bluuebunny/crossref_metadata_2025 huggingface dataset:
Emerging enzyme surface display systems for waste resource recovery
Authors: Davenport Beth , Hallam Steven J.
Published: November 2022

The current century marks an inflection point for human progress, as the developed world increasingly comes to recognize that the ecological and socioeconomic impacts of resource extraction must be balanced with more sustainable modes of growth that are less reliant on non‐renewable sources of energy and materials. This has opened a window of opportunity for cross‐sector development of biotechnologies that harness the metabolic problem‐solving power of microbial communities. In this context, recovery has emerged as an organizing principal to create value from industrial and municipal waste streams, and the search is on for new enzymes and platforms that can be used for waste resource recovery at scale. Enzyme surface display on cells or functionalized materials has emerged as a promising platform for waste valorization. Typically, surface display involves the use of substrate binding or catalytic domains of interest translationally fused with extracellular membrane proteins in a microbial chassis. Novel display systems with improved performance features include S‐layer display with increased protein density, spore display with increased resistance to harsh conditions, and intracellular inclusions including DNA‐free cells or nanoparticles with improved social licence for in situ applications. Combining these display systems with advances in bioprinting, electrospinning and high‐throughput functional screening have potential to transform outmoded extractive paradigms into ‘trans‐metabolic” processes for remediation and waste resource recovery within an emerging circular bioeconomy.
Disability policy and practice in Malawian employment and education
Authors: Wånggren Lena , Remnant Jen , Huque Sarah , Kachali Limbani , Sang Katherine J. C. , Ngwira Jenipher
Published: November 2022

Malawi is a landlocked country in Southern Africa with a population of 17.5 million. It has taken great strides in addressing disability inequality in recent years. Despite this, Malawian trade unions, educators and disability activists report wide‐reaching disability discrimination at an infrastructural and individual level. Situated at the intersections between disability studies and medical sociology, alongside work of postcolonial and Global South scholars, this article highlights how neo‐colonial and Anglocentric dominant framings of disability do not necessarily fit the Malawian workforce, as they ignore cultural and structural differences in the causes and maintenance of ill health and disability. Building on interviews with workers with disabilities, trade unionists, educators, government representatives and disability activists in Malawi’s two biggest cities, the article emphasises the need to address specific local contexts; while policy asserts a model of social oppression, in practice, disability inclusion requires recognition of the social determinants of disability and inequality, and the economic, political and cultural context within which disability resides. Sharing co‐designed approaches to engaging with disability definitions, stigma, language, infrastructure and resources, this article highlights the necessity of grounding disability and medical sociological theory in localised framings and lived experiences.
Exploring the sensory properties of buffalo (Bubalus bubalis) milk custards through a consumer‐based study performed with children
Authors: Vasile Franco Emanuel , Hryczyñski Lis Marlene , Fernandez Andrea Beatriz , Bustos Leandro Fabián , Romero Ana María , Mazzobre María Florencia
Published: November 2022

This work aimed to evaluate the impact of buffalo milk and nondairy ingredients on sensory properties and acceptability of custards intended for children. For this, a consumer study with 100 children aged 8 to 12 was performed. Three custard models were formulated using buffalo milk and variable amounts of corn starch, sucrose and colourant/flavouring. Compositional, mechanical and chromatic properties of custards were related to sensory characteristics and overall liking scores. Obtained results allowed understanding the consumers' preferences and identifying the drivers of liking. Buffalo milk constitutes a promising raw material for the formulation of custard intended for children.
Dioxins and furans in cow milk and dairy products: A review of the scientific literature
Authors: Domingo Jose L
Published: November 2022

Polychlorinated dibenzo‐p‐dioxins and dibenzofurans (PCDD/Fs) are a group of persistent organic pollutants with well‐known toxic effects and potential carcinogenicity. Human exposure to PCDD/Fs is mainly through food, including dairy products. The scientific information on the concentrations of PCDD/Fs in milk and dairy products is here reviewed. It also includes the intake of PCDD/Fs through the consumption of these products. PCDD/Fs concentrations in milk and dairy products are currently decreasing. A similar trend is also noted for their contributions to the total dietary intake of PCDD/Fs. No significant health risks due to exposure to PCDD/Fs through the consumption of dairy products are expected.
Preventive care visits with OB/GYNs and generalist physicians among reproductive‐age women with chronic conditions
Authors: Attanasio Laura , Ranchoff Brittany , Jeung Chanup , Goff Sarah , Geissler Kimberley
Published: November 2022

Objective

To examine services delivered during preventive care visits among reproductive‐age women with and without chronic conditions by physician specialty.

Data Sources

National Ambulatory Medical Care Surveys (2011–2018).

