bluuebunny/crossref_metadata_2025 huggingface dataset:
Management of children with danger signs in integrated community case management care in rural southwestern Uganda (2014–2018)
Authors: Matte Michael , Ntaro Moses , Kenney Jessica , Patel Palka , Wesuta Andrew Christopher , Kawungezi Peter Chris , Bwambale Shem , Ayebare David , Baguma Stephen , Bagenda Fred , Miller James S , Stone Geren , Mulogo Edgar Mugema
Published: June 2023

Background

In integrated community case management (iCCM) care, community health workers (CHWs) provide home-based management of fever, diarrhea and fast breathing for children aged <5 y. The iCCM protocol recommends that children with danger signs for severe illness are referred by CHWs to health facilities within their catchment area. This study examines the management of danger signs by CHWs implementing iCCM in a rural context.

Methods

A retrospective observational study that examined clinical records for all patients with danger signs evaluated by CHWs from March 2014 to December 2018 was conducted.

Results

In total, 229 children aged <5 y had been recorded as having a danger sign during 2014–2018. Of these children, 56% were males with a mean age of 25 (SD 16.9) mo, among whom 78% were referred by the CHWs as per the iCCM protocol. The age category of 12 to 35 mo had the highest numbers of prereferred and referred cases (54% and 46%, respectively).

Conclusions

CHWs play a key role in early symptomatic detection, prereferral treatment and early referral of children aged <5 y. Danger signs among children aged <5 y, if left untreated, can result in death. A high proportion of the children with danger signs were referred as per the iCCM protocol. Continuous CHW training is emphasized to reduce the number of referral cases that are missed. More studies need to focus on children aged 12–35 mo and why they are the most referred category. Policymakers should occasionally revise iCCM guidelines to detail the types of danger signs and how CHWs can address these.
Graffiti Writing as Creative Activism: Getting Up, Sheeplike Subversion, and Everyday Resistance
Authors: Baldini Andrea L
Published: June 2023

Is graffiti writing creative activism? In this paper, I challenge commonly held beliefs that graffiti writing is politically inert. On the contrary, I argue that graffiti writing is an example of creative activism. Rather than being a narcissistic form of vandalism, primarily directed at increasing one’s fame in front of an esoteric group, that is, fellow writers, writing is a form of everyday resistance allowing its practitioners to challenge authoritarian power. In questioning dominant hierarchies, graffiti is a powerful tool to help correct a specific instance of spatial injustice: the unequal distribution of access to urban surfaces for self-expression in the city, where corporations and political elites hold an unjustified monopoly over visual communication.
Genetic diversity and breed identification of Chinese and Vietnamese local chicken breeds based on microsatellite analysis
Authors: Zhuang Zhong , Zhao Long , Zong Weicheng , Guo Qixin , Li Xiaofan , Bi Yulin , Wang Zixiu , Jiang Yong , Chen Guohong , Li Bichun , Chang Guobin , Bai Hao
Published: June 2023

South Asia and Southeast Asia are the origins of domestic chickens and are rich in poultry genetic resources, resulting in many unique local chicken breeds. However, with the rapid intensification of poultry farming worldwide, many local chicken breeds are threatened with extinction. In response to China’s “One Belt, One Road” policy, it is imperative to strengthen the conservation and breeding of local chicken breeds in China and Vietnam. This study characterized 18 microsatellite molecular genetic markers to analyze the genetic diversity of 21 local chicken populations in southern China (Yunnan and Guangxi Provinces) and Vietnam, breed identification tags for microsatellite loci were constructed. The results showed that a total of 377 alleles were detected in all breeds, and the most alleles (44) and the highest polymorphic information content (0.7820) were detected at the LEI0094 locus. The average polymorphic information content (PIC) content of the whole population was 0.65, indicating moderate polymorphism. The genetic diversity of the whole population was rich, except for two loci MCW0111 and MCW0016, that showed heterozygote excess at microsatellite loci, and the population had high genetic differentiation. The Vietnamese breeds showed low pairwise fixation coefficient (FST) and Nei’s standard genetic distance (DS) between them. According to the neighbor-joining dendrogram constructed by DS and the analysis of population genetic structure using the structure program, Longshengfeng chicken, Yunlong dwarf chicken, Tengchong white chicken, Xiayan chicken, and Daweishan mini chicken are similar, and Xishuangbanna game fowl, Wuding chicken, and Lanping silky chicken are similar to Yanjin black-bone chicken. In addition, excluding Dongtao chicken, other Vietnamese breeds are clustered together, indicating that the southern chicken breeds are closely related and have experienced better breeding. Overall, the whole population is rich in genetic resources, and the chicken breeds in the three regions are genetically close because of geographical factors and human activities. Dongtao chicken in Vietnamese, Chinese Yunnan local chicken breeds (Gallus gallus spadiceus), and red jungle fowl chickens (Gallus gallus) may have the same origin. We also constructed unique microsatellite molecular markers for 20 cultivars using 15 microsatellite loci. This study provides valuable insights to facilitate breed identification, improve cultivar protection, and new germplasm construction.
Insights into the toxicity, biochemical activity, and molecular docking of Cymbopogon citratus essential oils and citral on Spodoptera littoralis (Lepidoptera: Noctuidae)
Authors: Moustafa Moataz A M , Hassan Nancy N , Alfuhaid Nawal Abdulaziz , Amer Alia , Awad Mona
Published: June 2023

