bluuebunny/crossref_metadata_2025 huggingface dataset:
A gene deriving from the ancestral sex chromosomes was lost from the X and retained on the Y chromosome in eutherian mammals
Authors: Hughes Jennifer F. , Skaletsky Helen , Nicholls Peter K. , Drake Alexis , Pyntikova Tatyana , Cho Ting-Jan , Bellott Daniel W. , Page David C.
Published: June 2022

Background

The mammalian X and Y chromosomes originated from a pair of ordinary autosomes. Over the past ~180 million years, the X and Y have become highly differentiated and now only recombine with each other within a short pseudoautosomal region. While the X chromosome broadly preserved its gene content, the Y chromosome lost ~92% of the genes it once shared with the X chromosome. PRSSLY is a Y-linked gene identified in only a few mammalian species that was thought to be acquired, not ancestral. However, PRSSLY’s presence in widely divergent species—bull and mouse—led us to further investigate its evolutionary history.

Results

We discovered that PRSSLY is broadly conserved across eutherians and has ancient origins. PRSSLY homologs are found in syntenic regions on the X chromosome in marsupials and on autosomes in more distant animals, including lizards, indicating that PRSSLY was present on the ancestral autosomes but was lost from the X and retained on the Y in eutherian mammals. We found that across eutheria, PRSSLY’s expression is testis-specific, and, in mouse, it is most robustly expressed in post-meiotic germ cells. The closest paralog to PRSSLY is the autosomal gene PRSS55, which is expressed exclusively in testes, involved in sperm differentiation and migration, and essential for male fertility in mice. Outside of eutheria, in species where PRSSLY orthologs are not Y-linked, we find expression in a broader range of somatic tissues, suggesting that PRSSLY has adopted a germ-cell-specific function in eutherians. Finally, we generated Prssly mutant mice and found that they are fully fertile but produce offspring with a modest female-biased sex ratio compared to controls.

Conclusions

PRSSLY appears to be the first example of a gene that derives from the mammalian ancestral sex chromosomes that was lost from the X and retained on the Y. Although the function of PRSSLY remains to be determined, it may influence the sex ratio by promoting the survival or propagation of Y-bearing sperm.
Blocking P2X purinoceptor 4 signalling alleviates cigarette smoke induced pulmonary inflammation
Authors: Schneider Sven , Merfort Irmgard , Idzko Marco , Zech Andreas
Published: June 2022

Background

Chronic obstructive pulmonary disease (COPD) is associated with elevated ATP levels in the extracellular space. Once released, ATP serves as danger signal modulating immune responses by activating purinergic receptors. Accordingly, purinergic signalling has been implicated in respiratory inflammation associated with cigarette smoke exposure. However, the role of P2X4-signalling has not been fully elucidated yet.

Methods

Here, we analysed the P2X4 mRNA expression in COPD patients as well as cigarette smoke-exposed mice. Furthermore, P2X4-signalling was blocked by either using a specific antagonist or genetic depletion of P2rx4 in mice applied to an acute and prolonged model of cigarette smoke exposure. Finally, we inhibited P2X4-signalling in macrophages derived from THP-1 before stimulation with cigarette smoke extract.

Results

COPD patients exhibited an increased P2X4 mRNA expression in cells isolated from the bronchoalveolar lavage fluid and peripheral mononuclear cells. Similarly, P2rx4 expression was elevated in lung tissue of mice exposed to cigarette smoke. Blocking P2X4-signalling in mice alleviated cigarette smoke induced airway inflammation as well as lung parenchyma destruction. Additionally, human macrophages derived from THP-1 cells released reduced concentrations of proinflammatory cytokines in response to cigarette smoke extract stimulation when P2X4 was inhibited.

Conclusion

Taken together, we provide evidence that P2X4-signalling promotes innate immunity in the immunopathologic responses induced by cigarette smoke exposure.
Metaplastic carcinoma of the breast with squamous differentiation: prognostic factors and multidisciplinary treatment
Authors: Tejera Hernández Ana Alicia , Vega Benítez Víctor Manuel , Pavcovich Ruiz Marta , Hernández Hernández Juan Ramón
Published: June 2022

Background

The objective of this study was to analyze the characteristics of patients diagnosed with metaplastic carcinoma of the breast with squamous differentiation and to identify the particular clinical and histological characteristics that need to be taken into account in this type of tumors.

Case presentation

Retrospective observational study of two patients managed at our hospital between 2014 and 2020 (15 months mean follow-up), plus all cases published in the last 7 years (8 patients). Thus, a total of 10 cases were analyzed, all with less than 2 years mean global survival. Studied variables were: age, medical background, tumor size, axillary involvement, radiological characteristics, surgical approach, complementary treatments, histologic characteristics, and progression of the disease. In 50% of cases, the disease appeared as a palpable mass of rapid growth, associated with axillary infiltration; 80% of the tumors were triple negative; 30% of them progressed to distant metastatic disease in 30%.