Study Design

We examined provision of specific services during preventive care visits by physician specialty among reproductive‐age female patients, overall and among women with five common chronic conditions (diabetes, hypertension, depression, hyperlipidemia, and asthma).

Data Collection/Extraction Methods

The sample included preventive visits to OB/GYNs or generalist physicians where the patient was female, age 18–44, and not pregnant.

Principal Findings

In OB/GYN preventive visits, reproductive health services were more likely to be provided, while non‐reproductive health services were less likely to be provided, both among reproductive‐age female patients overall and among those with chronic conditions. For example, pap tests were provided in 44.5% of OB/GYN preventive visits (95% CI: 40.6–48.4) and in 21.4% of generalist preventive visits (95% CI: 17.2–26.6). Lipid testing was provided in 2.8% of OB/GYN preventive visits (95% CI: 1.7–3.9) and in 30.3% of generalist preventive visits (95% CI: 26.1–34.6).

Conclusions

Understanding the full range of care received in preventive visits across settings could guide recommendations to optimize where reproductive‐age women with chronic conditions seek care.
Correlation of soft tissue and skeletal injuries in cases of violent death: A retrospective study of autopsy cases for forensic anthropology
Authors: Collini Federica , Muccino Enrico , Biehler‐Gomez Lucie , Cummaudo Marco , F. Gorio Maria Carlotta , Cattaneo Cristina
Published: November 2022

In forensic pathology, deaths due to mechanical injuries (blunt, sharp, and gunshot) require an autopsy in order to determine the cause and manner of death through a detailed examination of viscera, soft tissues, and the skeletal system. Sometimes, such as in cases of severe putrefaction, only the skeleton is observable. In such cases, the absence of bony defects does not mean that a trauma‐related death should not be considered: yet, how often will a lethal mechanical death produce a defect in the skeletal system? The present study involved a retrospective review of autopsy reports to investigate the frequencies of soft tissue and related skeletal injuries in cases of violent deaths. A total of 200 autopsy reports for cases of four mechanisms of injury including sharp force trauma (n = 50), gunshot (n = 50), blunt force trauma (n = 50), and mechanical asphyxia (n = 50) were examined. Manner of death, localization of bone fractures, and correspondence between external injuries and bone fractures were reported. Frequencies of bone fractures and degree of correspondence with soft tissue injuries for each trauma group were evaluated. The result showed that lethal blunt trauma always caused bone fractures; 94.0% of violent deaths by gunshot involved bones; 48.0% of sharp force soft tissue injuries involved the bone tissue; and hyoid bone fractures were observed in 20.0% of cases of mechanical asphyxia.
Geochronology, Geochemistry, Fluid Inclusion and C, O Isotope Compositions of Calcite Veins in the Paleogene of the Jiangling Basin, South China: Implications for Fluid Evolution and Brine Potash Mineralization
Authors: YU Xiaocan , WANG Chunlian , LIU Chenglin , WANG Jiuyi , SHEN Lijian
Published: November 2022

Deep‐seated potassium‐rich brines were identified in the Jiangling Basin, South China. Although magmatic‐hydrothermal sources have been proposed, the relationship between brine‐type potash mineralization and volcanism remains unclear. In this study, U‐Pb geochronology, geochemistry, fluid inclusion and C‐O isotopic compositions of hydrothermal vein minerals in the Jiangling Basin are examined. Laser ablation U‐Pb dating of calcite veins indicates that the ages are slightly younger than the formation age of the Balingshan basalt. Fluid inclusions in hydrothermal minerals show medium–low homogenization temperatures (160–220°C) and low salinities (0.14 to 4.9 wt% NaCl eqv.) and densities (0.882–0.944 g/cm3). The liquid compositions of fluid inclusions in calcite veins from sedimentary strata have higher contents of potassium, compared with those from basalt. The coupled negative δ13CPDB (–10.3‰ to −8.0‰) and positive δ18OSMOW (17.4‰ to 20.7‰) values imply that calcite precipitation resulted from CO2 degassing of the basaltic magmatic fluids, as indicated by the gas composition of these inclusions in hydrothermal minerals. Rare earth element patterns indicate that water‐rock interaction between hydrothermal fluids and sedimentary wall rocks contributed to the calcite precipitation in sedimentary strata. It is proposed that high‐temperature water‐rock interaction between magmatic fluids and sedimentary strata resulted in the potassium enrichment in fluids, interpreted as one of the sources of potassium‐rich brines in the Jiangling Basin.
Palynological Evidence of Late Pleistocene Soft‐sediment Deformation Event in the Northeastern Margin of the Tibetan Plateau
Authors: WEI Lijie , LI Zhenhong , DONG Xiaopeng , CUI Jiawei , HUANG Ting , KOU Linlin
Published: November 2022