Insecticide resistance is a significant problem in insect management that can result from several processes including target-site change and increased activity of detoxifying enzymes. Spodoptera littoralis is one of the most resistant insect pests. For more effective insect management, alternatives to synthetic pesticides are encouraged. One of these alternatives is essential oils (EOs). Cymbopogon citratus EO and its main constituent citral were, therefore, considered in this study. The results revealed that C. citratus EO and citral exhibited significant larvicidal activity against S. littoralis, and the former was insignificantly more toxic than the latter. Additionally, treatments significantly affected the activity of detoxification enzymes. Cytochrome P-450 and glutathione-S-transferase were inhibited, while carboxylesterases, a-esterase and β-esterase, were induced. The molecular docking study indicated that citral bonded with the amino acids cysteine (CYS 345) and histidine (HIS 343) of cytochrome P-450. This result suggests that interaction with cytochrome P-450 enzyme is one key mechanism by which C. citratus EO and citral act in S. littoralis. The results of our study are hoped to contribute to a better understanding of the mechanism of action of essential oils at the biochemical and molecular levels and provide safer and more efficient pest management solutions for S. littoralis.
Surgical treatment of snapping proximal hamstring tendon syndrome: the resolution of snapping and excellent patient satisfaction
Authors: Mitchell Cecilia V , Lamba Abhinav , Okoroha Kelechi R , Economopoulos Kostas J , Spinner Robert J , Krych Aaron J
Published: June 2023

Snapping proximal hamstring is an uncommon phenomenon, with few case reports documenting surgical treatment. The purpose of this study is to report snapping resolution, minimum 2-year post-operative patient-reported outcome (PRO), satisfaction scores and complications from patients who underwent surgical release of the conjoint tendon from the sacrotuberous ligament with reattachment to the ischial tuberosity. Prospectively collected data from two institutional databases were retrospectively reviewed for patients who underwent hamstring repair for partial- or full-thickness tears. Patients were included if they demonstrated ‘snapping proximal hamstrings’ on preoperative physical examination, including ultrasound confirmation, and repair subsequently performed. Patients were excluded if they had reconstruction of the proximal hamstring tendon or claimed worker’s compensation. With a total of 20 patients (15 females and 5 males), successful resolution of snapping was reported in 100% of the cohort. For patients with pre- and post-surgical lower-extremity functional scores (LEFS), post-surgical LEFS were significantly higher than pre-surgical LEFS (pre-surgical: 17.0 ± 4.0, post-surgical: 73.6 ± 3.3, P < 0.001). Average post-operative PROs were as follows: International Hip Outcome Tool-12, 92.3 ± 8.3; modified Harris Hip Score, 93.2 ± 7.8; Non-arthritic Hip Score, 92.5 ± 6.8; Hip Outcome Score-Sports Specific Subscale, 94.4 ± 6.7; LEFS, 73.9 ± 3.4; and median visual analog scale of 0 with an interquartile range of 0-1. Patient satisfaction was ‘very satisfied’ in 19 (95%) patients and ‘satisfied’ in 1 (5%) patient. At a minimum 2-year follow-up, patients who underwent surgical treatment for chronic snapping of the proximal hamstrings demonstrated complete resolution of painful posterior snapping, reported high PROs and satisfaction, and had no reported post-operative complications.
Last year’s model? Investment arbitration, negotiation, and the gap between Model BITs and IIAs
Authors: Haftel Yoram Z , Link Morr , Broude Tomer
Published: June 2023

With more than 3000 international investment agreements (IIAs) worldwide, states negotiate similar agreements multiple times with numerous partners. Accordingly, many states have developed template agreements known as ‘Model bilateral investment treaties (BITs)’. Nevertheless, concluded IIAs commonly deviate from the corresponding Model BITs, albeit to varying degrees. Investigating this variation, we examine the impact of Model Countries and their Partner Countries’ investor–state dispute settlement (ISDS) experience. Specifically, we argue that the Model Country adopts changes sought by the Partner Country during the negotiation process in order to accommodate the latter’s preferences, which were shaped by lessons learned from ISDS cases. Empirically, we introduce novel measures of divergence between Model BITs and IIAs, based on the concept and scheme of state regulatory space, with respect to several key aspects of investment rules. Coding a large number of Model BITs and IIAs on these variables and controlling for a host of alternative explanations, we find that the higher number of investment claims filed against the Partner Country, but not the Model Country, is associated with greater divergence between the Model Country’s Model BITs and its IIAs. This effect is especially noticeable with respect to important substantive investment rules.
Latest classification of ependymoma in the molecular era and advances in its treatment: a review
Authors: Yamaguchi Junya , Ohka Fumiharu , Motomura Kazuya , Saito Ryuta
Published: June 2023

