bluuebunny/crossref_metadata_2025 huggingface dataset:
Whole-genome sequencing reveals the genetic mechanisms of domestication in classical inbred mice
Authors: Liu Ming , Yu Caixia , Zhang Zhichao , Song Mingjing , Sun Xiuping , Piálek Jaroslav , Jacob Jens , Lu Jiqi , Cong Lin , Zhang Hongmao , Wang Yong , Li Guoliang , Feng Zhiyong , Du Zhenglin , Wang Meng , Wan Xinru , Wang Dawei , Wang Yan-Ling , Li Hongjun , Wang Zuoxin , Zhang Bing , Zhang Zhibin
Published: September 2022

Background

The laboratory mouse was domesticated from the wild house mouse. Understanding the genetics underlying domestication in laboratory mice, especially in the widely used classical inbred mice, is vital for studies using mouse models. However, the genetic mechanism of laboratory mouse domestication remains unknown due to lack of adequate genomic sequences of wild mice.

Results

We analyze the genetic relationships by whole-genome resequencing of 36 wild mice and 36 inbred strains. All classical inbred mice cluster together distinctly from wild and wild-derived inbred mice. Using nucleotide diversity analysis, Fst, and XP-CLR, we identify 339 positively selected genes that are closely associated with nervous system function. Approximately one third of these positively selected genes are highly expressed in brain tissues, and genetic mouse models of 125 genes in the positively selected genes exhibit abnormal behavioral or nervous system phenotypes. These positively selected genes show a higher ratio of differential expression between wild and classical inbred mice compared with all genes, especially in the hippocampus and frontal lobe. Using a mutant mouse model, we find that the SNP rs27900929 (T>C) in geneAstn2significantly reduces the tameness of mice and modifies the ratio of the twoAstn2 (a/b)isoforms.

Conclusion

Our study indicates that classical inbred mice experienced high selection pressure during domestication under laboratory conditions. The analysis shows the positively selected genes are closely associated with behavior and the nervous system in mice. Tameness may be related to theAstn2mutation and regulated by the ratio of the twoAstn2 (a/b)isoforms.
The neuropathologic findings in a case of progressive cavitating leukoencephalopathy due to NDUFV1 pathogenic variants
Authors: Becker Nicole , Sharma Aditi , Gosse Matthew , Kubat Brooke , Conway Kyle S.
Published: September 2022

Pathogenic variants in the NDUFV1 gene, which codes for complex I of the mitochondrial respiratory chain, have been associated with a variety of clinical phenotypes, including a progressive cavitating leukoencephalopathy. The neuropathology of NDUFV1-associated leukoencephalopathy is not well-described. We present a report of a 24-year-old female with two pathogenic variants in the NDUFV1 gene, together with antemortem skeletal muscle biopsy and postmortem neuropathologic examination. Autopsy neuropathology showed a cavitating leukoencephalopathy with extensive white matter involvement, regions of active demyelination, and sparing of the subcortical U-fibers. Muscle biopsy showed subtle but distinct histologic abnormalities by light microscopy, and ultrastructural analysis demonstrated mitochondrial abnormalities including abnormal subsarcolemmal mitochondrial accumulation, electron-dense inclusions, and enlarged mitochondria with abnormal cristae. Our report is the first comprehensive description of the neuropathology in a patient with compound heterozygous variants in the NDUFV1 gene and progressive cavitating leukoencephalopathy. This case is evidence of pathogenicity of one NDUFV1 variant (c.565 T > C, p.S189P), which has not been previously described as pathogenic. These findings, in combination with the ultrastructural abnormalities in the mitochondria by electron microscopy, support the mitochondrial nature of the pathology. Together, this case highlights the link between mitochondrial abnormalities and demyelinating processes in the central nervous system (CNS).
Applying mixed methods to pilot feasibility studies to inform intervention trials
Authors: Aschbrenner Kelly A. , Kruse Gina , Gallo Joseph J. , Plano Clark Vicki L.
Published: September 2022

Background

Pilot feasibility studies serve a uniquely important role in preparing for larger scale intervention trials by examining the feasibility and acceptability of interventions and the methods used to test them. Mixed methods (collecting, analyzing, and integrating quantitative and qualitative data and results) can optimize what can be learned from pilot feasibility studies to prepare rigorous intervention trials. Despite increasing use of mixed method designs in intervention trials, there is limited guidance on how to apply these approaches to address pilot feasibility study goals. The purpose of this article is to offer methodological guidance for how investigators can plan to integrate quantitative and qualitative methods within pilot feasibility studies to comprehensively address key research questions.

Methods

We used an informal consensus-based process informed by key methodological resources and our team’s complementary expertise as intervention researchers and mixed methodologists to develop guidance for applying mixed methods to optimize what can be learned from pilot feasibility studies. We developed this methodological guidance as faculty in the Mixed Methods Research Training Program (MMRTP) for the Health Sciences (R25MH104660) funded by the National Institutes of Health through the Office of Behavioral and Social Science Research.

Results

We provide the following guidance for applying mixed methods to optimize pilot feasibility studies: (1) identify feasibility domain(s) that will be examined using mixed methods, (2) align quantitative and qualitative data sources for the domain(s) selected for mixing methods, (3) determine the timing of the quantitative and qualitative data collection within the flow of the pilot study, (4) plan integrative analyses using joint displays to understand feasibility, and (5) prepare to draw meta-inferences about feasibility and implications for the future trial from the integrated data.