The northeastern margin of the Tibetan Plateau is the youngest part of the Tibetan Plateau where tectonic activity is intense and climate change is complex. In this study, combined with field investigations, we explored accelerator mass spectrometry 14C and optically stimulated luminescence dating and palynological analysis of the sedimentary sequence in the Qingshuihe Basin to explain the origin of soft‐sediment deformation layer. Dating and palynological results from the Sanchahe section in the basin revealed a detailed history of vegetation variation and associated climate change from ∼18 to ∼5 ka BP. The results indicate that the permafrost developed at ∼18–11.7 ka BP, and the soft‐sediment deformation structures formed at ∼11.7–5 ka BP. Together with the characteristics of the deformation (meter‐scale, continuous symmetrical wave) and paleoclimate, we suggest that the soft‐sediment deformation layer in the late Pleistocene was cryoturbated under climatic conditions. The discovery of a series of cryoturbations in the Qingshuihe Basin has further enriched the regional distribution of periglacial phenomena in the west of the Ordos Plateau, expanded the distribution range of periglacial phenomena, and provided evidence for exploring the temporal and spatial changes in permafrost in northern China at the end of the late Pleistocene.
Genesis of the Sinongduo Carbonate‐hosted Pb‐Zn‐Ag Deposit in the Central Lhasa Terrane, Tibet
Authors: RAN Fengqin , TANG Juxing , YANG Zongyao , DUO Ji , REN Dongxing , GUO Wenbo , WU Xin , HAO Jinyue , HE Yifei , SUN Yang
Published: November 2022

The Sinongduo mining region includes two types of mineralizations: the epithermal and the carbonate‐hosted Pb‐Zn‐Ag deposits. Despite being studied for many years, the ore formation process and genesis of the carbonate‐hosted Pb‐Zn‐Ag deposits remain poorly understood. The Pb‐Zn‐Ag ore bodies occur as veins and are hosted by limestone and dolostone of the Permian Xiala Formation. Three sulfide mineralization substages have been identified at the Sinongduo carbonate‐hosted deposit. Indium coupled with Cu, Co and Sn was incorporated into sphalerite as substitutions: 2Zn2+ ↔ Cu+ + In3+, (3n/2 + 1)Zn2+ ↔ Co2+ + nIn3+ or (2n + 1)Zn2+ ↔ Co2+ + n(Cu+ + In3+) (n > 1) and 4Zn2+ ↔ Sn2+ + 2In3+. Sphalerite and pyrite in the mineralization stage display δ34S values in a narrow range of +5.7‰ to +11.3‰, which are similar to those of Palaeocene igneous rocks, indicative of a magmatic source of sulfur. We present systematic carbon‐hydrogen‐oxygen isotope results that further support a magmatic source for the ore‐forming fluids that were influenced by meteoric water. Furthermore, the Pb isotope compositions of sulfide minerals in the Sinongduo carbonate‐hosted deposit overlap with the values of coeval Linzizong volcanic rocks and are similar to those of Indian Ocean sediments, indicating upper crustal sources of metals. We conclude that the Sinongduo carbonate‐hosted Pb‐Zn‐Ag deposit is a medium‐ to low‐temperature magmatic‐hydrothermal deposit related to Linzizong magmatism.
Real‐world outcomes of anti‐EGFR therapy in advanced non–small cell lung cancer EGFR mutated in Peru
Authors: Galvez‐Nino Marco , Ruiz Rossana , Roque Katia , Coanqui Ofelia , Valdivieso Natalia , Olivera Mivael , Ganti Apar Kishor , Mas Luis
Published: November 2022

Background

Despite the advances in the management of advanced non–small cell lung cancer (NSCLC), the access to genetic profiling and target therapies remains a challenge in Latin America, even in countries with a higher rate of targetable mutations. The aim of this study is to evaluate the clinical outcomes of anti‐epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) treatment in a Peruvian real‐world setting.

Methods

This is a retrospective study of recurrent or advanced NSCLC EGFR mutated patients diagnosed and treated with anti‐EGFR TKI at Instituto Nacional de Enfermedades Neoplásicas (INEN) between January 1, 2015 to December 31, 2020. The outcomes were objective response rate (ORR), progression free survival (PFS), and overall survival (OS).

Results

We identify 613 stage IV or recurrent NSCLC patients who were tested for EGFR mutations and found a pathogenic mutation in 39.5% of patients. Only 51.2% of them received anti‐EGFR TKI as institutional treatment. ORR was 58%, after median follow‐up of 32 months, the estimated median PFS was 13.9 months (11.1–16.7 months), and the estimated median OS was 21.7 months (18.5–24.9 months). No differences were found in PFS according to line of treatment or brain metastases at diagnosis (p = 0.46 and p = 0.07, respectively), respect to OS there were no differences line of treatment (p = 0.12), significant difference were found in presence of brain metastases (p = 0.006).