Conclusions

This unusual carcinoma requires a complex multidisciplinary treatment. Its prognosis is unfavorable due to its high local aggressiveness, with rapid progression and appearance of metastatic disease. The predominance of different histological components may determine the response to medical treatments.
Comprehensive identification and characterization of the HERV-K (HML-9) group in the human genome
Authors: Jia Lei , Liu Mengying , Yang Caiqin , Li Hanping , Liu Yongjian , Han Jingwan , Zhai Xiuli , Wang Xiaolin , Li Tianyi , Li Jingyun , Zhang Bohan , Yu Changyuan , Li Lin
Published: June 2022

Background

Human endogenous retroviruses (HERVs) result from ancestral infections caused by exogenous retroviruses that became incorporated into the germline DNA and evolutionarily fixed in the human genome. HERVs can be transmitted vertically in a Mendelian fashion and be stably maintained in the human genome, of which they are estimated to comprise approximately 8%. HERV-K (HML1-10) transcription has been confirmed to be associated with a variety of diseases, such as breast cancer, lung cancer, prostate cancer, melanoma, rheumatoid arthritis, and amyotrophic lateral sclerosis. However, the poor characterization of HML-9 prevents a detailed understanding of the regulation of the expression of this family in humans and its impact on the host genome. In light of this, a precise and updated HERV-K HML-9 genomic map is urgently needed to better evaluate the role of these elements in human health.

Results

We report a comprehensive analysis of the presence and distribution of HERV-K HML-9 elements within the human genome, with a detailed characterization of the structural and phylogenetic properties of the group. A total of 23 proviruses and 47 solo LTR elements were characterized, with a detailed description of the provirus structure, integration time, potential regulated genes, transcription factor binding sites (TFBS), and primer binding site (PBS) features. The integration time results showed that the HML-9 elements found in the human genome integrated into the primate lineage between 17.5 and 48.5 million years ago (mya).

Conclusion

The results provide a clear characterization of HML-9 and a comprehensive background for subsequent functional studies.
Global burden of the COVID-19 associated patient-related delay in emergency healthcare: a panel of systematic review and meta-analyses
Authors: Mogharab Vahid , Ostovar Mahshid , Ruszkowski Jakub , Hussain Syed Zohaib Maroof , Shrestha Rajeev , Yaqoob Uzair , Aryanpoor Poorya , Nikkhoo Amir Mohammad , Heidari Parasta , Jahromi Athar Rasekh , Rayatdoost Esmaeil , Ali Anwar , Javdani Farshid , Farzaneh Roohie , Ghanaatpisheh Aref , Habibzadeh Seyed Reza , Foroughian Mahdi , Ahmadi Sayyed Reza , Akhavan Reza , Abbasi Bita , Shahi Behzad , Hakemi Arman , Bolvardi Ehsan , Bagherian Farhad , Motamed Mahsa , Boroujeni Sina Taherzadeh , Jamalnia Sheida , Mangouri Amir , Paydar Maryam , Mehrasa Neda , Shirali Dorna , Sanmarchi Francesco , Saeed Ayesha , Jafari Narges Azari , Babou Ali , Kalani Navid , Hatami Naser
Published: June 2022

Background

Apart from infecting a large number of people around the world and causing the death of many people, the COVID-19 pandemic seems to have changed the healthcare processes of other diseases by changing the allocation of health resources and changing people’s access or intention to healthcare systems.

Objective

To compare the incidence of endpoints marking delayed healthcare seeking in medical emergencies, before and during the pandemic.

Methods

Based on a PICO model, medical emergency conditions that need timely intervention was selected to be evaluated as separate panels. In a systematic literature review, PubMed was quarried for each panel for studies comparing the incidence of various medical emergencies before and during the COVID-19 pandemic. Markers of failure/disruption of treatment due to delayed referral were included in the meta-analysis for each panel.

Result

There was a statistically significant increased pooled median time of symptom onset to admission of the acute coronary syndrome (ACS) patients; an increased rate of vasospasm of aneurismal subarachnoid hemorrhage; and perforation rate in acute appendicitis; diabetic ketoacidosis presentation rate among Type 1 Diabetes Mellitus patients; and rate of orchiectomy among testicular torsion patients in comparison of pre-COVID-19 with COVID-19 cohorts; while there were no significant changes in the event rate of ruptured ectopic pregnancy and median time of symptom onset to admission in the cerebrovascular accident (CVA) patients.

Conclusions

COVID-19 has largely disrupted the referral of patients for emergency medical care and patient-related delayed care should be addressed as a major health threat.
Inhibitory effect of Isatis tinctoria L. water extract on DNCB-induced atopic dermatitis in BALB/c mice and HaCaT cells
Authors: Min Ga-Yul , Kim Tae In , Kim Ji-Hye , Cho Won-Kyung , Yang Ju-Hye , Ma Jin-Yeul
Published: June 2022

Background

Isatis tinctoria L(PLG) is a medicinal herb from the roots ofIsatis indigotica Fort(Family Cruciferae). Previous studies have shown that PLG has anti-inflammatory and therapeutic effects against conditions such as acute and chronic hepatitis, various respiratory inflammations, and cancer. The purpose of this study was to define the pharmacological effects of PLG on inflammatory reactions and skin hyperkeratosis, which are the main symptoms of atopic dermatitis (AD), in vivo and in vitro.

Methods

For the AD in vivo experiment, 2,4-dinitrochlorobenzene (DNCB) induction and oral administration of PLG were performed on male BALB/c mice for four weeks. For in vitro experiments, keratinocytes were activated using TNF-α/IFN-γ in cultured human keratinocyte (HaCaT) cells. PLG inhibited inflammatory chemokine production and blocked the nuclear translocation of NF-κB p65 in activated keratinocytes.