Conclusions

By effectively integrating quantitative and qualitative data within pilot feasibility studies, investigators can harness the potential of mixed methods for developing comprehensive and nuanced understandings about feasibility. Our guidance can help researchers to consider the range of key decisions needed during intervention pilot feasibility testing to achieve a rigorous mixed methods approach generating enhanced insights to inform future intervention trials.
Imatinib inhibits pericyte-fibroblast transition and inflammation and promotes axon regeneration by blocking the PDGF-BB/PDGFRβ pathway in spinal cord injury
Authors: Yao Fei , Luo Yang , Liu Yan-Chang , Chen Yi-Hao , Li Yi-Teng , Hu Xu-Yang , You Xing-Yu , Yu Shui-Sheng , Li Zi-Yu , Chen Lei , Tian Da-Sheng , Zheng Mei-Ge , Cheng Li , Jing Jue-Hua
Published: September 2022

Background

Fibrotic scar formation and inflammation are characteristic pathologies of spinal cord injury (SCI) in the injured core, which has been widely regarded as the main barrier to axonal regeneration resulting in permanent functional recovery failure. Pericytes were shown to be the main source of fibroblasts that form fibrotic scar. However, the mechanism of pericyte-fibroblast transition after SCI remains elusive.

Methods

Fibrotic scarring and microvessels were assessed using immunofluorescence staining after establishing a crush SCI model. To study the process of pericyte-fibroblast transition, we analyzed pericyte marker and fibroblast marker expression using immunofluorescence. The distribution and cellular origin of platelet-derived growth factor (PDGF)-BB were examined with immunofluorescence. Pericyte-fibroblast transition was detected with immunohistochemistry and Western blot assays after PDGF-BB knockdown and blocking PDGF-BB/PDGFRβ signaling in vitro. Intrathecal injection of imatinib was used to selectively inhibit PDGF-BB/PDGFRβ signaling. The Basso mouse scale score and footprint analysis were performed to assess functional recovery. Subsequently, axonal regeneration, fibrotic scarring, fibroblast population, proliferation and apoptosis of PDGFRβ+ cells, microvessel leakage, and the inflammatory response were assessed with immunofluorescence.

Results

PDGFRβ+ pericytes detached from the blood vessel wall and transitioned into fibroblasts to form fibrotic scar after SCI. PDGF-BB was mainly distributed in the periphery of the injured core, and microvascular endothelial cells were one of the sources of PDGF-BB in the acute phase. Microvascular endothelial cells induced pericyte-fibroblast transition through the PDGF-BB/PDGFRβ signaling pathway in vitro. Pharmacologically blocking the PDGF-BB/PDGFRβ pathway promoted motor function recovery and axonal regeneration and inhibited fibrotic scar formation. After fibrotic scar formation, blocking the PDGFRβ receptor inhibited proliferation and promoted apoptosis of PDGFRβ+ cells. Imatinib did not alter pericyte coverage on microvessels, while microvessel leakage and inflammation were significantly decreased after imatinib treatment.

Conclusions

We reveal that the crosstalk between microvascular endothelial cells and pericytes promotes pericyte-fibroblast transition through the PDGF-BB/PDGFRβ signaling pathway. Our finding suggests that blocking the PDGF-BB/PDGFRβ signaling pathway with imatinib contributes to functional recovery, fibrotic scarring, and inflammatory attenuation after SCI and provides a potential target for the treatment of SCI.
Child Marriage Acceptability Index (CMAI) as an essential indicator: an investigation in South and Central Sulawesi, Indonesia
Authors: Ratnaningsih Muliani , Wibowo Heribertus Rinto , Goodwin Nicholas J. , Rezki Ade Ayu Kartika Sari , Ridwan R. , Hadyani Ratnakanya Nitya , Minnick Emilie , Ulum Derry Fahrizal , Kostaman Tanti Kosmiyati , Faizah Sitti Nur
Published: September 2022

Background

Child marriage remains an important social issue in Indonesia. Child marriages were reported from 14.67% in 2008 to 10.82% in 2019. However, 22 out of 34 provinces in Indonesia still had high child marriage rates above the national average in 2019. This study aims to assess child marriage acceptability in the two locations in Indonesia by gender inequality, financial security, education rates, legal frameworks, dowry, and sexual and gender-based violence (SGBV).

Methods

This study used a quantitative approach with a cross-sectional study design. A total of 1000 respondents consisting of 500 households in Bone District, South Sulawesi and 500 households in Palu, Sigi, and Donggala District in Central Sulawesi participated in the study. Data analyses were conducted based on the Child Marriage Acceptability Index (CMAI) using the bivariate correlation, ANOVA (analysis of variance), and logistic regression.

Results

This study found several significant factors that contributed to child marriage acceptance in Central and South Sulawesi: household financial security (p = 0.016), dowry (p < 0.001) and legal frameworks (p = 0.017) based on ANOVA analysis. After conducting a bivariate correlation, dowry (p < 0.001) and sexual and gender-based violence (p < 0.001) remain significant factors. Dowry (p < 0.001), with expected B = 0.122, and sexual and gender-based violence (p < 0.001, with expected B = 0.064) remains significant after the linear regression analysis.

Conclusions

Dowry practice and sexual and gender-based violence were the most significant factors contributing to child marriage acceptance in Central and South Sulawesi. There is a need to conduct interventions to prevent child marriage, including providing sexual and reproductive health education.
A case study of the construction of inter-embedded multi-ethnic community of urban migrants in Nanyang
Authors: Sun Qiang , Liu Dongxu
Published: September 2022