Ependymoma is a rare central nervous system (CNS) tumour occurring in all age groups and is one of the most common paediatric malignant brain tumours. Unlike other malignant brain tumours, ependymomas have few identified point mutations and genetic and epigenetic features. With advances in molecular understanding, the latest 2021 World Health Organization (WHO) classification of CNS tumours divided ependymomas into 10 diagnostic categories based on the histology, molecular information and location; this accurately reflected the prognosis and biology of this tumour. Although maximal surgical resection followed by radiotherapy is considered the standard treatment method, and chemotherapy is considered ineffective, the validation of the role of these treatment modalities continues. Although the rarity and long-term clinical course of ependymoma make designing and conducting prospective clinical trials challenging, knowledge is steadily accumulating and progress is being made. Much of the clinical knowledge obtained from clinical trials to date was based on the previous histology-based WHO classifications, and the addition of new molecular information may lead to more complex treatment strategies. Therefore, this review presents the latest findings on the molecular classification of ependymomas and advances in its treatment.
Urgent need to mitigate disparities in federal funding for cancer research
Authors: Haghighat Shida , Jiang Chunsu , El-Rifai Wael , Zaika Alexander , Goldberg David S , Kumar Shria
Published: June 2023

We evaluate National Cancer Institute (NCI) funding distribution to the most common cancers, considering their respective public health burdens, and explore associations between funding and racial and ethnic burden of disease. The NCI’s Surveillance, Epidemiology and End Results, US Cancer Statistics database, and Funding Statistics were used to calculate funding-to-lethality (FTL) scores. Breast and prostate cancer had the first (179.65) and second (128.90) highest FTL scores, and esophagus and stomach cancer ranked 18th (2.12) and 19th (1.78). We evaluated whether there were differences between the FTL and cancer incidence and/or mortality within individual racial and ethnic groups. NCI funding correlated highly with cancers afflicting a higher proportion of non-Hispanic White individuals (Spearman correlation coefficient = 0.84; P < .001). Correlation was stronger for incidence than mortality. These data reveal that funding across cancer sites is not concordant with lethality and that cancers with high incidence among racial and ethnic minorities receive lower funding.
Partial breast irradiation compared with whole breast irradiation: a systematic review and meta-analysis
Authors: Shumway Dean A , Corbin Kimberly S , Farah Magdoleen H , Viola Kelly E , Nayfeh Tarek , Saadi Samer , Shah Vishal , Hasan Bashar , Shah Sahrish , Mohammed Khaled , Riaz Irbaz Bin , Prokop Larry J , Murad M Hassan , Wang Zhen
Published: June 2023

Background

Early-stage breast cancer is among the most common cancer diagnoses. Adjuvant radiotherapy is an essential component of breast-conserving therapy, and several options exist for tailoring its extent and duration. This study assesses the comparative effectiveness of partial-breast irradiation (PBI) compared with whole-breast irradiation (WBI).

Methods

A systematic review was completed to identify relevant randomized clinical trials and comparative observational studies. Independent reviewers working in pairs selected studies and extracted data. Randomized trial results were pooled using a random effects model. Prespecified main outcomes were ipsilateral breast recurrence (IBR), cosmesis, and adverse events (AEs).

Results

Fourteen randomized clinical trials and 6 comparative observational studies with 17 234 patients evaluated the comparative effectiveness of PBI. PBI was not statistically significantly different from WBI for IBR at 5 years (RR = 1.34, 95% CI = 0.83 to 2.18; high strength of evidence [SOE]) and 10 years (RR = 1.29, 95% CI = 0.87 to 1.91; high SOE). Evidence for cosmetic outcomes was insufficient. Statistically significantly fewer acute AEs were reported with PBI compared with WBI, with no statistically significant difference in late AEs. Data from subgroups according to patient, tumor, and treatment characteristics were insufficient. Intraoperative radiotherapy was associated with higher IBR at 5, 10, and over than 10 years (high SOE) compared with WBI.

Conclusions

Ipsilateral breast recurrence was not statistically significantly different between PBI and WBI. Acute AEs were less frequent with PBI. This evidence supports the effectiveness of PBI among selected patients with early-stage, favorable-risk breast cancer who are similar to those represented in the included studies.
The influence of the “cancer” label on perceptions and management decisions for low-grade prostate cancer
Authors: Berlin Alejandro , Ramotar Matthew , Santiago Anna T , Liu Zhihui , Li Joyce , Wolinsky Howard , Wallis Christopher J D , Chua Melvin L K , Paner Gladell P , van der Kwast Theodorus , Cooperberg Matthew R , Vickers Andrew J , Urbach David R , Eggener Scott E
Published: June 2023

Background

Grade Group 1 (GG1) prostate cancer should be managed with active surveillance (AS). Global uptake of AS remains disappointingly slow and heterogeneous. Removal of cancer labels has been proposed to reduce GG1 overtreatment. We sought to determine the impact of GG1 disease terminology on individual’s perceptions and decision making.

Methods

Discrete choice experiments were conducted on 3 cohorts: healthy men, canonical partners (partners), and patients with GG1 (patients). Participants reported preferences in a series of vignettes with 2 scenarios each, permuting key opinion leader–endorsed descriptors: biopsy (adenocarcinoma, acinar neoplasm, prostatic acinar neoplasm of low malignant potential [PAN-LMP], prostatic acinar neoplasm of uncertain malignant potential), disease (cancer, neoplasm, tumor, growth), management decision (treatment, AS), and recurrence risk (6%, 3%, 1%, <1%). Influence on scenario selection were estimated by conditional logit models and marginal rates of substitution. Two additional validation vignettes with scenarios portraying identical descriptors except the management options were embedded into the discrete choice experiments.