Results

As a result of oral administration of PLG, dermis and epidermis thickening, as well as eosinophil and mast cell infiltration, were attenuated in AD skin lesions. In addition, the levels of immunoglobulin E (IgE), pro-inflammatory cytokines, and the MAPK/NF-κB signaling pathway were decreased in serum and dorsal skin tissues. Furthermore, PLG inhibited inflammatory chemokine production and blocked the nuclear translocation of NF-κB p65 in activated keratinocytes. In addition, epigoitrin and adenosine, the standard compounds of PLG, were identified as candidate AD compounds.

Conclusions

These results indicate that PLG is a potent therapeutic agent for attenuating symptoms of AD.
Participation and dropout of Hockey New South Wales participants in 2017 and 2018: a longitudinal study
Authors: Owen Katherine B. , Foley Bridget C. , Eime Rochelle , Rose Catriona , Reece Lindsey J.
Published: June 2022

Background

Sports have a focus on increasing participation, which contributes to increasing population levels of physical activity, social cohesion and longevity of the sport. The primary aim of this study was to examine reasons for drop-out of a popular team sport in Australia, Field Hockey and identify opportunities to increase participation.

Methods

This longitudinal study obtained routinely collected registered player data from Hockey New South Wales over two consecutive years, and survey data from registered players who dropped out. Logistic regression models identified demographic subgroups who were more likely to drop out of sport, and the reasons for dropping out.

Results

In 2018, 8463 (31%) of hockey players did not return to play hockey after the previous season and 805 (10%) of these completed a survey. Specific groups who were more likely to stop playing included 5–6 years (OR: 2.1, 95% CI 1.8–2.6; reference: 12–17 years), females (OR: 1.1, 95% CI 1.0–1.2; reference: males), Indigenous (OR: 1.2, 95% CI 1.1–1.4; reference: non-Indigenous), most disadvantaged (OR: 1.1, 95% CI 1.0–1.2; reference: least disadvantaged) or regional and remote (1.1, 95% CI 1.0–1.2; reference: major cities). Top reasons for drop out were medical/age (17%), change in circumstances (16%) and high cost (13%), lack of time (13%) and lack of enjoyment (7%).

Conclusions

Although Hockey successfully reaches a large proportion of underrepresented groups in sport, these groups are more likely to drop out. Sports should consult these groups to develop enjoyable, flexible, and modifiable versions of the game that are appropriate to their needs.
A comparison of ClearSight noninvasive cardiac output and pulmonary artery bolus thermodilution cardiac output in cardiac surgery patients
Authors: Wang Yuefu , Huang Weiqin , Han Jiange , Tian Yu , Wang Chunrong , Li Lihuan
Published: June 2022

Background

The ClearSight system measures blood pressure non-invasively and determines cardiac output by analyzing the continuous pressure waveform. We performed a multi-center clinical study in China to test the equivalence of cardiac output measured with the ClearSight system (CSCO) and cardiac output measured with the pulmonary artery catheter bolus thermodilution (TDCO) method.

Methods

We included adult patients undergoing cardiac surgery in three Chinese hospitals and measured TDCO and CSCO simultaneously after induction of anesthesia. Hemodynamic stability was required during measurement of TDCO and CSCO. At least four TDCO determinations were performed. The corresponding CSCO was determined as the average over a 30-s period following the injection of each bolus. A data pair for the comparison included the average of three or four accepted TDCO values and the average of the matching CSCO values. Main outcomes included Bland-Altman analysis of bias and standard deviation (SD) and the percentage error (PE).

Results

One hundred twenty-five subjects were enrolled, and 122 TDCO and CSCO data pairs were available for analysis. Ninety-five (75.4%) data pairs were collected in hemodynamically stable conditions, mean (SD) CSCO was 4.21 (0.78) l/min, and mean TDCO was 3.90 (0.67) l/min. Bias was 0.32 (0.51) l/min, and PE was 25.2%. Analyzing all 122 data pairs resulted in a mean CSCO of 4.19 (0.82) l/min and a mean TDCO of 3.83 (0.71) l/min. Resulting bias was 0.36 (0.53) l/min, and PE was 26.4%.

Conclusions

CSCO and TDCO agreed with a low systematic bias. Besides, mean PE was well below the pre-defined 30%. Hemodynamic stability only had a small impact on the analysis. We conclude that CSCO is equivalent to TDCO in cardiac surgery patients.

The trial was retrospectively registered in ClinicalTrials.gov, identifier NCT03807622; January 17, 2019
Assessment of biosafety and toxicity of hydrophilic gel for implantation in experimental in vitro and in vivo models
Authors: Bezdieniezhnykh N. , Lykhova A. , Kozak T. , Zadvornyi T. , Borikun T. , Voronina O. , Lukianova N.
Published: June 2022

Background

The assessment of biosafety of pharmacologically active substances is crucial for determining the feasibility of their medical use. There are controversial issues regarding the use of substances of different origins as implants.

Methods

We have conducted the comprehensive studies to determine the in vivo toxicity and in vitro genotoxicity of new generation of hydrophilic gel for implantation (production name of the substance “Activegel”) to detail its characteristics and assess its biosafety.