As the domestic interprovincial migrants, Uygur traders have been engaged in the Hetian jade trade from Xinjiang Uygur Autonomous Region to the city of Nanyang in Henan Province. Having lived in the private rented houses around the market in the early days, they moved into the government-built public rental housing in 2017, an independently managed community. They have maintained their past residential pattern of living around the market, and gradually develop the community into an inter-embedded multi-ethnic community together with other ethnic groups. Through the history of the formation of the Uygur community in Nanyang Stone Town, this paper presents the process of interaction between the ethnic minority migrants and the local community, examines the responses and influence of the market, society, government, and individuals in this process, aiming to understand how the minority community was formed, to deepen understanding of the “inter-embedded multi-ethnic community", and, in turn, to promote research and reflection on the development of the ethnic community during urbanization in China. This study suggests that such communities surrounding the market are socially extended based on inter-embedded livelihood. The open national market is the core of the social structure of inter-embedded ethnic groups, and market exchange is one of the main relations generated in the current interactions between the ethnic groups. The government’s efforts to build inter-embedded communities are conducive to transforming the relationships among ethnic groups from limited interaction to comprehensive and balanced development. Moreover, the improvement of common living environments and increase in exchanges are conducive to upgrading interactions between individuals to extensive and in-depth exchanges among different ethnic groups.
Retention index of FDG-PET/CT SUVmax of the primary tumor in non-small cell lung cancer as a predictor of lymph node metastasis: a retrospective study
Authors: Ema Toshinari , Kojima Hideaki , Mizuno Shinji , Hirai Tatsuo , Oka Mikako , Neyatani Hiroshi , Funai Kazuhito , Shiiya Norihiko
Published: September 2022

Background

Accurate staging of non-small cell lung cancer is key in treatment planning and prediction of prognosis. We investigated the correlation between the maximum standardized uptake value (SUVmax) retention index (RI) of the primary tumor and lymph node metastasis in non-small cell lung carcinoma. We also evaluated the tendencies according to the histological types.

Methods

We retrospectively evaluated 218 non-small cell lung cancer (NSCLC) tumors from 217 patients who underwent preoperative fluorodeoxyglucose-positron emission tomography/computed tomography (PET/CT) followed by lung surgery and lymph node resection between July 2015 and August 2020. All primary tumors were calculated as the SUVmax at 50 min (SUVmaxearly [SUVmaxe]) and 120 min (SUVmaxdelayed [SUVmaxd]), and RI. The clinicopathological factors of interest were compared based on lymph node metastasis status and NSCLC histopathological subtype.

Results

The median SUVmaxe and SUVmaxd of the primary tumors were 3.3 and 4.2, respectively, and the median RI was 0.25. The RI was significantly higher in the pN(+) (n = 44) group (0.30) compared to the pN0 (n = 174) group (0.24) (p = 0.01). In patients with adenocarcinoma (n = 145), the RI was also significantly higher in the pN(+) (n = 29) group (0.29) compared to the pN0 (n = 116) group (0.16) (p < 0.01). A high RI of the primary tumor was an independent risk factor for lymph node metastasis, particularly in patients with adenocarcinoma (odds ratio: 12.30, p < 0.05).

Conclusions

The RI of primary NSCLC tumors can help predict lymph node metastases, particularly in patients with adenocarcinoma.
Efficacy and safety of JAK inhibitors in the treatment of psoriasis and psoriatic arthritis: a systematic review and meta-analysis
Authors: Sarabia Samantha , Ranjith Brandan , Koppikar Sahil , Wijeratne Don Thiwanka
Published: September 2022

Background

JAK inhibitors are a relatively new class of medications that may be useful in the treatment of moderate-to-severe psoriasis and psoriatic arthritis (PsA). The objective of this study was to determine the efficacy of several JAK inhibitors in treating psoriasis and PsA and examine safety concerns.

Methods

MEDLINE, Cochrane and EMBASE were searched for randomized controlled trials and observational studies comparing any JAK inhibitor to placebo. The primary outcomes were a 75% improvement in the Psoriasis Area and Severity Index (PASI75) and a 20% improvement in the American College of Rheumatology composite score (ACR20). A secondary outcome was the proportion of patients achieving a “0” or “1” on the static Physician Global Assessment scale. Odds ratios were used to compare the proportion of patients reaching these targets in the max dose intervention group vs. the placebo group. A random effects model was used to account for heterogeneity.

Results

In total, 15 RCTs were included in the study and no observational studies. This encompassed 6757 patients in total. When the results were combined, the calculated odds ratio for PASI75 amongst tofacitinib vs. placebo was OR 14.35 [95%CI 7.65, 26.90], for PASI75 amongst non-tofacitinib JAK inhibitors vs. placebo it was OR 6.42 [95%CI 4.89, 8.43], for ACR20 amongst all JAK inhibitors versus placebo was OR 5.87 [95%CI 4.39, 7.85]. There was no significant difference in prevalence of serious adverse events between intervention and control in any of these studies.

Conclusion

JAK inhibitors show promise for safely treating moderate-to-severe psoriasis and psoriatic arthritis.
One of the 5-aminosalicylates drug, mesalamine as a drug repurposing lead against breast cancer
Authors: Swami Dayanand , Siddiqui Shafina , Kumar Urwashi , Devarajan Shine , Aich Jyotirmoi
Published: September 2022

Background

Breast cancer is the world's second leading cause of death in women. The problem of chemoresistance in breast cancer is proving to be a challenge for researchers and several oncologists all around the world. Current treatment modalities are associated with severe toxicities and lower efficiency. Hence, there is an unmet need for the development of novel drugs that can be used as adjuvants in breast chemotherapy. One of the strategies used to overcome this problem and that has received scientific coverage over the years is ‘Drug Repurposing’. For this purpose, a list of 5-aminosalicylates drugs were evaluated for their drug repurposing potential in breast cancer. Mesalamine, sulfasalazine, balsalazide, and olsalazine were docked with high expression signatures in cancer cells such as EGFR (epidermal growth factor receptor), ERα (Estrogen Receptor alpha), Aromatase, mTOR (mammalian target of rapamycin), ALOX5 (Arachidonate 5-lipoxygenase), and Topoisomerase II.

Results

Docking analysis revealed that the selected ligands (drug) exhibited good binding affinity for all receptors. Based on the specificity with receptors, mesalamine was further selected for in vitro functional validation in a breast cancer cell line. Cell-based cytotoxicity assay in MCF-7 (Michigan Cancer Foundation-7) cells demonstrated the anticancer potential of mesalamine in breast cancer with IC-50 (Inhibitory Concentration) of 6.358 µM.