Results

Across cohorts (194 healthy men, 159 partners, and 159 patients), noncancer labels PAN-LMP or prostatic acinar neoplasm of uncertain malignant potential and neoplasm, tumor, or growth were favored over adenocarcinoma and cancer (P < .01), respectively. Switching adenocarcinoma and cancer labels to PAN-LMP and growth, respectively, increased AS choice by up to 17%: healthy men (15%, 95% confidence interval [CI] = 10% to 20%, from 76% to 91%, P < .001), partners (17%, 95% CI = 12% to 24%, from 65% to 82%, P < .001), and patients (7%, 95% CI = 4% to 12%, from 75% to 82%, P = .063). The main limitation is the theoretical nature of questions perhaps leading to less realistic choices.

Conclusions

“Cancer” labels negatively affect perceptions and decision making regarding GG1. Relabeling (ie, avoiding word “cancer”) increases proclivity for AS and would likely improve public health.
Delayed placement of an inflatable penile prosthesis is associated with a high complication rate in men with a history of ischemic priapism
Authors: Barham David W , Chang Chrystal , Hammad Muhammed , Pyrgidis Nikolaos , Swerdloff Daniel , Gross Kelli , Hatzichristodoulou Georgios , Hsieh Tung-Chin , Hotaling James M , Jenkins Lawrence C , Jones James M , Modgil Vaibhav , Osmonov Daniar , Pearce Ian , Perito Paul , Sadeghi-Nejad Hossein , Suarez-Sarmiento Jr. Alfredo , Sempels Maxime , Service C Austin , Simhan Jay , Yafi Faysal A , Gross Martin S ,   the PUMP (Prosthetic Urology Multi-institutional Partnership) collaborators
Published: June 2023

Background

Corporal fibrosis is known to result from prolonged priapism; however, the impact of the timing of penile prosthesis placement after priapism on complication rates is poorly understood.

Aim

We sought to evaluate the impact of timing of inflatable penile prosthesis (IPP) placement on complications in men with a history of ischemic priapism.

Methods

We performed a multicenter, retrospective cohort study of patients with a history of priapism undergoing IPP placement by 10 experienced implantation surgeons. We defined early placement as ≤6 months from priapism to IPP. We identified a 1:1 propensity-matched group of men without a history of priapism and compared complication rates between men who had early placement, late placement, and no history of priapism.

Outcomes

Our primary outcome was postoperative noninfectious complications, and secondary outcomes included intraoperative complications and postoperative infection.

Results

A total of 124 men were included in the study with a mean age of 50.3 ± 12.7 years. A total of 62 had a history of priapism and 62 were matched control subjects. The median duration of priapism was 37 (range, 3-168) hours and the median time from ischemic priapism to IPP placement was 15 months (range, 3 days to 23 years). Fifteen (24%) men underwent early (≤6 months) IPP placement at a median time of 2 months (range, 3 days to 6 months) following the ischemic priapism event. The remaining 47 (76%) underwent placement >6 months following priapism at a median time of 31.5 months (range, 7 months to 23 years). The complication rate in the delayed placement group was 40.5% compared with 0% in the early placement group and control group. Cylinder-related complications such as migration or leak accounted for 8 (57%) of 14 of the postoperative noninfectious complications. Full-sized cylinders were used in all patients who had a cylinder related complication.

Clinical Implications

Priapism patients should be referred to prosthetic experts early to decrease complication rates in those needing an IPP.

Strengths and Limitations

This is a multicenter study from experienced prosthetic urologists but is limited by the retrospective nature and small number of patients in the early placement group.

Conclusion

IPP complication rates are high in men with a history of ischemic priapism, especially when implantation is delayed beyond 6 months.
Imported cases of malaria in Brazil from South American countries: a retrospective ecological study from 2009 to 2022
Authors: Martins-Filho Paulo Ricardo , Araújo Francy Waltília Cruz , Lima Shirley Verônica Melo Almeida , Santiago Bianca Marques , Damascena Nicole Prata , Araújo Analany Pereira Dias , Silva Melina Calmon , Machado Carlos Eduardo Palhares
Published: June 2023

The Legal Amazon region serves as a hotspot for imported malaria from other South American countries, with over 75% of cases concentrated in municipalities that cover extensive Indigenous territories. These areas have witnessed substantial escalations in deforestation and illegal mining activities over the years.
Defect in Automated Antigen Excess Detection Discovered after Reviewing Serum Free Light Chain Results in Context with Clinical Findings
Authors: Lao Kriselle Maris , Pokharel Ashbita , Elzieny Mai Mohamed Mohamed Ibrahim , Sykes Elizabeth , Truscott Steven M
Published: June 2023

Serum κ and λ free light chains can be markedly elevated in monoclonal gammopathies; consequently, serum free light chain (sFLC) immunoassays are susceptible to inaccuracies caused by antigen excess. As a result, diagnostics manufacturers have attempted to automate antigen excess detection. A 75-year-old African-American woman had laboratory findings consistent with severe anemia, acute kidney injury, and moderate hypercalcemia. Serum and urine protein electrophoresis and sFLC testing were ordered. The sFLC results initially showed mildly elevated free λ light chains and normal free κ. The pathologist noted that sFLC results were discrepant with the bone marrow biopsy, electrophoresis, and immunofixation results. After manual dilution of the serum, repeat sFLC testing revealed significantly higher λ sFLC results. Antigen excess causing falsely low sFLC quantitation may not be detected by immunoassay instruments as intended. Correlation with clinical history, serum and urine protein electrophoresis results, and other laboratory findings is essential when interpreting sFLC results.
Efficient compliance checking of RDF data
Authors: Robaldo Livio , Pacenza Francesco , Zangari Jessica , Calegari Roberta , Calimeri Francesco , Siragusa Giovanni
Published: June 2023