Results

In vivo studies have shown the absence of clinical manifestations of intoxication in animals and no abnormalities in their physiological condition, general and biochemical blood tests. Evaluation of the site of the gel application showed no inflammatory reaction and evidenced on normal state of tissues of animal skin. The results of the genotoxicity test indicated that the gel did not affect the parameters of DNA comets and the formation of micronuclei, accordingly, had no genotoxic effect on human peripheral blood lymphocytes. When studying the effect of the gel on malignantly transformed cells in vitro, it was found that the gel for implantation did not change the proliferative activity and viability of human breast cancer cells.

Conclusions

Comprehensive in vitro and in vivo study using various experimental model systems showed that the hydrophilic gel for implantation “Activegel” is non-toxic.
Stroke Kinematics, Temporal Patterns, Neuromuscular Activity, Pacing and Kinetics in Elite Breaststroke Swimming: A Systematic Review
Authors: Nicol Emily , Pearson Simon , Saxby David , Minahan Clare , Tor Elaine
Published: June 2022

Background

Breaststroke is a technically complex stroke characterised by discontinuous propulsive phases, large intracyclic velocity variation and low mean velocity. The performance of this stroke at an elite level is influenced by a number of biomechanical, physiological and psychological factors. The present systematic review aimed to synthesise the biomechanical factors influencing elite breaststroke swimming performance. This review aims to provide elite coaches and performance scientists with a breadth of knowledge from which training and racing interventions can be developed.

Methods

Electronic searches of Medline, Scopus and SPORTDiscus databases were conducted in May 2020 and March 2022. Search results that were peer-reviewed, published in English and published during or after the year 2000 were considered for review. The methodological rigour of studies was assessed using a risk of bias scale previously used for the evaluation of sports science research.

Results

Thirty-eight articles were included in the present review. Articles investigated elite breaststroke performance in relation to one of the following areas: stroke kinematics, temporal patterns, neuromuscular activity, pacing and kinetics.

Discussion

Kinematic, temporal and neuromuscular activity comparisons between groups of various race distance, performance or experience level, and athlete sex were common in the literature. These analyses demonstrated differences in stroke rate, stroke length, propulsive time, recovery time, glide time, sum of total integrated EMG and triceps brachii activation patterns between groups. The evaluation of various pacing strategies, and the relationship between kinetics and breaststroke performance was comparatively rare within the literature. Further research into the relationship between kinetics and breaststroke performance, and the manipulation of pacing strategy would increase the breadth of knowledge from which coaches and performance scientists can develop evidence-based training and racing interventions.
Exploring the relationship between individual characteristics and argumentative discourse styles: the role of achievement goals and personality traits
Authors: Chen Yunshan , Li Xiaoran , Li Yanyan
Published: June 2022

Different argumentative discourse styles will have different effects on science learning. Some researchers proposed that two learners’ individual characteristics, including achievement goals and personality traits, could be potential factors that induce different argumentative discourse styles. However, the related empirical evidence revealing how the achievement goals and personality traits are related to discourse styles is limited. Therefore, the current study attempted to fill in this gap by conducting a self-designed collaborative scientific argumentation activity and 40 undergraduates participated. Students were arranged into ten groups with four based on their standpoints of the topic, and each team had two supporters and two opponents. Students’ achievement goals and personality traits were obtained through questionnaires, and their argumentative discourse styles were characterized by the actual argumentative moves they made during the collaborative argumentation. Through correlation analysis and stepwise regression analysis, the findings reveal that achievement goals could positively and negatively predict different types of argumentative discourse styles while the personality traits could positively predict three types of argumentative discourse styles. Pedagogical implications and future research are discussed at the end of this paper.
Updated overall survival outcomes in ENZAMET (ANZUP 1304), an international, cooperative group trial of enzalutamide in metastatic hormone-sensitive prostate cancer (mHSPC).
Authors: Davis Ian D. , Martin Andrew James , Zielinski Robert Richard , Thomson Alastair , Tan Thean Hsiang , Sandhu Shahneen , Reaume M. Neil , Pook David William , Parnis Francis , North Scott A. , Marx Gavin M. , McCaffrey John , McDermott Raymond S. , Lawrence Nicola Jane , Horvath Lisa , Frydenberg Mark , Chowdhury Simon , Chi Kim N. , Stockler Martin R. , Sweeney Christopher ,   The Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP)
Published: June 2022