Conclusions

Significant morphological alterations were observed in breast cells treated with mesalamine. Further studies are warranted to explore the anticancer effect of mesalamine in breast cancer and its role in combination therapies to be used as an adjuvant in chemotherapy.
Cap-snatching inhibitors of influenza virus are inhibitory to the in vitro transcription of rice stripe virus
Authors: Lin Wenzhong , Zha Qingchen , Zhang Wenwen , Wu Guanwei , Yan Fei , Wu Zujian , Du Zhenguo
Published: September 2022

Rice stripe virus (RSV) is one of the most important viral pathogens of rice in East Asia. The transcription of RSV is initiated by cap-snatching, a mechanism shared by influenza virus (IFV). This lends the possibility that antiviral compounds targeting the cap-snatching of IFV, many of which have been commercially available, may inhibit RSV transcription. A convenient and inexpensive system allowing researchers to test this idea, however, has been unavailable to date. Here, we show that purified RSV performs transcription in vitro and the transcription was readily detectable by nested reverse transcription-polymerase chain reaction (RT-PCR). With this system, we tested the effects of 2,4-dioxo-4-phenylbutanoic acid (DPBA) and pimodivir, two well-known IFV cap-snatching inhibitors, as well as ribavirin, a broad-spectrum antiviral compound whose targets remain elusive. In reaction mixtures containing 2.5 ng/µL of purified RSV, DPBA and pimodivir abolished RSV transcription at a concentration of 10 and 100 µM, respectively. In contrast, no inhibitory effect was detected from ribavirin, even at a concentration as high as 400 µM. These results suggest that at least some cap-snatching inhibitors of IFV are inhibitory to RSV transcription. These compounds, which can be identified with the experimental system described here, may serve as starting points in developing antivirals against RSV or related plant viruses.
Long-term outcomes and prognosis factors of vagus nerve stimulation in patients with refractory epilepsy
Authors: Xu Cuiping , Lin Hua , Xu Jiwen , Zhang Xiaohua , Hao Guiliang , Liu Qiang Qiang , Ding Chengyun , Wang Shan , Zhao Quanjun , Bai Xiaojun , Chen Kui , Ni Duanyu , Li Yongjie , Yu Tao , Wang Yuping
Published: September 2022

Background

Vagus nerve stimulation (VNS) is an effective treatment for patients with refractory epilepsy, yet with varied predictive factors and heterogeneous long-term outcomes. Adjustment of VNS parameters is critical for obtaining favorable efficacy. In this study, we aimed to investigate the long-term outcomes and the possible predictive factors of VNS in patients with refractory epilepsy.

Methods

Eighty-six patients (59 males and 27 females) who underwent VNS implantation for treatment of refractory epilepsy between May 2016 and May 2017 at five Epilepsy Centers were enrolled. The clinical data, including sex, age at epilepsy onset, VNS implantation, epilepsy duration, seizure type, MRI findings, history of neurosurgical operations, and responder rate (responders were those with ≥50% seizure reduction), were analyzed.

Results

Four-year follow-up data were available for 76 patients (53 males and 23 females). The mean current intensity at the last follow-up was 1.8 ± 0.3 mA (range: 0.75–2.5 mA). The mean seizure reduction was 36.2% at 6 months, 38.5% at 1 year, 69.4% at 3 years, and 56.7% at 4 years. A favorable outcome of ≥50% reduction in seizure frequency occurred in 40.0% of the patients at 6 months, 55.9% at 1 year with 4 patients being seizure-free, 63.2% at 3 years with 5 patients being seizure-free, and 68.4% at 4 years with 5 patients being seizure-free. Earlier onset age (P < 0.001) and shorter duration (P = 0.042) were associated with favorable prognosis. Compared with generalized tonic-clonic seizures, tonic seizures had a favorable outcome (P = 0.026). Twenty-three patients underwent neurosurgical operations before VNS implantation, and the responder rate was 60.9% at the last follow-up.

Conclusions

VNS is an adjunctive and effective treatment for patients with refractory epilepsy who are not good candidates for surgical resection or have failed to respond to surgical treatment. The stimulation efficacy increases over time after implantation, and earlier exposure to VNS improves the prognosis.
Patterns of facial and blink reflex abnormalities in type 2 diabetes mellitus patients with short disease duration: a clue to subclinical cranial neuropathy
Authors: Tawfik Gihan Abd El Fattah , Sultan Hussein El Moghazy , Younis Gihan Abd El Lattif , El Emairy Wafaa Samir
Published: September 2022

Background

Cranial neuropathies occur in 3 to 14% of diabetic patients. Motor conduction study of the facial nerve and blink reflex study are electrophysiologic techniques used to assess the facio-trigeminal pathway in diabetic patients. The patterns of facial and blink reflex abnormalities are inconsistent among studies. This study aimed to assess the subclinical facial nerve and blink reflex abnormalities patterns in short-duration type 2 diabetes mellitus patients. This cross-sectional study included 30 type 2 diabetic patients with disease duration ≤ 5 years. We included only patients with the Toronto clinical neuropathy score ≤ 5. We enrolled 30 age- and sex-matched healthy subjects as a control group. We performed facial nerve motor conduction and blink reflex studies. Patients with prior history of cranial nerve lesions, stroke, or any other disease-causing polyneuropathy or drug-induced neuropathy were excluded from the study.

Results

Thirty diabetic patients were included, 20 females (66.7%) and ten males (33.3%). Their mean age was 52.63 ± 8.94 years. None of the patients had clinical evidence of neuropathy. There were significant differences between patients and controls in the distal latencies and amplitudes of facial nerve compound muscle action potentials and contralateral R2 late response latencies of the blink reflex. We detected subclinical cranial abnormalities in 6 diabetic patients (20%). One of them (3.3%) had facial nerve conduction abnormalities, four of them (13.4%) had blink reflex abnormalities, and one of them (3.3%) had both facial nerve and blink reflex abnormalities.