Conclusion

Our study demonstrates that erlotinib for advanced NSCLC harboring EGFR‐activating mutations is effective even in patients usually excluded from clinical trial, like those previously exposed to one or more lines of chemotherapy or with brain metastases.
A single‐nucleus transcriptomics study of alcohol use disorder in the nucleus accumbens
Authors: van den Oord Edwin J. C. G. , Xie Lin Y. , Zhao Min , Aberg Karolina A. , Clark Shaunna L.
Published: November 2022

Gene expression studies offer promising opportunities to better understand the processes underlying alcohol use disorder (AUD). As cell types differ in their function, gene expression profiles will typically vary across cell types. When studying bulk tissue, failure to account for this cellular diversity has a detrimental impact on the ability to detect disease associations. We therefore assayed the transcriptomes of 32,531 individual nuclei extracted from the nucleus accumbens (NAc) of nine donors with AUD and nine controls (72% male). Our study identified 17 clearly delineated cell types. We detected 26 transcriptome‐wide significant differentially expressed genes (DEGs) that mainly involved medium spiny neurons with both D1‐type and D2‐type dopamine receptors, microglia (MGL) and oligodendrocytes. A higher than expected number of DEGs replicated in an existing single nucleus gene expression study of alcohol dependence in the prefrontal cortex (enrichment ratio 1.91, p value 0.019) with two genes remaining significant after a Bonferroni correction. Our most compelling result involved CD53 in MGL that replicated in the same cell type in the prefrontal cortex and was previously implicated in studies of DNA methylation, bulk gene expression and genetic variants. Several DEGs were previously reported to be associated with AUD (e.g., PER1 and MGAT5). The DEGs for MSN.3 seemed involved in neurodegeneration, disruption of circadian rhythms, alterations in glucose metabolism and changes in synaptic plasticity. For MGL, the DEGs implicated neuroinflammation and immune‐related processes and for OLI, disruptions in myelination. This identification of the specific cell‐types from which the association signals originate will be key for designing proper follow‐up experiments and, eventually, novel clinical interventions.
Toward an ontology of identity‐related constructs in addiction, with examples from nicotine and tobacco research
Authors: Notley Caitlin , West Robert , Soar Kirstie , Hastings Janna , Cox Sharon
Published: November 2022

Background and aims

We aimed to create a basic set of definitions and relationships for identity‐related constructs, as part of the Addiction Ontology and E‐Cigarette Ontology projects, that could be used by researchers with diverse theoretical positions and so facilitate evidence synthesis and interoperability.

Methods

We reviewed the use of identity‐related constructs in psychological and social sciences and how these have been applied to addiction with a focus on nicotine and tobacco research. We, then, used an iterative process of adaptation and review to arrive at a basic set of identity‐related classes with labels, definitions and relationships that could provide a common framework for research.

Results

We propose that ‘identity’ be used to refer to ‘a cognitive representation by a person or group of themselves’, with ‘self‐identity’ referring to an individual's identity and ‘group identity’ referring to an identity held by a social group. Identities can then be classified at any level of granularity based on the content of the representations (e.g. ‘tobacco smoker identity’, ‘cigarette smoker identity’ and ‘vaper identity’). We propose distinguishing identity from ‘self‐appraisal’ to capture the distinction between the representation of oneself (e.g. as an ‘ex‐smoker’) and (i) the importance and (ii) the positive or negative evaluation that we attach to what is represented. We label an identity that is appraised as enduring as a ‘core identity’, related to ‘strong identity’ because of the appraisal as important. Identities that are appraised positively or negatively involve ‘positive self‐appraisal’ and ‘negative self‐appraisal’ respectively. This allows us to create ‘logically defined classes’ of identity by combining them (e.g. ‘positive core cigarette smoker identity’ to refer to a cigarette smoker self‐identity that is both positive and important). We refer to the totality of self‐identities of a person as a ‘composite self‐identity’.

Conclusions

An ontology of identity constructs may assist in improving clarity when discussing theories and evidence relating to this construct in addiction research.
Behavioral excess and disruptive conduct: A historical and taxonomic approach to the origin of the ‘impulse control disorders’ diagnostic construct
Authors: Fusaroli Michele , Pellegrini Luca , Fusaroli Riccardo , Raschi Emanuel , Menchetti Marco , Poluzzi Elisabetta
Published: November 2022

Aims

Impulse control disorders (ICDs) are iatrogenic and idiopathic conditions with psychosocial and economic consequences for the affected individuals and their families (e.g. bankruptcy and divorce). However, the definition of ICDs has changed over time, and ICDs are not consistently included within existing taxonomies. We discuss the origins of the ICD diagnostic construct and its unsolved tensions.

