Published: June 2023

Background:

The prevalence of antimicrobial prescriptions for healthcare-associated infections (HAI) in South Africa is largely unknown. This study aimed to estimate the point prevalence of pediatric antibiotic and antifungal usage in 3 South African academic hospitals.

Methods:

This cross-sectional study included hospitalized neonates and children (0–15 years). We used the World Health Organization methodology for antimicrobial point prevalence studies, with weekly surveys to achieve a sample size of ~400 at each site.

Results:

Overall, 1,946 antimicrobials were prescribed to 1,191 patients. At least 1 antimicrobial was prescribed for 22.9% [95% confidence interval (CI): 15.5–32.5%] of patients. The prevalence of antimicrobial prescribing for HAI was 45.6%. In the multivariable analysis, relative to children 6–12 years, neonates [adjusted relative risk (aRR): 1.64; 95% CI: 1.06–2.53], infants (aRR: 1.57; 95% CI: 1.12–2.21) and adolescents (aRR: 2.18; 95% CI: 1.45–3.29) had significantly increased risk of prescriptions for HAI. Being preterm (aRR: 1.33; 95% CI: 1.04–1.70) and underweight (aRR: 1.25; 95% CI: 1.01–1.54) was predictive of antimicrobial usage for HAI. Having an indwelling device, surgery since admission, blood transfusions and classification as rapidly fatal on McCabe score also increased the risk of prescriptions for HAI.

Conclusions:

The high prevalence of antimicrobial prescribing for HAI to treat children with recognized risk factors in academic hospitals in South Africa is concerning. Concerted efforts need to be made to strengthen hospital-level infection prevention and control measures, with a critical review of antimicrobial usage through functional antibiotic stewardship programs to preserve the available antimicrobial armamentarium at the hospital level.
Chemotherapy for pain: reversing inflammatory and neuropathic pain with the anticancer agent mithramycin A
Authors: Xu Zheyun , Lee Man-Cheung , Sheehan Kayla , Fujii Keisuke , Rabl Katalin , Rader Gabriella , Varney Scarlett , Sharma Manohar , Eilers Helge , Kober Kord , Miaskowski Christine , Levine Jon D. , Schumacher Mark A.
Published: June 2023

The persistence of inflammatory and neuropathic pain is poorly understood. We investigated a novel therapeutic paradigm by targeting gene networks that sustain or reverse persistent pain states. Our prior observations found that Sp1-like transcription factors drive the expression of TRPV1, a pain receptor, that is blocked in vitro by mithramycin A (MTM), an inhibitor of Sp1-like factors. Here, we investigate the ability of MTM to reverse in vivo models of inflammatory and chemotherapy-induced peripheral neuropathy (CIPN) pain and explore MTM's underlying mechanisms. Mithramycin reversed inflammatory heat hyperalgesia induced by complete Freund adjuvant and cisplatin-induced heat and mechanical hypersensitivity. In addition, MTM reversed both short-term and long-term (1 month) oxaliplatin-induced mechanical and cold hypersensitivity, without the rescue of intraepidermal nerve fiber loss. Mithramycin reversed oxaliplatin-induced cold hypersensitivity and oxaliplatin-induced TRPM8 overexpression in dorsal root ganglion (DRG). Evidence across multiple transcriptomic profiling approaches suggest that MTM reverses inflammatory and neuropathic pain through broad transcriptional and alternative splicing regulatory actions. Mithramycin-dependent changes in gene expression following oxaliplatin treatment were largely opposite to and rarely overlapped with changes in gene expression induced by oxaliplatin alone. Notably, RNAseq analysis revealed MTM rescue of oxaliplatin-induced dysregulation of mitochondrial electron transport chain genes that correlated with in vivo reversal of excess reactive oxygen species in DRG neurons. This finding suggests that the mechanism(s) driving persistent pain states such as CIPN are not fixed but are sustained by ongoing modifiable transcription-dependent processes.