Automated compliance checking, i.e. the task of automatically assessing whether states of affairs comply with normative systems, has recently received a lot of attention from the scientific community, also as a consequence of the increasing investments in Artificial Intelligence technologies for the legal domain (LegalTech). The authors of this paper deem as crucial the research and implementation of compliance checkers that can directly process data in RDF format, as nowadays more and more (big) data in this format are becoming available worldwide, across a multitude of different domains. Among the automated technologies that have been used in recent literature, to the best of our knowledge, only two of them have been evaluated with input states of affairs encoded in RDF format. This paper formalizes a selected use case in these two technologies and compares the implementations, also in terms of simulations with respect to shared synthetic datasets.
Knowledge injection of Datalog rules via Neural Network Structuring with KINS
Authors: Magnini Matteo , Ciatto Giovanni , Omicini Andrea
Published: June 2023

We propose a novel method to inject symbolic knowledge in form of Datalog formulæ into neural networks (NN), called Knowledge Injection via Network Structuring (KINS). The idea behind our method is to extend NN internal structure with ad-hoc layers built out of the injected symbolic knowledge. KINS does not constrain NN to any specific architecture, neither requires logic formulæ to be ground. Moreover, it is robust w.r.t. both lack of data and imperfect/incomplete knowledge. Experiments are reported, involving multiple datasets and predictor types, to demonstrate how KINS can significantly improve the predictive performance of the neural networks it is applied to.
Revealing the Structural Organization of Gamma-irradiated Starch Granules Using Polarization-resolved Second Harmonic Generation Microscopy
Authors: Chen Ming-Chi , Govindaraju Indira , Wang Wei-Hsun , Chen Wei-Liang , Mumbrekar Kamalesh Dattaram , Mal Sib Sankar , Sarmah Bhaswati , Baruah Vishwa Jyoti , Srisungsitthisunti Pornsak , Karunakara Naregundi , Mazumder Nirmal , Zhuo Guan-Yu
Published: June 2023

Starch is a semi-crystalline macromolecule with the presence of amorphous and crystalline components. The amorphous amylose and crystalline amylopectin regions in starch granules are susceptible to certain physical modifications, such as gamma irradiation. Polarization-resolved second harmonic generation (P-SHG) microscopy in conjunction with SHG-circular dichroism (CD) was used to assess the three-dimensional molecular order and inherent chirality of starch granules and their reaction to different dosages of gamma irradiation. For the first time, the relationship between starch achirality (χ21/χ16 and χ22/χ16) and chirality (χ14/χ16) determining susceptibility tensor ratios has been elucidated. The results showed that changes in the structure and orientation of long-chain amylopectin were supported by the decrease in the SHG anisotropy factor and the χ22/χ16 ratio. Furthermore, SHG-CD illustrated the molecular tilt angle by revealing the arrangement of amylopectin molecules pointing either upward or downward owing to molecular polarity.
The magnetic, spectroscopic, and photometric variability of the Wolf–Rayet star WR 55
Authors: Järvinen S P , Hubrig S , Jayaraman R , Cikota A , Schöller M
Published: June 2023

Studies of magnetic fields in the most evolved massive stars, the Wolf–Rayet stars, are of special importance because they are progenitors of certain types of supernovae. The first detection of a magnetic field of the order of a few hundred gauss in the WN7 star WR 55, based on a few FORS2 low-resolution spectropolarimetric observations, was reported in 2020. In this work, we present new FORS2 observations allowing us to detect magnetic and spectroscopic variability with a period of 11.90 h. No significant frequencies were detected in TESS and ASAS-SN photometric observations. Importantly, magnetic field detections are achieved currently only in two Wolf–Rayet stars, WR 6 and WR 55, both showing the presence of corotating interacting regions.
Polycomb protein SCML2 mediates paternal epigenetic inheritance through sperm chromatin
Authors: Sakashita Akihiko , Ooga Masatoshi , Otsuka Kai , Maezawa So , Takeuchi Chikara , Wakayama Sayaka , Wakayama Teruhiko , Namekawa Satoshi H
Published: June 2023

Sperm chromatin retains small amounts of histones, and chromatin states of sperm mirror gene expression programs of the next generation. However, it remains largely unknown how paternal epigenetic information is transmitted through sperm chromatin. Here, we present a novel mouse model of paternal epigenetic inheritance, in which deposition of Polycomb repressive complex 2 (PRC2) mediated-repressive H3K27me3 is attenuated in the paternal germline. By applying modified methods of assisted reproductive technology using testicular sperm, we rescued infertility of mice missing Polycomb protein SCML2, which regulates germline gene expression by establishing H3K27me3 on bivalent promoters with other active marks H3K4me2/3. We profiled epigenomic states (H3K27me3 and H3K4me3) of testicular sperm and epididymal sperm, demonstrating that the epididymal pattern of the sperm epigenome is already established in testicular sperm and that SCML2 is required for this process. In F1 males of X-linked Scml2-knockout mice, which have a wild-type genotype, gene expression is dysregulated in the male germline during spermiogenesis. These dysregulated genes are targets of SCML2-mediated H3K27me3 in F0 sperm. Further, dysregulation of gene expression was observed in the mutant-derived wild-type F1 preimplantation embryos. Together, we present functional evidence that the classic epigenetic regulator Polycomb mediates paternal epigenetic inheritance through sperm chromatin.
TP53 germline pathogenic variants in modern humans were likely originated during recent human history
Authors: Kou Si Hoi , Li Jiaheng , Tam Benjamin , Lei Huijun , Zhao Bojin , Xiao Fengxia , Wang San Ming
Published: June 2023