LBA5004

Background: The first planned interim analysis of ENZAMET, with 243 deaths after a median follow-up of 34 months, revealed a clinically meaningful overall survival benefit in mHSPC with the addition of enzalutamide to standard of care (hazard ratio 0.67, 95% CI 0.52 to 0.86, p=0.002, Davis et al, NEJM 2019). We now present updated overall survival (OS) findings from the prespecified analysis triggered to occur after 470 deaths. Methods: We randomly assigned participants (pts) with mHSPC to treatment with testosterone suppression (TS) plus either a conventional non-steroidal anti-androgen (NSAA) or enzalutamide. Stratification factors included age, volume of disease (high vs low according to the CHAARTED definition), and planned use of concurrent docetaxel assigned by the treating physician (docetaxel yes vs no). Results: We randomized 1125 pts with a median age of 69 years, including 503 in the docetaxel stratum, and 602 with high volume metastatic disease. OS results in the table below are based on 476 deaths, a median follow-up of 68 months, and a cut-off date of 19JAN2022. The hazard rate for death was 30% lower among all those assigned enzalutamide versus control (p<0.0001). Outcomes by volume status are shown (Table) as well as the subgroups of interest with M1 high or low volume disease at diagnosis selected for concurrent docetaxel. Conclusions: Enzalutamide added to TS, compared with an active comparator of NSAA, provided clinically meaningful improvements in OS for the combined overall cohort, which persisted with an additional 3 years of follow-up. The benefits were more pronounced in pts with low volume disease, and were also seen in the subgroup with M1 high volume mHSPC despite the relatively high survival with TS+docetaxel+NSAA. ENZAMET was led by ANZUP Cancer Trials Group and the University of Sydney NHMRC Clinical Trials Centre, with funding support from Astellas. Clinical trial information: NCT02446405. [Table: see text]
Randomized phase III trial on trabectedin (ET-743) single agent versus clinician’s choice chemotherapy in recurrent ovarian, primary peritoneal, or fallopian tube cancers of BRCA-mutated or BRCAness phenotype patients (MITO23).
Authors: Scambia Giovanni , Raspagliesi Francesco , Valabrega Giorgio , Colombo Nicoletta , Pisano Carmen , Cassani Chiara , Tognon Germana , Tamberi Stefano , Mangili Giorgia , Mammoliti Serafina , De Giorgi Ugo , Greco Filippo , Mosconi Anna Maria , Breda Enrico , Artioli Grazia , Andreetta Claudia , Casanova Claudia , Ceccherini Rita , Frassoldati Antonio , Lorusso Domenica
Published: June 2022

LBA5504

Background: Trabectedin demonstrated antitumor activity when administered as single agent in relapsed platinum sensitive ovarian cancer (OC), with an overall response rate (ORR) ranging from 26 to 43% and a median PFS of 5 months. In addition, trabectedin showed 39.4% RR, 4.5 months median progression free survival (PFS) and 18 months median overall survival (OS) in a single arm phase 2 trial in recurrent BRCA mutated and/or the BRCAness phenotype OC patients. Methods: In this open-label, phase III, randomized trial, we assigned recurrent OC patients harboring BRCA 1/2 mutations or with BRCAness phenotype (defined as patients who had received and responded to at least 2 previous platinum-based treatments) to receive trabectedin 1.3 mg/mq q 21d or physician’s choice chemotherapy (among carboplatin, gemcitabine, weekly paclitaxel, pegylated liposomal doxorubicine or topotecan). The primary endpoint was OS. Secondary endpoints were PFS, ORR and Duration of Response (DoR). The sample size was calculated based on the assumption that trabectedin would increase median OS from 10 to 15 months (two-sided log-rank test at the error alfa= 0.05 and a power of 80%). Medians and lifetables were computed using the Kaplan-Meier method and analyzed using the log-rank test. Cox proportional hazards model was used to assess the effect of treatment. Results: Two hundred and forty-four patients were randomized and analyzed based on the intent-to-treat principle. At a median follow up of 40 months, the median PFS was 4.4 and 4.9 months (HR= 1.03 p=0.848) and median OS was 17.9 and 15.8 months (HR=1.15 p=0.304), in the control and experimental arm, respectively. ORR was 20.2% in the group of patients receiving standard chemotherapies and 15.4% in the group of patients treated with trabectedin. No superior effect was reported for Trabectedin in the pre-specified sub-group analysis according to BRCA mutational status, type of chemotherapy and platinum-free interval. No new signal of toxicity were reported for all the chemotherapies employed. Conclusions: Trabectedin as single agent does not improve survival outcomes when compared to standard chemotherapy in BRCA mut and BRCAness phenotype OC patients. Clinical trial information: NCT02993705.
Neoadjuvant nivolumab (NIVO) + platinum-doublet chemotherapy (chemo) versus chemo for resectable (IB–IIIA) non-small cell lung cancer (NSCLC): Association of pathological regression with event-free survival (EFS) in CheckMate 816.
Authors: Provencio-Pulla Mariano , Spicer Jonathan , Taube Janis M. , Martin Claudio , Spigel David R. , Wang Changli , Girard Nicolas , Lu Shun , Mitsudomi Tetsuya , Awad Mark M. , Felip Enriqueta , Brahmer Julie R. , Broderick Stephen , Swanson Scott , Kerr Keith , Li Li , Cai Junliang , Bushong Judith , Tran Phuong , Forde Patrick M.
Published: June 2022