Methods

To contextualize the ICD diagnostic construct, we provided an overview of its origins in past centuries and followed its development across multiple editions of the Diagnostic and Statistical Manual and the International Classification of Diseases, as well as its definition within emerging ontologies.

Results

Two independent roots of the ICD construct emerged: (a) the interest in behavioral excess as expressed in encyclopedic compilations (18th century) and (b) the juridical debate on disruptive conduct and responsibility (19th–20th centuries). These roots underlie the repeated taxonomic remodeling observed throughout the 20th and 21st centuries and three critical issues persisting in both clinical practice and research. First, the number of ICDs keeps increasing across the spectrum of human behaviors, disregarding common pathogenetic and phenomenological grounds. Secondly, ICDs substantially overlap with other mental conditions. Impulsivity is often neglected as a minor inconvenience or side effect when co‐occurring with major diagnoses (e.g. depression) and therefore inadequately managed. Finally, ICDs’ definitions display an unsolved tension between being conceived as hobby, moral fault or pathological drive, which may be responsible for stigma and delayed intervention.

Conclusion

The reasons that made impulse control disorders (ICDs) difficult to define from their first conceptualization are the same reasons that now complicate taxonomic efforts and diagnosis. Tracing back ICDs’ roots and criticalities can help to define a common and less ambiguous theoretical framework, which may also result in the demise of the ICD construct and a move towards more clearly defined and more useful ontologies.
Clinical outcomes of non‐surgical root canal obturations using NeoMTA: A retrospective series of case reports
Authors: Walsh Ryan M. , Attar Sayeed , Turner Casey L. , Pistocchi Robert , Allen Lauren , Woodmansey Karl F.
Published: November 2022

NeoMTA is a commercially available tricalcium silicate‐based cement intended for contact with pulp and periradicular tissues. The purpose of this study was to retrospectively evaluate the outcomes of non‐surgical root canal treatments with NeoMTA obturations. Patients were treated in a private endodontic practice between 2015 and 2018. All cases, including initial treatments and retreatments, were either fully obturated with NeoMTA, or using gutta‐percha with NeoMTA as an endodontic sealer. Outcomes were assessed using follow‐up examination data with digital periapical radiographs with a minimum of a 1‐year recall. Teeth were classified based on the clinical examination as: healed/healing (success), or non‐healed (failure). 265 teeth were included with an average follow‐up time of 1.3 years. The overall success rate was 91.7%. Only the presence of a pre‐operative periapical radiolucency was found to significantly affect success. Comparison of obturation techniques demonstrated no effect on outcomes. NeoMTA is suitable for endodontic obturation.
Circ_0000471 suppresses the progression of ovarian cancer through mediating mir‐135b‐5p/dusp5 axis
Authors: Yu Shanshan , Yu Maowen , Chen Jianjun , Tang Hongbo , Gong Wuqing , Tan Hui
Published: November 2022

Background

Ovarian cancer (OC) is a common gynecologic cancer with high incidence and mortality. We attempted to investigate the role of circular RNA_0000471 (circ_0000471) in OC progression and its associated mechanism.

Methods

Reverse transcription‐quantitative polymerase chain reaction (RT‐qPCR) and western blot assay were conducted to measure RNA and protein expression, respectively. Cell proliferation was analyzed by Cell Counting Kit‐8 (CCK8) assay, colony formation assay, and 5‐Ethynyl‐2′‐deoxyuridine (EdU) assay. Cell apoptosis was assessed by flow cytometry. Cell migration and invasion were analyzed by wound healing assay and transwell assay, respectively. Dual‐luciferase reporter assay and RNA immunoprecipitation (RIP) assay were conducted to verify the target relationships. Xenograft tumor model was established to assess the role of circ_0000471 on tumor growth in vivo.

Results

Circ_0000471 expression was down‐regulated in OC tissues and cell lines. Circ_0000471 overexpression blocked the proliferation, migration, and invasion and triggered the apoptosis of OC cells. Circ_0000471 served as a molecular sponge for microRNA‐135b‐5p (miR‐135b‐5p), and circ_0000471 overexpression‐mediated anti‐tumor influences in OC cells were largely reversed by the overexpression of miR‐135b‐5p. Dual specificity phosphatase 5 (DUSP5) was a target of miR‐135b‐5p, and miR‐135b‐5p silencing‐induced anti‐tumor effects were largely counteracted by the interference of DUSP5. Circ_0000471 increased DUSP5 expression by sponging miR‐135b‐5p in OC cells. Circ_0000471 overexpression restrained the growth of xenograft tumors in vivo.