TP53 is crucial for maintaining genome stability and preventing oncogenesis. Germline pathogenic variation in TP53 damages its function, causing genome instability and increased cancer risk. Despite extensive study in TP53, the evolutionary origin of the human TP53 germline pathogenic variants remains largely unclear. In this study, we applied phylogenetic and archaeological approaches to identify the evolutionary origin of TP53 germline pathogenic variants in modern humans. In the phylogenic analysis, we searched 406 human TP53 germline pathogenic variants in 99 vertebrates distributed in eight clades of Primate, Euarchontoglires, Laurasiatheria, Afrotheria, Mammal, Aves, Sarcopterygii and Fish, but we observed no direct evidence for the cross-species conservation as the origin; in the archaeological analysis, we searched the variants in 5031 ancient human genomes dated between 45045 and 100 years before present, and identified 45 pathogenic variants in 62 ancient humans dated mostly within the last 8000 years; we also identified 6 pathogenic variants in 3 Neanderthals dated 44000 to 38515 years before present and 1 Denisovan dated 158 550 years before present. Our study reveals that TP53 germline pathogenic variants in modern humans were likely originated in recent human history and partially inherited from the extinct Neanderthals and Denisovans.
Multiple meningiomas: Epidemiology, management, and outcomes
Authors: Fahlström Andreas , Dwivedi Shourye , Drummond Katharine
Published: June 2023

Meningiomas are the most common nonmalignant brain tumor in adults, with an increasing incidence of asymptomatic meningiomas diagnosed on more ubiquitous neuroimaging. A subset of meningioma patients bear 2 or more spatially separated synchronous or metachronous tumors termed “multiple meningiomas” (MM), reported to occur in only 1%–10% of patients, though recent data indicate higher incidence. MM constitute a distinct clinical entity, with unique etiologies including sporadic, familial and radiation-induced, and pose special management challenges. While the pathophysiology of MM is not established, theories include independent origin in disparate locations through unique genetic events, and the “monoclonal hypothesis” of a transformed neoplastic clone with subarachnoid seeding precipitating numerous distinct meningiomas. Patients with solitary meningiomas carry the risk of long-term neurological morbidity and mortality, as well as impaired health-related quality of life, despite being a generally benign and surgically curable tumor. For patients with MM, the situation is even less favorable. MM should be regarded as a chronic disease, and in many cases, the management goal is disease control, as cure is seldom possible. Multiple interventions and lifelong surveillance are sometimes necessary. We aim to review the MM literature and create a comprehensive overview, including an evidence-based management paradigm.
The joint impacts of sex and race/ethnicity on incidence of grade 1 versus grades 2–3 meningioma across the lifespan
Authors: Walsh Kyle M , Price Mackenzie , Neff Corey , Komisarow Jordan M , Wimberly Courtney E , Kruchko Carol , Barnholtz-Sloan Jill S , Ostrom Quinn T
Published: June 2023

Background

Previous research has identified older age, African-American race, and female sex as meningioma risk factors, but there is limited information on their joint effects, or on how these demographic factors vary across strata of tumor grade.

Methods

The Central Brain Tumor Registry of the United States (CBTRUS) is a population-based registry combining data from the CDC’s National Program of Cancer Registries and NCI’s Surveillance, Epidemiology and End Results Program which covers ~100% of the U.S. population and aggregates incidence data on all primary malignant and nonmalignant brain tumors. These data were used to explore the joint impacts of sex and race/ethnicity on average annual age-adjusted incidence rates of meningioma. We calculated meningioma incidence rate ratios (IRRs) by sex and race/ethnicity, across strata of age and tumor grade.

Results

Compared to individuals who are non-Hispanic White, individuals who are non-Hispanic Black had significantly higher risk of grade 1 (IRR = 1.23; 95% CI: 1.21–1.24) and grade 2–3 meningioma (IRR = 1.42; 95% CI: 1.37–1.47). The female-to-male IRR peaked in the fifth decade of life across all racial/ethnic groups and tumor grades, but was 3.59 (95% CI: 3.51–3.67) for WHO grade 1 meningioma and 1.74 (95% CI: 1.63–1.87) for WHO grade 2–3 meningioma.

Conclusions

This study reveals the joint effects of sex and race/ethnicity on meningioma incidence throughout the lifespan and across strata of tumor grade, highlighting incidence disparities among females and African-Americans that may inform future strategies for tumor interception.
Bevacizumab, Irinotecan, and Biweekly Trifluridine/Tipiracil for Metastatic Colorectal Cancer: MODURATE, a Phase Ib Study
Authors: Taniguchi Hiroya , Yamazaki Kentaro , Masuishi Toshiki , Kawakami Takeshi , Onozawa Yusuke , Honda Kazunori , Kadowaki Shigenori , Narita Yukiya , Tsushima Takahiro , Hamauchi Satoshi , Todaka Akiko , Yokota Tomoya , Ando Masashi , Mori Keita , Shirasu Hiromichi , Yasui Hirofumi , Muro Kei
Published: June 2023

Background

In this phase Ib study MODURATE, we optimized the dosing schedule and tested the efficacy and safety of trifluridine/tipiracil, irinotecan, and bevacizumab in patients with metastatic colorectal cancer with fluoropyrimidine and oxaliplatin treatment failure.