LBA8511

Background: Several studies have shown an association of pathological response, a common efficacy endpoint in neoadjuvant therapy trials, with survival for chemo in various cancers including resectable NSCLC. However, the association between pathological complete response (pCR) and survival as well as the degree of pathological regression that may be predictive of EFS for neoadjuvant immunotherapy has not been rigorously studied. CheckMate 816 (NCT02998528), a randomized phase 3 study of neoadjuvant NIVO + chemo vs chemo in resectable NSCLC, met both of its primary endpoints with a statistically significant and clinically meaningful improvement in EFS and pCR. Here, we report a post hoc analysis from CheckMate 816, characterizing the association between pathological regression and EFS. Methods: Adults with resectable NSCLC were randomized to NIVO 360 mg + platinum-doublet chemo Q3W or chemo alone Q3W for 3 cycles. Primary endpoints were EFS and pCR (0% residual viable tumor [RVT] in the primary tumor [PT] and lymph nodes [LN] based on immune-related pathological response criteria), both assessed by blinded independent review. Major pathological response (MPR; ≤10% RVT in the PT and LN) was a secondary endpoint. In this post hoc analysis, EFS was assessed based on depth of pathological regression (measured by %RVT) in the PT only. Also, a time-dependent receiver operating characteristic curve analysis assessed the predictive ability of %RVT (PT only) for EFS outcome at 2 years, using area under the curve (AUC) to summarize the overall diagnostic accuracy (0.5 = random chance; 1 = perfect accuracy). Results: Baseline characteristics in patients (pts) with pathologically evaluable samples were well balanced between the NIVO + chemo and chemo arms, similar to the overall population. In both treatment arms, EFS (minimum follow-up, 21 months) was improved in pts with vs without pCR or MPR (Table). %RVT appeared to be predictive of EFS at 2 years for NIVO + chemo (AUC = 0.74) but an association was not clear for chemo (AUC = 0.54). 2-year EFS rates for NIVO + chemo were 90%, 60%, 57%, and 39% for pts with 0–5%, >5–30%, >30–80%, and >80% RVT, respectively. Conclusions: In CheckMate 816, pathological response (pCR and MPR) in the PT was associated with improved EFS with neoadjuvant NIVO + chemo. Additionally, depth of pathological regression appeared to be predictive of improved EFS. Clinical trial information: NCT02998528. [Table: see text]
Primary Retroperitoneal Lymph Node Dissection for Patients With Pathologic Stage II Nonseminomatous Germ Cell Tumor—N1, N2, and N3 Disease: Is Adjuvant Chemotherapy Necessary?
Authors: Tachibana Isamu , Kern Sean Q. , Douglawi Antoin , Tong Yan , Mahmoud Mohammad , Masterson Timothy A. , Adra Nabil , Foster Richard S. , Einhorn Lawrence H. , Cary Clint
Published: June 2022

PURPOSE

According to National Comprehensive Cancer Network guidelines, adjuvant chemotherapy (AC) has been advocated after primary retroperitoneal lymph node dissection (RPLND) to reduce the risk of relapse in pathologic nodal (pN) stage pN2 or pN3, whereas surveillance is preferred for pN1. We sought to explore the oncologic efficacy of primary RPLND alone for pathologic stage II in nonseminomatous germ cell tumors (NSGCTs) to reduce overtreatment with chemotherapy.

METHODS

Patients with pathologic stage II NSGCT after primary RPLND between 2007 and 2017 were identified. Patients were excluded for elevated preoperative serum tumor markers, receipt of AC, or if pure teratoma or primitive neuroectodermal tumor elements were found in the retroperitoneal pathology.

RESULTS

We identified 117 patients with active NSGCT in the retroperitoneum after primary RPLND. We excluded seven patients who lacked meaningful follow-up and 13 patients who received AC. There were 97 patients treated with RPLND alone: 41 pN1, 46 pN2, and 10 pN3. In total, 77 of 97 patients had not recurred after a median follow-up time of 52 months. The 2-year recurrence-free survival (RFS) was 80.3%, and the 5-year RFS was 79%. No differences in RFS were noted among nodal stage—pN1, pN2, and pN3—on Kaplan-Meier analysis. Lymphovascular invasion in the orchiectomy specimen, a high-risk pathologic feature, was also predictive of recurrence after primary RPLND. All 20 patients who recurred were treated with first-line chemotherapy and remained continuously disease free.

CONCLUSION

Most men with pathologic stage II disease treated with surgery alone in our series never experienced a recurrence. We did not observe a difference in recurrences between patients with pN1 and pN2. The recommendation for AC for pN2 disease may be overtreatment in most patients.
Real-World Adherence to Patient-Reported Outcome Monitoring as a Cancer Care Quality Metric
Authors: Takvorian Samuel U. , Anderson Ryan T. , Gabriel Peter E. , Poznyak Dmitriy , Lee Sooin , Simon Sam , Barrett Kirsten , Shulman Lawrence N.
Published: June 2022

PURPOSE:

Routine collection of patient-reported outcomes (PROs) for patients with advanced solid malignancies is an evidence-based practice and critical component of high-quality cancer care, but real-world adherence is poorly characterized. We sought to describe real-world adherence to PRO monitoring and its potential predictors.

METHODS:

We conducted a retrospective cross-sectional study using deidentified electronic health record data from a National Cancer Institute Cancer Center, encompassing one academic and two community sites. Participants included individuals with lung cancer receiving systemic therapy from January 1 to December 31, 2019. The primary outcome was patient-level adherence, defined as the proportion of treatment visits during which a PRO questionnaire (spanning symptoms, functional status, and global quality-of-life domains) was completed within 30 days. Practice-level performance was calculated as unadjusted mean patient-level adherence. We modeled patient-level adherence using multivariable ordinary least squares regression and identified covariates associated with adherence using a significance threshold of P < .05.

RESULTS:

In 2019, there were 18,604 encounters for 1,105 patients with lung cancer (mean [standard deviation] age 65.8 [10.2] years; 621 [56.2%] female; 216 [19.6%] Black) receiving systemic therapy. The mean patient-level PRO adherence ranged from 27.2% to 70.0% across sites and was 49.4% overall. Advanced age (≥ 65 years) and Black or African American race were negatively associated with PRO adherence ( P < .01).