Conclusion

Overexpression of circ_0000471 inhibited OC development by targeting miR‐135b‐5p/DUSP5 axis, indicating that circ_0000471 may be a new potential target for OC treatment.
Identifying best‐practice features of diabetic retinopathy treatment models for Aboriginal and Torres Strait Islander Australians
Authors: Gilden Rosamond , McKenzie Rosemary , Anjou Mitchell D.
Published: November 2022

Objective

Indigenous Australians are nearly three times more likely to have diabetes than non‐Indigenous Australians. The prevalence of diabetes‐related vision impairment for Indigenous Australians is 5.5% compared to 1.5% for non‐Indigenous Australians, and treatment rates are lower for Indigenous Australians. Despite this situation, there is limited evidence on effective service delivery models for diabetic retinopathy care and treatment. This study seeks to identify best‐practice features of diabetic retinopathy care that could be used to inform current and future service delivery models for Indigenous Australians with diabetic retinopathy.

Setting

All states, territories and geographic remoteness categories in Australia.

Participants

Eight ophthalmologists engaged in providing eye healthcare to Indigenous Australians.

Design

Semi‐structured interviews were conducted. The Framework Approach was used to conduct a thematic analysis of the interviews to facilitate identification of key themes and issues that emerged from these discussions.

Results

Seven best‐practice features for service delivery of diabetic retinopathy treatment for Indigenous Australians were identified. These were: cultural safety, affordability and accessibility, partnerships with key stakeholders, timeliness, integration with primary care, clarity of guidelines, and clinician attitude and motivation.

Conclusion

The findings from this study identified seven best‐practice features for diabetic retinopathy treatment. These have the potential to inform and influence how care is delivered to Indigenous Australians. Although further research is warranted to capture other service provider inputs and Indigenous end‐user perspectives, these features in the meantime can begin to inform the decisions of the Indigenous eyecare sector on policy reforms and best‐practice diabetic retinopathy treatment approaches.
Prognostic significance of age on superficial spreading melanoma after resection: lessons from SEER database involving 12 536 patients
Authors: Sun Jie , Zhou Jie‐Song , Wang Yu‐Chong , Dai Hai‐Ying , Sun Meng‐Yan , Lv Chuan
Published: November 2022

Background

This study sought to analyse the impact of elderly age on long‐term prognosis of superficial spreading melanoma (SSM) after surgery.

Methods

A population‐based cohort of patients undergoing resection for SSM from 2004 to 2015 was collected, using data from National Cancer Institute‘ Surveillance, Epidemiology, and End Results (SEER)* Stat software. Patients were divided into the non‐elderly group (≤70 years) and elderly group (>70 years). Baseline characteristics and long‐term survivals were compared between the two groups. A 1:1 propensity score matching (PSM) was used to reduce the risk of bias. The impact of the elderly age on overall survival (OS) and cause‐specific mortality (CSM) was estimated by Cox‐regression and competing‐risk regression models.

Results

Among 12 536 patients with SSM after resection included into the cohort, 8664 patients were ≤70 years, and 3872 were >70 years. Patients in the elderly group had higher incidences of multiple tumours, worse tumour stage and infiltration degree, lymphatic metastasis, and larger size of primary lesions. Using PSM, 3581 pairs of patients were created. On matched analysis, the elderly group was associated with worse OS and CSM. On multivariable Cox‐regression and competing‐risk regression analyses, elderly age was identified as an independent risk factor of OS and CSM after adjusting for other prognostic variables.

Conclusions

The elderly age of patients was independently associated with worse OS and CSM after resection of SSM when baseline and tumour characteristics were balanced. Adjuvant therapy and individualized strategy on follow‐up should be made for elderly patients after resection of SSM.
Surgical management of injured ADF personnel deployed to Afghanistan 2001–2021
Authors: Pilgrim Charles H. C. , Brennan Leonard
Published: November 2022

Introduction

A comprehensive review of the surgical management of injuries sustained by deployed members of the Australian Defence Force (ADF) during Operation SLIPPER and HIGHROAD in Afghanistan has not previously been undertaken. Understanding the mechanism of injury, injury types sustained and surgical intervention undertaken should provide valuable information for future health planning and surgical capability determination.

Methods

Retrospective chart review of scanned medical records of injured personnel identified through casualty register examination was undertaken.

Results

There were 259 ADF personnel injured in Afghanistan between January 2002 and December 2021, of which 53 were seriously (SI), or very seriously injured (VSI). Case notes for 90 of 101 casualties including those sustaining VSI, SI and those classified as being in satisfactory condition, but likely requiring surgery and/or returned to Australia following trauma, were available for review. Most patients with VSI/SI required surgery (93%) and most were returned to Australia following injury (91%). Almost two‐thirds (64.4%) of initial surgery was undertaken at a Role 2 E medical treatment facility (MTF). Gun‐shot wound (GSW) was the commonest injuring mechanism (47%) followed by blast injury (39.6%). Orthopaedic (32.2%) and soft tissue initial wound surgery (47.1%) were the commonest surgical procedures.