Methods

We included a dose escalation (3 + 3 design) and an expansion cohort. Patients were administered trifluridine/tipiracil (25-35 mg/m2 twice daily, days 1-5), irinotecan (150–180 mg/m2, day 1), and bevacizumab (5 mg/kg, day 1) every 2 weeks. The recommended phase II dose (RP2D) in the dose escalation cohort was administered to at least 15 patients in both cohorts combined.

Results

Twenty-eight patients were enrolled. Five dose-limiting toxicities were observed. RP2D was defined as trifluridine/tipiracil 35 mg/m2, irinotecan 150 mg/m2, and bevacizumab 5 mg/kg. Of 16 patients who received RP2D, 86% (14/16) experienced grade ≥3 neutropenia without febrile neutropenia. Dose reduction, delay, and discontinuation occurred in 94%, 94%, and 6% of patients, respectively. Three patients (19%) showed partial response and 5 had stable disease for >4 months, with a median progression-free and overall survival of 7.1 and 21.7 months, respectively.

Conclusion

Biweekly trifluridine/tipiracil, irinotecan, and bevacizumab administration may have moderate antitumor activity with high risk of severe myelotoxicity in previously treated patients with metastatic colorectal cancer [UMIN Clinical Trials Registry (UMIN000019828) and Japan Registry of Clinical Trials (jRCTs041180028)].
Unmasking hidden genetic, vocal, and size variation in the Masked Flowerpiercer along the Andes supports two species separated by Northern Peruvian Low
Authors: Martínez-Gómez Silvia C , Lara Carlos Esteban , Remsen J V , Brumfield Robb T , Cuervo Andrés M
Published: June 2023

Genetic divergence among isolated populations is not always reflected in phenotypic differentiation. We investigated the genetic and phenotypic differentiation in Diglossa cyanea (Thraupidae; Masked Flowerpiercer), a widely distributed species in the tropical Andes. We found strong evidence for 2 main lineages separated by the Marañón River valley in the Northern Peruvian Low (NPL). These 2 lineages show a deep sequence divergence in mitochondrial DNA (mtDNA; ~6.7% uncorrected p-distance, n = 122), spectral frequency and song structure (with exclusive final whistles in southern populations, n = 88), and wing length (the northern populations are smaller, n = 364). The 2 divergent D. cyanea mitochondrial lineages were not sister to each other, suggesting a possible paraphyly with respect to D. caerulescens (Bluish Flowerpiercer) that remains to be tested with nuclear genomic data. No genetic variation, size difference, or song structure was observed within the extensive range of the southern group (from the NPL to central Bolivia) or within all sampled northern populations (from the NPL to Venezuela). These vocal differences appear to have consequences for song discrimination, and species recognition, according to a previously published playback experiment study. We propose that the southern taxon be elevated to species rank as D. melanopis, a monotypic species (with the proposed name Whistling Masked-Flowerpiercer). In turn, we provide a redefinition of D. cyanea (Warbling Masked-Flowerpiercer), which is now restricted to the northern half of the tropical Andes as a polytypic species with 3 subspecies (tovarensis, obscura, and cyanea). Based on our results, the subspecies dispar should be treated as a junior synonym of cyanea. Our study highlights the need to continue amassing complementary data sets from field observations, experiments, and collection-based assessments to better characterize the evolutionary history, biogeography, bioacoustics, and taxonomy of Neotropical montane birds.
Gibberellins Promote Seed Conditioning by Up-Regulating Strigolactone Receptors in the Parasitic Plant Striga hermonthica
Authors: Yap Jia Xin , Tsuchiya Yuichiro
Published: June 2023

Dormant seeds of the root parasitic plant Striga hermonthica sense strigolactones from host plants as environmental cues for germination. This process is mediated by a diversified member of the strigolactone receptors encoded by HYPOSENSITIVE TO LIGHT/KARRIKIN INSENSITIVE2 genes. It is known that warm and moist treatment during seed conditioning gradually makes dormant Striga seeds competent to respond to strigolactones, although the mechanism behind it is poorly understood. In this report, we show that plant hormone gibberellins increase strigolactone competence by up-regulating mRNA expression of the major strigolactone receptors during the conditioning period. This idea was supported by a poor germination phenotype in which gibberellin biosynthesis was depleted by paclobutrazol during conditioning. Moreover, live imaging with a fluorogenic strigolactone mimic, yoshimulactone green W, revealed that paclobutrazol treatment during conditioning caused aberrant dynamics of strigolactone perception after germination. These observations revealed an indirect role of gibberellins in seed germination in Striga, which contrasts with their roles as dominant germination-stimulating hormones in non-parasitic plants. We propose a model of how the role of gibberellins became indirect during the evolution of parasitism in plants. Our work also highlights the potential role for gibberellins in field applications, for instance, in elevating the sensitivity of seeds toward strigolactones in the current suicidal germination approach to alleviate the agricultural threats caused by this parasite in Africa.
The current state of neuropalliative care in developing countries. Where are we now?
Authors: Abdul-Rahman Toufik , Badar Sarah M , Ali Mohammed Ahsan , Kundu Mrinmoy , Ademeta Esther , Awuah Wireko Andrew
Published: June 2023