CONCLUSION:

Across this real-world cohort of patients undergoing treatment for lung cancer, adherence to PRO monitoring lagged that achieved in seminal clinical trials, with potential age- and race-based disparities, demonstrating an implementation gap that could be addressed with standardized reporting of an adherence-based quality metric.
Circulation and Capitalism in a Maritime Bazaar
Authors: Bishara Fahad Ahmad
Published: June 2022

This article takes a single genre of the Persian Gulf pearl dive—the chau manual, used to determine the weight-based value of a pearl—and draws on it to think about circulation and commodification in the Indian Ocean world. In reading the chau manual, as well as other writings, it highlights the active processes by which economic actors in the region thought about, and indeed produced, capitalism at sea. As technologies—as means of doing—chau manuals allowed pearl merchants to move from the specificities and idiosyncrasies of nature to the abstractions of the market. More generally, texts like these formed part of the infrastructure through which circulation took place in the maritime marketplace. By thinking through these marketplace genres, we can gain a more textured sense of the processes of knowing, measuring, abstracting, and circulating that underpinned the maritime—a process of active economic thinking that went into the making of global capitalism in a corner of the Indian Ocean world.
Witnessing the Action of Current Events from the Comfort of your Chair: The Place of the Photographic Magazine 'The Graphic'
Authors: Kinoshita Naoyuki , Honda Erumi
Published: June 2022

Translated from the Japanese by Honda Erumi

First published (in Japanese) by Kashiwa Shobo in June, 2005
Dear Heung-Soon [translated by Young Min Moon]
Authors: Im Heung-Soon
Published: June 2022

Translated from the Korean by Young Min Moon

All color photographs by Heung-Soon Im
The Pacific Rim Divide of “Japan’s Modern Divide”
Authors: Aoki Eiko
Published: June 2022

Note from the Editor: Photography exhibitions can have a significant influence on the course of future photographic work. As Eiko Aoki points out, both of the photographers she discusses were influenced by exhibitions they encountered. Once the temporal span of an exhibition has ended, its contents can continue to circulate, as part of a larger historical archive, in the form of a catalog. The exhibition “Japan’s Modern Divide” has a substantial catalog which includes writings by Judith Keller, Amanda Maddox, Ryuichi Kaneko, Kotaro Iizawa and Jonathan M. Reynolds, and translations of Yamamoto Kansuke poems by John Solt. In this form, the ideas generated by the exhibition can impact future work.
Acute thermal stress elicits interactions between gene expression and alternative splicing in a fish of conservation concern
Authors: Thorstensen Matt J. , Turko Andy J. , Heath Daniel D. , Jeffries Ken M. , Pitcher Trevor E.
Published: June 2022

Transcriptomic research provides a mechanistic understanding of an organism's response to environmental challenges such as increasing temperatures, which can provide key insights into the threats posed by thermal challenges associated with urbanization and climate change. Differential gene expression and alternative splicing are two elements of the transcriptomic stress response that may work in tandem, but relatively few studies have investigated these interactions in fishes of conservation concern. We studied the imperilled redside dace (Clinostomus elongatus) as thermal stress is hypothesized to be an important cause of population declines. We tested the hypothesis that gene expression–splicing interactions contribute to the thermal stress response. Wild fish exposed to acute thermal stress were compared with both handling controls and fish sampled directly from a river. Liver tissue was sampled to study the transcriptomic stress response. With a gene set enrichment analysis, we found that thermally stressed fish showed a transcriptional response related to transcription regulation and responses to unfolded proteins, and alternatively spliced genes related to gene expression regulation and metabolism. One splicing factor, prpf38b, was upregulated in the thermally stressed group compared with the other treatments. This splicing factor may have a role in the Jun/AP-1 cellular stress response, a pathway with wide-ranging and context-dependent effects. Given large gene interaction networks and the context-dependent nature of transcriptional responses, our results highlight the importance of understanding interactions between gene expression and splicing for understanding transcriptomic responses to thermal stress. Our results also reveal transcriptional pathways that can inform conservation breeding, translocation and reintroduction programs for redside dace and other imperilled species by identifying appropriate source populations.
Grammatical awareness and language performance: examining gendered differences among Saudi EFL (English as a foreign language) learners
Authors: Alharbi Ayed T
Published: June 2022

Background: Despite the many studies that have been conducted on the learners of English as a foreign language (EFL) regarding grammar ability in various contexts, some gaps are still unbridged and need researching. Therefore, this study addresses the research gap in the Saudi context concerning the grammatical competence of Saudi EFL (English as foreign language) learners.

Methods: This study described the Saudi EFL learners’ level of awareness in developing grammatical forms. It also assessed Saudi EFL students' level of performance in grammar learning. Finally, it quantitatively explored what, if any, gendered differences exist in the grammar acquisition of Saudi EFL learners. The study employed descriptive and inferential statistics to analyze the data. The study sample comprised 50 Saudi EFL students out of the population of 120 students enrolled in EFL programs at Qassim University, Saudi Arabia with sample size being determined using online sampling calculator Raosoft.

Results: The results of the present study show that the Saudi EFL learners manifest a favorable level of awareness in developing grammatical forms while they still not having attained mastery of English grammar. Results also indicate that grammatical competence and level of awareness are more advanced among the Saudi EFL female learners compared to their male counterparts.