Conclusion

Subclinical cranial neuropathy can occur in short-duration type 2 diabetes mellitus patients. We detected different blink reflex patterns and facial conduction study abnormalities. We recommend blink reflex and facial nerve conduction studies as simple tests for the early evaluation of neurological subclinical affection in patients with short disease duration of T2DM as they may appear in the absence of peripheral neuropathy.
Neuroimaging oxytocin modulation of social reward learning in schizophrenia
Authors: Mouchlianitis Elias D. , Tracy Derek K. , Wigton Rebekah , Vanes Lucy D. , Fett Anne-Kathrin , Shergill Sukhi S.
Published: September 2022

Background

Conventional pharmacological approaches have limited effectiveness for schizophrenia. There is interest in the application of oxytocin, which is involved in social cognition. Clinical trials have yielded mixed results, with a gap in understanding neural mechanisms.

Aims

To evaluate the behavioural impact of oxytocin administration on a social learning task in individuals with schizophrenia, and elucidate any differential neural activity produced.

Method

We recruited 20 clinically stable right-handed men diagnosed with schizophrenia or schizoaffective disorder. In a double-blind cross-over randomised controlled study, 40 IU of oxytocin or placebo were administered before functional magnetic resonance imaging of participants playing a multi-round economic exchange game of trust. Participants had the role of investors (investment trials) receiving repayment on their investments (repayment trials), playing one session against a computer and a second against a player believed to be human.

Results

During investment trials, oxytocin increased neural signalling in the right lateral parietal cortex for both human and computer player trials, and attenuated signalling in the right insula for human player trials. For repayment trials, oxytocin elicited signal increases in left insula and left ventral caudate, and a signal decrease in right amygdala during the human player trials; conversely it resulted in right dorsal caudate activation during the computer player trials. We did not find a significant change in behavioural performance associated with oxytocin administration, or any associations with symptoms.

Conclusions

During a social learning task oxytocin modulates cortical and limbic substrates of the reward-processing network. These perturbations can be putatively linked to the pathoaetiology of schizophrenia.
Adjuvant Therapy of Nivolumab Combined With Ipilimumab Versus Nivolumab Alone in Patients With Resected Stage IIIB-D or Stage IV Melanoma (CheckMate 915)
Authors: Weber Jeffrey S. , Schadendorf Dirk , Del Vecchio Michele , Larkin James , Atkinson Victoria , Schenker Michael , Pigozzo Jacopo , Gogas Helen , Dalle Stéphane , Meyer Nicolas , Ascierto Paolo A. , Sandhu Shahneen , Eigentler Thomas , Gutzmer Ralf , Hassel Jessica C. , Robert Caroline , Carlino Matteo S. , Di Giacomo Anna Maria , Butler Marcus O. , Muñoz-Couselo Eva , Brown Michael P. , Rutkowski Piotr , Haydon Andrew , Grob Jean-Jacques , Schachter Jacob , Queirolo Paola , de la Cruz-Merino Luis , van der Westhuizen Andre , Menzies Alexander M. , Re Sandra , Bas Tuba , de Pril Veerle , Braverman Julia , Tenney Daniel J. , Tang Hao , Long Georgina V.
Published: September 2022

PURPOSE

Ipilimumab and nivolumab have each shown treatment benefit for high-risk resected melanoma. The phase III CheckMate 915 trial evaluated adjuvant nivolumab plus ipilimumab versus nivolumab alone in patients with resected stage IIIB-D or IV melanoma.

PATIENTS AND METHODS

In this randomized, double-blind, phase III trial, 1,833 patients received nivolumab 240 mg once every 2 weeks plus ipilimumab 1 mg/kg once every 6 weeks (916 patients) or nivolumab 480 mg once every 4 weeks (917 patients) for ≤ 1 year. After random assignment, patients were stratified by tumor programmed death ligand 1 (PD-L1) expression and stage. Dual primary end points were recurrence-free survival (RFS) in randomly assigned patients and in the tumor PD-L1 expression-level < 1% subgroup.

RESULTS

At a minimum follow-up of approximately 23.7 months, there was no significant difference between treatment groups for RFS in the all-randomly assigned patient population (hazard ratio, 0.92; 95% CI, 0.77 to 1.09; P = .269) or in patients with PD-L1 expression < 1% (hazard ratio, 0.91; 95% CI, 0.73 to 1.14). In all patients, 24-month RFS rates were 64.6% (combination) and 63.2% (nivolumab). Treatment-related grade 3 or 4 adverse events were reported in 32.6% of patients in the combination group and 12.8% in the nivolumab group. Treatment-related deaths were reported in 0.4% of patients in the combination group and in no nivolumab-treated patients.

CONCLUSION

Nivolumab 240 mg once every 2 weeks plus ipilimumab 1 mg/kg once every 6 weeks did not improve RFS versus nivolumab 480 mg once every 4 weeks in patients with stage IIIB-D or stage IV melanoma. Nivolumab showed efficacy consistent with previous adjuvant studies in a population resembling current practice using American Joint Committee on Cancer eighth edition, reaffirming nivolumab as a standard of care for melanoma adjuvant treatment.
False Gospels of Efficiency
Authors: Vail David D.
Published: September 2022

This article examines the conflicts over knowledge, expertise, spiritual promises, and agroecological realities that collided in the construction of an early-1900s rural water conservation district in Cache Valley, Utah. Out of these tensions emerged a field-based view of conservation that oscillated between hydrologists' teachings of rational management through irrigation and local dry farming practices that seemed to acknowledge the valley's limitations—all in a futile effort to make the land faithful to an agri-spiritual aesthetic that persuaded scientists and farmers alike to rebuild District No. 1 over and over again. From debates about whose expertise to follow to economic devastation from illicit dealings of dubious financiers and unruly environmental conditions, the saga of Cache County Water Conservation District No. 1 reveals an irrigated rural western landscape that was as unpredictable as it was inescapable.
From Bread to Cake
Authors: Morris Craig , Bolingbroke David
Published: September 2022