The need for improved palliative care in developing countries is great. Of 58 million people who die every year, 45 million die in developing countries. An estimated 60% (27 million) of these people in poor nations would benefit from palliative care, and this number is growing as chronic diseases such as cancer rise rapidly. Yet a combination of highly restrictive policies on opioid prescription and a lack of awareness within the medical profession conspire to deprive patients of palliative care. Human rights advocates argue that this neglect is a breach of human rights that is tantamount to torture. This editorial explores the neuropalliative approach and addresses the current state of neuropalliative care in developing countries.
Tofacitinib as monotherapy in cutaneous polyarteritis nodosa: a case series
Authors: Roy Debaditya , Sathyanarayana Vanitha Agrahara , Nagaraju Bhavya , Rao Vijay K R
Published: June 2023

Objective

Cutaneous polyarteritis nodosa (CPAN) is a distinct clinical entity represented by a chronic, relapsing, benign course, with rare systemic involvement. Treatment is with CSs, CYC or other conventional synthetic DMARDs (csDMARDs). In this case series, we aimed to share our varied clinical experience of successfully treating patients with CPAN, with tofacitinib in a refractory/relapsing course or as upfront monotherapy without CSs/csDMARDs.

Methods

We report this retrospective case series managed at our rheumatology centre in Bangalore from 2019 to 2022. Four patients identified as CPAN on biopsy were able to achieve disease-free remission with tofacitinib as part of their treatment, with no relapse on further follow-up. Our patients presented with subcutaneous nodules and cutaneous ulcers. After systemic evaluation, all the patients underwent skin biopsy, which showed fibrinoid necrosis in the vessel walls of the dermis, with a histopathological impression of CPAN. They were initially treated with a conventional approach of CSs with/without csDMARDs. On experiencing a refractory/relapsing course, tofacitinib was tried in all the patients as either CS sparing or upfront monotherapy without concomitant csDMARDs.

Results

Use of tofacitinib resulted in improvement of ulcers and paraesthesia and in gradual healing of skin lesions, albeit with scarring, with no further recurrence or relapse over a follow-up period of 6 months for all the patients. The therapeutic effect of tofacitinib was consistent when used either as CS sparing or as upfront monotherapy, thereby proving the drug to be a promising option that warrants larger trials in future to treat the subset of patients with established CPAN.

Conclusion

Tofacitinib could be used for disease-free remission as monotherapy for CPAN either upfront or as CS sparing, even without concomitant csDMARDs, in those patients who are dependent on CSs or multiple DMARDs.
Bioactive nanoglass regulating the myogenic differentiation and skeletal muscle regeneration
Authors: Winston Dagogo Dorothy , Li Ting , Lei Bo
Published: June 2023

Bioactive glass nanoparticles (BGNs) are widely used in the field of biomedicine, including drug delivery, gene therapy, tumor therapy, bioimaging, molecular markers and tissue engineering. Researchers are interested in using BGNs in bone, heart and skin regeneration. However, there is inadequate information on skeletal muscle tissue engineering, limited information on the biological effects of BGNs on myoblasts, and the role of bioactive glass composite materials on myogenic differentiation is unknown. Herein, we report the effects of BGNs with different compositions (60Si-BGN, 80Si-BGN, 100Si-BGN) on the myogenic differentiation in C2C12 cells and in vivo skeletal tissue regeneration. The results showed that 80Si-BGN could efficiently promote the myogenic differentiation of C1C12 cells, including the myotube formation and myogenic gene expression. The in vivo experiment in a rat skeletal muscle defect model also confirmed that 80Si-BGN could significantly improve the complete regeneration of skeletal muscle tissue during 4 weeks implantation. This work firstly demonstrated evidence that BGN could be the bioactive material in enhancing skeletal muscle regeneration.
The Darwinian Returns to Scale
Authors: Baqaee David Rezza , Farhi Emmanuel , Sangani Kunal
Published: June 2023

How does an increase in market size, say due to globalization, affect welfare? We study this question using a model with monopolistic competition, heterogeneous markups, and fixed costs. We characterize changes in welfare and decompose changes in allocative efficiency into three different effects: (1) reallocations across firms with heterogeneous price elasticities due to intensifying competition, (2) reallocations due to the exit of marginally profitable firms, and (3) reallocations due to changes in firms’ markups. Whereas the second and third effects have ambiguous implications for welfare, the first effect, which we call the Darwinian effect, always increases welfare regardless of the shape of demand curves. We nonparametrically calibrate demand curves with data from Belgian manufacturing firms and quantify our results. We find that mild increasing returns at the microlevel can catalyze large increasing returns at the macrolevel. Between 70 and 90% of increasing returns to scale come from improvements in how a larger market allocates resources. The lion’s share of these gains are due to the Darwinian effect, which increases the aggregate markup and concentrates sales and employment in high-markup firms. This has implications for policy: an entry subsidy, which harnesses Darwinian reallocations, can improve welfare even when there is more entry than in the first best.