Discussion

Surgical management of military trauma was undertaken at multiple sites by multiple surgical teams from different nationalities delivering exceptional results and conforming to modern principles of damage control surgery. The military trauma system is distinctly different from its civilian counterpart with dispersion of assets requiring multiple episodes of casualty movement between echelons of care rather than centralization at level 1 trauma centres. Despite this, excellent results are achievable. Strengthening lines of communication and documentation would reinforce the ability of the military trauma system to continue to provide such results, and regular oversight and review of surgical caseload would align military trauma surgery with civilian standards. The benchmark set by the United States Department of Defense Trauma Registry should be replicated for Australian led combat operations and modified to facilitate interoperability to support future coalition combat operations.
Evaluation of treosulfan cumulative exposure in paediatric patients through population pharmacokinetics and dosing simulations
Authors: Rosser Sebastian P. A. , Lee Samiuela , Kohli Shruti , Keogh Steven J. , Chung Jason , O'Brien Tracey , Fraser Christopher , McLachlan Andrew J. , Shaw Peter J. , Nath Christa E.
Published: November 2022

Aim

To investigate the pharmacokinetics (PK) of intravenous treosulfan in paediatric patients undergoing haematopoietic stem cell transplantation (HSCT) for a broad range of diseases and to explore the impact of different dosing regimens on treosulfan exposure (area under the concentration–time curve, AUC0→∞) through dosing simulations.

Methods

A prospective multicentre PK study was conducted using treosulfan concentration data (n = 423) collected from 53 children (median age 3.5, range 0.2–17.0 years) receiving three daily age‐guided doses (10–14 g/m2). Population PK modelling was performed using NONMEM software, utilising a stepwise forward selection backward elimination method and likelihood‐ratio test for screening covariates to describe PK variability. Monte Carlo simulation was used to generate patient PK data for 10 000 virtual paediatric patients and cumulative AUC0→∞ values were evaluated using age, body surface area (BSA) and model‐based dosing regimens, targeting 4800 mg*h/L.

Results

Treosulfan concentration data were described using a one‐compartment PK model with first‐order elimination. Population mean (95% CI) estimates for clearance (CL) and volume of distribution (V) were 16.3 (14.9–18.1) L/h and 41.9 (38.8–45.1) L, respectively. Allometrically scaled body weight was the best covariate descriptor for CL and V, and maturational age further explained variability in CL. Dosing simulations indicated that in young patient groups (<2 years), a model‐based dosing regimen more accurately achieved the target AUC0→∞ (58.3%) over the age (42.6%) and BSA‐based (51.3%) regimens.

Conclusion

Treosulfan disposition was described through allometric body weight and maturational age descriptors. Model‐informed dosing is recommended for patients under 2 years. Treosulfan PK parameters and AUC0→∞ were not influenced by patient disease.
Artesunate, a new antimalarial clinical drug, exhibits potent anti‐AML activity by targeting the ROS/Bim and TFRC/Fe2+ pathways
Authors: Liu Yi , Li Han , Luo Zhihong , Yu You , Yang Jingzhao , Zhang Min , Law Betty Yuen Kwan , Huang Zan , Li Wenhua
Published: November 2022

Background and Purpose

Artesunate, approved by the Food and Drug Administration in 2020 as a new treatment for severe malaria, also shows anti‐tumour activity against acute myeloid leukaemia (AML). However, the underlying molecular mechanism(s) of artesunate‐induced apoptosis and differentiation of AML is not clearly elucidated.

Experimental Approach

The biological effects of artesunate on AML were explored in vitro, using cells from AML patients and leukaemia cell lines, and in vivo, using female C57BL/6 or nude nu/nu BALB/c mice. Underlying mechanisms in vitro were examined with the Trypan blue dye exclusion assay, western blotting and flow cytometry. Effects of artesunate in C57BL/6 mice intravenously injected with murine AML cells (C1498‐GFP) were assessed by numbers of AML cells and by survival.

Key Results

In vitro, artesunate promoted apoptosis and differentiation in both leukaemia cell lines and patient‐derived primary leukaemia cells. Mechanistically, artesunate promoted cell apoptosis by triggering reactive oxygen species (ROS) production and increasing expression of the pro‐apoptotic protein Bim. Interestingly, transferrin receptor 1 (TFRC)‐mediated regulation of intracellular iron homeostasis also played an essential role in AML cell differentiation induced by artesunate. In vivo, artesunate slowed AML progression and prolonged survival in a mouse leukaemia model. Notably, artesunate displayed no apparent toxicity towards healthy haematopoietic stem cells, bone marrow mononuclear cells or experimental animals.