This article deepens our understanding of Cold War–era agricultural history by examining the relationship between Pacific Northwest soft white wheat and Japanese importers and consumers. Recent historiography of wheat during the Cold War has focused on telling how the United States turned to wheat exports in the “developing world” as a tool and weapon to achieve US hegemony and negate the influence of the Soviet Union. This article argues that the Pacific Northwest wheat industry's relationship with wheat consumers and importers in Japan shifts the Cold War wheat narrative away from staples like bread to confectionary products made with soft white flour. Japanese buyers and consumers purchased soft white wheat not to feed the hungry but instead to serve a growing market for cakes and other confectionary products. This relationship helps understand the current wheat market in the Pacific Northwest, where soft white wheat exports dominate.
ALGORITMOS PREDITIVOS, BOLHAS SOCIAIS E CÂMARAS DE ECO VIRTUAIS NA CULTURA DO CANCELAMENTO E OS RISCOS AOS DIREITOS DE PERSONALIDADE E À LIBERDADE HUMANA
Authors: Siqueira Dirceu Pereira , Vieira Ana Elisa Silva Fernandes
Published: September 2022

Objetivo: O presente artigo tem por objetivo analisar os riscos da cultura do cancelamento no ambiente virtual ao direito à liberdade e aos direitos de personalidade, identificar de que forma a utilização de algoritmos para a predição dos usuários e a criação de bolhas sociais virtuais com viés discriminatório contribui o cancelamento.Metodologia: Utiliza o método hipotético-dedutivo e parte da hipótese de que as bolhas virtuais e câmaras de eco fortalecem e expandem discursos de cancelamento e esses discursos violam os direitos de personalidade e a dignidade humana, logo, não podem ser considerados como manifestações de cidadania e liberdade de expressão. Como técnica de investigação, utiliza a revisão bibliográfica em artigos, livros, físicos e eletrônicos, nas bases de dados nacionais e em fontes secundárias como a análise documental em jornais e notícias.Resultados: A cultura do cancelamento é uma prática que se manifesta na intolerância às visões opostas, que é amplificada pelas bolhas sociais virtuais pelas câmaras de eco, que atinge a vida online e offline. O discurso de cancelamento representa riscos aos direitos de personalidade e dignidade humana e rompe com a noção de liberdade. Deve-se criar políticas públicas de educação para a cidadania digital, que estimulem a pluralidade e a liberdade de expressão, sem a violação a direitos fundamentais.Contribuições: A contribuição que se espera com a pesquisa é a relação entre a cultura do cancelamento diante das bolhas sociais virtuais, da desinformação e da predição algorítmica e os riscos que esses fenômenos representam à liberdade e aos direitos de personalidade.
O CROWDFUNDING DE INVESTIMENTO EM NÚMEROS NO BRASIL E A PERSPECTIVA DE AMPLIAÇÃO DE SEU ACESSO À POPULAÇÃO BRASILEIRA
Authors: Ragil Rodrigo Rocha Feres , Neves Rubia Carneiro
Published: September 2022

Contextualização: O desenvolvimento do Crowdfunding de Investimento desde a sua regulação pela ICVM n. 588 em 2017.Objetivo:Avaliar a hipótese segundo a qual a regulação trazida pela Instrução CVM n. 588 de 2017 está cumprindo os objetivos que levaram à sua instituição, isto é, democratizar e ampliar o acesso ao mercado de valores mobiliários para empreendimentos nascentes de reconhecido potencial.Método: Revisão bibliográfica e análise de normas e dados, quantitativos e qualitativos, a respeito de plataformas eletrônicas de investimento participativo, volume de recursos captado, investidores, sociedades empresárias e áreas investidas entre 2014 e 2020.Resultados: Percebeu-se considerável aumento dos números do Crowdfunding de Investimento a partir de 2017 e do seu potencial para financiar empreendimentos empresariais. Observou-se concentração de aplicação dentre os investidores do sexo masculino, com idade inferior a 40 anos, portadores de diploma de Ensino Superior e com renda média elevada, nas regiões Sul e Sudeste, e em algumas atividades, tendo sido o maior volume captado pelos setores financeiro, imobiliário e de tecnologia.Conclusões: Os resultados mapeados parecem indicar a necessidade de aperfeiçoar a regulação visando a fomentar a ampliação de utilização do Crowdfunding de Investimento, eis que verificada pouca diversidade quanto a três aspectos: regiões do país em que são ofertados valores mobiliários via Crowdfunding de Investimento; perfil dos investidores; abrangência de atividades em que se investiu. Analisando-se o recente Edital de Audiência Pública SDM CVM n. 02/2020, não foi possível identificar na proposta de alteração normativa por ele trazida regras, mecanismos ou perspectivas para ampliar a baixa diversificação verificada no país.
Synthesis and characterization of new metal-organic frameworks by the use of 2-pyridyl oximes or alcohols in combination with poly-carboxylic ligands
Authors: Μυλωνάς-Μαργαρίτης Ιωάννης
Published: September 2022