Conclusions: The outcomes of this research imply that Saudi EFL learners have sufficient performance in grammar learning but need further nurturance. Implications of this study will serve as a basis for English language learning development interventions in the benefit of the students.
Outcomes in intervention research on snakebite envenomation: a systematic review
Authors: Bhaumik Soumyadeep , Beri Deepti , Tyagi Jyoti , Clarke Mike , Sharma Sanjib Kumar , Williamson Paula R , Jagnoor Jagnoor
Published: June 2022

Introduction:

A core outcome set (COS) is a minimal list of consensus outcomes that should be used in all intervention research in a specific domain. COS enhance the ability to undertake meaningful comparisons and to understand the benefits or harms of different treatments. A first step in developing a COS is to identify outcomes that have been used previously. We did this global systematic review to provide the foundation for development of a region-specific COS for snakebite envenomation. 

Methods:

We searched 15 electronic databases, eight trial registries, and reference lists of included studies to identify reports of relevant trials, protocols, registry records and systematic reviews. We extracted verbatim data on outcomes, their definitions, measures, and time-points. Outcomes were classified as per an existing outcome taxonomy, and we identified unique outcomes based on similarities in the definition and measurement of the verbatim outcomes.

Results:

We included 107 records for 97 studies which met our inclusion criteria. These reported 538 outcomes, with a wide variety of outcome measures, definitions, and time points for measurement. We consolidated these into 88 unique outcomes, which we classified into core areas of mortality (1, 1.14 %), life impact (6, 6.82%), resource use (15, 17.05%), adverse events (7, 7.95%), physiological/clinical (51, 57.95%), and composite (8, 9.09%) outcomes. The types of outcomes varied by the type of intervention, and by geographic region. Only 15 of the 97 trials (17.04%) listed Patient Related Outcome Measures (PROMS).

Conclusion:

Trials evaluating interventions for snakebite demonstrate heterogeneity on outcomes and often omit important information related to outcome measurement (definitions, instruments, and time points). Developing high quality, region-specific COS for snakebite could inform the design of future trials and improve outcome reporting. Measurement of PROMS, resource use and life impact outcomes in trials on snakebite remains a gap.
Collaborative faculty development transforms evaluation at a school of osteopathic medicine: an exploratory grounded theory study
Authors: Bustamante-Helfrich Blandine , Santa Maria Emma , Bradley Jessica , Warden Douglas , Sengupta Anamika , Phillips-Madson Robyn , Ungaretti Toni
Published: June 2022

Background:Faculty development (FD) initiatives for medical educators must keep pace with educators’ expanding roles and responsibilities in the 21stcentury to effectively support and guide professional growth. Successful initiatives will be comprehensive and systematic, rather than episodic. Our research explores the impact of a collaborative, individualized, and focused FD program. The purpose of this pilot study is: (1) to describe the innovative design and implementation of the incipient FD program at University of the Incarnate Word School of Osteopathic Medicine (UIWSOM), San Antonio, Texas; and (2) to present insights from a preliminary process evaluation of the program’s initial launch to inform and facilitate broadscale implementation.     

Methods:We used a longitudinal, holistic approach to redesign the UIWSOM FD program to provide evidence-informed and experiential learning for faculty. We performed a process evaluation of the initial iteration of the FD program using an inductive qualitative research approach. We applied principles of constructivist grounded theory to analyze faculty’s responses collected during semi-structured interviews.

Results:Three themes emerged from our analysis: communication, advocacy, and reciprocal learning.  We found that effective communication, advocacy for faculty success, and reciprocal value between faculty and program developers undergirded the core concept of authentic engagement.  Faculty’s perceptions of the quality of engagement of those implementing the program overshadowed the quality of the logistics. 

Conclusions:Our pilot study identified authentic engagement as critical to faculty’s positive experience of this new FD initiative.  Practical implications for other health professions schools with similar FD initiatives include consideration of the relational aspects.  Future studies should expand the process evaluation to determine key factors driving perceived program success for other skill domains and amongst clinical faculty, and include a long-range outcome evaluation of the fully implemented program.
Pain in amyotrophic lateral sclerosis: a narrative review
Authors: Kwak Soyoung
Published: June 2022

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative condition characterized by loss of motor neurons, resulting in motor weakness of the limbs and/or bulbar muscles. Pain is a prevalent but neglected symptom of ALS, and it has a significant negative impact on the quality of life of patients and their caregivers. This review outlines the epidemiology, clinical characteristics, underlying mechanisms, and management strategies of pain in ALS to improve clinical practice and patient outcomes related to pain. Pain is a prevalent symptom among patients with ALS, with a variable reported prevalence. It may occur at any stage of the disease and can involve any part of the body without a specific pattern. Primary pain includes neuropathic pain and pain from spasticity or cramps, while secondary pain is mainly nociceptive, occurring with the progression of muscle weakness and atrophy, prolonged immobility causing degenerative changes in joints and connective tissue, and long-term home mechanical ventilation. Prior to treatment, the exact patterns and causes of pain must first be identified, and the treatment should be tailored to each patient. Treatment options can be classified into pharmacological treatments, including nonsteroidal anti-inflammatory drugs, antiepileptic drugs, drugs for cramps or spasticity, and opioid; and nonpharmacological treatments, including positioning, splints, joint injections, and physical therapy. The development of standardized and specific assessment tools for pain-specific to ALS is required, as are further studies on treatments to reduce pain, diminish suffering, and improve the quality of life of patients with ALS.