O στόχος της διατριβής είναι η σύνθεση και χαρακτηρισμός νέων πολυμερών ένταξης από μικτά συστήματα υποκαταστατών και η περαιτέρω μελέτη τους ως μαγνητικοί σένσορες για την απορρόφηση τοξικών ειδών. Για τη σύνθεση τους χρησιμοποιήθηκαν 2-πύριδυλ οξίμες ή πύριδυλ-αλκοόλες προκειμένου να σχηματιστεί/σταθεροποιηθεί η ανόργανη δομική υπομονάδα, καθώς και πολυτοπικοί καρβοξυλικοί υποκαταστάτες (δι-, τρι- και τέτρα- τοπικοί) (1,4-δικαρβοξυλικό βενζόλιο/τερεφθαλικό οξύ, 1,3,5-τρικαρβοξυλικό βενζόλιο/τριμεσικό οξύ, 1,2,4,5-τετρακαρβοξυλικό βενζόλιο/πυρομεταλλικό οξύ. Όλες οι ενώσεις παρείχθησαν υπο σολβο-θερμικές συνθήκες. Η επιλογή των υποκαταστατών είναι σημαντική καθώς επηρεάζει τις ιδιότητες των παραχθέντων ουσιών. Οι πυριδυλ-οξίμες και αλκοόλες έχουν ευρέως χρησιμοποιηθεί στο πεδίο των Μονομοριακών Μαγνητών και έχει αποδειχθεί ότι έχουν την δυνατότητα σταθεροποίησης μικρών και μεγάλων μεταλλικών πλειάδων, οι οποίες παρουσιάζουν ενδιαφέρουσες μαγνητικές ιδιότητες. Παρ' όλα αυτά δεν έχουν συστηματικά χρησιμοποιηθεί και εξερευνηθεί στο πεδίο των Metal-Organic Frameworks (MOFs). Oι πολυκαρβοξυλικοί υποκαταστάτες είναι από τους πρώτους στο πεδίο των MOFs για την παραγωγή πολυμέρων δύο ή τριων διαστάσεων. Συνδυαζόντας αυτές τις δύο κατηγορίες οργανικών υποκαταστατών στοχεύουμε τη σχεδιασμένη απομόνωση μικρών ή μεγάλων ανόργανων υπομονάδων, προκειμένου να παρασκευαστούν MOFs με ενδιαφέρουσες τοπολογίες και μαγνητικές ιδιότητες. Το κύριο μειονέκτημα εξερεύνησης συστημάτων μικτών-υποκαταστατών είναι ότι υπάρχουν περισσότερα από ένα κύρια προϊόντα (παραπροϊόντα) τα οποία μπορούν να απομονωθούν κατά τη διαδικασία σύνθεσης πριν το τελικό πολυμερές ένταξης/ΜΟF. Αυτού του είδους τα συστήματα δεν είναι γενικά υψηλής απόδοσης ή θερμοδυναμικά σταθερά και γι' αυτό το λόγο απαιτείται η βαθύτερη κατανόηση και εξερεύνηση τους προκειμένου να κατανοηθούν οι συνθήκες κατά τις οποίες κρυσταλλώνουν/λαταβυθίζονται κύρια προϊόντα απουσία των παραπροϊόντων. Αυτό επιτυγχάνεται με αλλαγή των πειραματικών συνθηκών. Όλες οι παραγόμενες ενώσεις έχουν χαρακτηριστεί με κρυσταλλογραφία ακτίνων-Χ, ακρινογραφία κόνεως, φασματοσκοπία υπεριώδους, μελέτη μάζας και μαγνητισμό. Επίσης μελετήθηκη απορρόφηση των τοξικών για το περιβάλλον ουσιών.
Maximising impactful and locally relevant mental health research: ethical considerations
Authors: Calia Clara , Chakrabarti Amit , Sarabwe Emmanuel , Chiumento Anna
Published: September 2022

Background:Achieving ethical and meaningful mental health research in diverse global settings requires approaches to research design, conduct, and dissemination that prioritise a contextualised approach to impact and local relevance.

Method:Through three case studies presented at the 2021 Global Forum on Bioethics in Research meeting on the ethical issues arising in research with people with mental health conditions, we consider the nuances to achieving ethical and meaningful mental health research in three diverse settings. The case studies include research with refugees Rwanda and Uganda; a neurodevelopmental cohort study in a low resource setting in India, and research with Syrian refugees displaced across the Middle East.

Results:Key considerations highlighted across the case studies include how mental health is understood and experienced in diverse contexts to ensure respectful engagement with communities, and to inform the selection of contextually-appropriate and feasible research methods and tools to achieve meaningful data collection.  Related to this is a need to consider how communities understand and engage with research to avoid therapeutic misconception, exacerbating stigma, or creating undue inducement for research participation, whilst also ensuring meaningful benefit for research participation. Central to achieving these is the meaningful integration of the views and perspectives of local stakeholders to inform research design, conduct, and legacy. The case studies foreground the potential tensions between meeting local community needs through the implementation of an intervention, and attaining standards of scientific rigor in research design and methods; and between adherence to procedural ethical requirements such as ethical review and documenting informed consent, and ethical practice through attention to the needs of the local research team.

Conclusions:We conclude that engagement with how to achieve local relevance and social, practice, and academic impact offer productive ways for researchers to promote ethical research that prioritises values of solidarity, inclusion, and mutual respect.
Transient osteoporosis of the hip with a femoral neck fracture during follow-up: a case report
Authors: Tabata Yusuke , Matsui Shuhei , Miyamoto Masabumi , Omori Koichiro , Tabata Yoichiro , Majima Tokifumi
Published: September 2022

We report a case of transient osteoporosis of the hip with a femoral neck fracture found during follow-up. A 53-year-old man presented with left hip pain without trauma. The pain did not improve after 2 weeks and he was brought to our hospital by ambulance. Magnetic resonance imaging (MRI) of the left hip joint showed diffuse edema in the bone marrow, which was identified by low signal intensity on T1-weighted images, high signal intensity on T2-weighted images, and increased signal intensity on short tau inversion recovery. This edema extended from the femoral head and neck to the intertrochanteric area. He was diagnosed with transient osteoporosis of the left hip. Rest gradually improved his pain; however, 3 weeks later, his left hip pain worsened without trauma. X-ray, computed tomography, and MRI results of the hip joint demonstrated a left femoral neck fracture, and osteosynthesis was performed. Differential diagnoses included avascular necrosis of the femoral head, infection, complex regional pain syndrome, rheumatoid arthritis, leukemia, and other cancers. Transient osteoporosis of the hip generally has a good prognosis with spontaneous remission within a few months to 1 year. However, a sufficient length of follow-up from condition onset to full recovery is necessary to avoid all probable complications such as fractures.
SUSTAINABLE DEVELOPMENT OF RUSSIAN REGIONS: ASSESSMENT, ANALYSIS
Authors: Vakulenko Olesya S. , Grachev Sergey A.
Published: September 2022

Relevance. The depletion of natural resources, the problems of poverty, malnutrition and inequality are some examples from the endless list of problems of humanity. They actualized the issue of sustainable development.

Problem. Despite the relevance, there is a lack of a standardized methodological approach to assessing the parameters of sustainable development, which is a research problem.

Goal. Formation of a standardized methodical approach for assessing the parameters of sustainable development and identification of donor regions.

Methods. In the course of the study, methods of analysis and synthesis were used to form the estimated parameters, comparison to evaluate the results obtained, formalization to standardize the approach.

Results. The combination of methods made it possible to form and test an approach based on the author’s sustainable development index, taking into account the risk of changes in development, in 66 regions of the Russian Federation over a 20-year period. The result was the identification of the region most prepared for donation in the economic sphere – the Krasnodar Territory.
ORFEU DA CONCEIÇÃO: UMA TRAGÉDIA NÃO NEGRA
Authors: Costa Ronald Augusto da
Published: September 2022

O que pretendemos com esse artigo é analisar dois aspectos da peça Orfeu da Conceição, de Vinicius de Moraes. Em primeiro lugar demonstraremos que em termos de modelo compositivo, o autor escreveu a obra a partir de uma dialética da apropriação-expropriação de signos da tradição ocidental.  Isto é, Vinicius, como um típico modernista tardio, serve-se de dados do passado estético-literário tendo em vista sua transfiguração ou atualização para o presente. O segundo aspecto que abordaremos diz respeito às tensões e às vacilações semânticas que informam a peça desde o pano de fundo racial. Essas tensões indicam em sua estrutura discursiva o alinhamento acrítico do autor com a estereotipia e o preconceito relativamente à representação de personagens negros e ao tratamento do legado cultural e religioso afro-brasileiros. Se no primeiro aspecto é possível afirmar que o poeta logrou êxito, já no segundo aspecto concluímos que Vinícius fracassou, porque não conseguiu conferir aos seres de ficção negros uma dimensão mais profunda e complexa.
Diferentes conformações da timidez
Authors: Gasparete Luiz Philip Fávero
Published: September 2022

Este artigo aborda as opiniões do crítico de arte Rodrigo Naves a respeito de certo cânone das artes plásticas difundido a partir do modernismo de 1922 e de seus desdobramentos, como a antropofagia. O trabalho procura contextualizar as reservas do autor em relação a artistas que se notabilizaram junto a esses movimentos, como Anita Malfatti e Tarsila do Amaral, bem como em relação aos critérios empregados pelos intelectuais modernistas em reflexões sobre pintores brasileiros. O método utilizado é a análise de diferentes textos do crítico de modo a sublinhar as premissas teóricas, históricas e estéticas que fundamentam sua posição. De resto, buscam-se também elementos para compreender a linhagem das artes plásticas composta por Rodrigo Naves em A forma difícil, da qual estão excluídos muitos dos nomes do cânone modernista.
Um outro Modernismo
Authors: Lopes Denilson
Published: September 2022

Há uma recorrência bibliográfica de um suposto isolamento intelectual de Mário Peixoto e de Limite (1931) na história do cinema, talvez mesmo na história cultural brasileira. Gostaria de problematizar essas duas afirmativas para argumentar em favor de uma aproximação de Limite diferente da realizada pelo seu pertencimento a uma tradição experimental bem como de um mapeamento de uma rede intelectual a afetiva a que Mário Peixoto pertencia a partir de uma leitura dos diários de Mário Peixoto e setenta depoimentos de parentes, amigos, colegas e contemporâneos de Mário depositados no Arquivo Mário Peixoto, no Rio de Janeiro.  Os depoimentos somam algo em torno de pelo menos mil e quinhentas páginas. Creio que esse material inédito pode contribuir para ampliar o conhecimento não só de Mário Peixoto e de sua obra, mas da história cultural e do cenário intelectual do Rio de Janeiro, em especial, nos anos 30. Para tanto minha terceira hipótese é a de supor um outro Modernismo, no qual o extrativismo, em especial, associado a “longa decadência” do ouro em Minas Gerais e, sobretudo, à decadência do café no Vale do Paraíba é central e gera uma sensibilidade histórica aristocrática, sem deixar de ser crítica.
Numa estação ferroviária: Sérgio Sant’Anna encontra Oswald e Mário de Andrade
Authors: Farinaccio Pascoal
Published: September 2022

Propõe-se aqui a análise do conto “Um homem sozinho numa estação ferroviária”, de Sérgio Sant’Anna, publicado originalmente em 1989 no livro A senhorita Simpson. Nele, Sant’Anna encena um encontro imaginário entre Oswald e Mário de Andrade ocorrido na década de 1920, em uma cidade do interior paulista, por ocasião da inauguração de uma biblioteca pública. Com notável capacidade de síntese, o contista alcança explorar diferenças de personalidades entre os dois escritores paulistas, colocando também em perspectiva crítica dilemas enfrentados pelo Modernismo brasileiro, em especial a problemática em torno da incorporação das vanguardas europeias em país marcado pela defasagem artística e subdesenvolvimento econômico. Busca-se demostrar como Sant’Anna, através de sua aguda e sutil reflexão ficcional sobre o Modernismo, introduz uma leitura muito particular e uma tomada de posição no que se refere aos destinos socioculturais do país em intenso diálogo com os legados de Oswald e Mário de Andrade.