Conclusion and Implications

Artesunate is a safe agent with significant anti‐leukaemia effects in mice and may serve as a promising chemotherapeutic strategy for patients with AML, based on two different mechanisms, targeting the ROS/Bim and the TFRC/Fe2+ pathways.
Transcriptional regulation of NDUFA4L2 by NFIB induces sorafenib resistance by decreasing reactive oxygen species in hepatocellular carcinoma
Authors: Zhou Li , Mao Lin‐Hong , Li Xia , Wang Qing‐Liang , Chen Si‐Yuan , Chen Zhi‐Ji , Lei Jing , Liu Hong‐Tao , Liao Si‐Qi , Ran Tao , Li Xiao‐Qin , Zhou Zhi‐Hang , He Song
Published: November 2022

Sorafenib is one a first‐line therapeutic drugs for advanced hepatocellular carcinoma (HCC). However, only 30% of patients benefit from sorafenib due to drug resistance. We and other groups have revealed that nuclear factor I B (NFIB) regulates liver regeneration and carcinogenesis, but its role in drug resistance is poorly known. We found that NFIB was more upregulated in sorafenib‐resistant SMMC‐7721 cells compared to parental cells. NFIB knockdown not only sensitized drug‐resistant cells to sorafenib but also inhibited the proliferation and invasion of these cells. Meanwhile, NFIB promoted the proliferation and invasion of HCC cells in vitro and facilitated tumor growth and metastasis in vivo. Knocking down NFIB synergetically inhibited tumor growth with sorafenib. Mechanically, gene expression profiling and subsequent verification experiments proved that NFIB could bind with the promoter region of a complex I inhibitor NDUFA4L2 and promote its transcription. Transcriptional upregulation of NDUFA4L2 by NFIB could thus inhibit the sorafenib‐induced reactive oxygen species accumulation. Finally, we found that NFIB was highly expressed in HCC tissues, and high NFIB expression level was associated with macrovascular invasion, advanced tumor stage, and poor prognosis of HCC patients (n = 156). In summary, we demonstrated that NFIB could transcriptionally upregulate NDUFA4L2 to enhance both intrinsic and acquired sorafenib resistance of HCC cells by reducing reactive oxygen species induction.
Pembrolizumab in Asian patients with microsatellite‐instability‐high/mismatch‐repair‐deficient colorectal cancer
Authors: Yoshino Takayuki , Andre Thierry , Kim Tae Won , Yong Wei Peng , Shiu Kai‐Keen , Jensen Benny Vittrup , Jensen Lars Henrik , Punt Cornelis J. A. , Smith Denis , Garcia‐Carbonero Rocio , Alcaide‐Garcia Julia , Gibbs Peter , de la Fouchardiere Christelle , Rivera Fernando , Elez Elena , Le Dung T. , Adachi Noriaki , Fogelman David , Marinello Patricia , Diaz Luis A.
Published: November 2022

The phase 3 KEYNOTE‐177 study evaluated pembrolizumab versus chemotherapy with or without bevacizumab or cetuximab in patients with newly diagnosed, microsatellite‐instability‐high (MSI‐H)/mismatch‐repair‐deficient (dMMR) metastatic colorectal cancer (mCRC). Primary endpoints were progression‐free survival (PFS) per RECIST v1.1 by blinded independent central review (BICR) and overall survival (OS). Secondary endpoints were overall response rate (ORR) per RECIST v1.1 by BICR and safety. Here, we report results from the post hoc analysis of patients who were enrolled in Asia from the final analysis (FA) of KEYNOTE‐177. A total of 48 patients from Japan, Korea, Singapore, and Taiwan (pembrolizumab, n = 22; chemotherapy, n = 26) were included. At FA, median time from randomization to data cutoff (February 19, 2021) was 45.3 (range 38.1–57.8) months with pembrolizumab and 43.9 (range 36.6–55.1) months with chemotherapy. Median PFS was not reached (NR; 95% confidence interval [CI] 1.9 months–NR) with pembrolizumab versus 10.4 (95% CI 6.3–22.0) months with chemotherapy (hazard ratio [HR] 0.56, 95% CI 0.26–1.20). Median OS was NR (range 13.8 months–NR) versus 30.0 (14.7–NR) months (HR 0.65, 95% CI 0.27–1.55) and ORR was 50% (95% CI 28–72) versus 46% (95% CI 27–67). Grade 3/4 treatment‐related adverse events (TRAEs) were reported by two patients (9%) in the pembrolizumab arm and 20 (80%) in the chemotherapy arm. Immune‐mediated adverse events or infusion reactions were reported by six patients (27%) and 10 patients (40%), respectively. No deaths due to TRAEs occurred. These data support first‐line pembrolizumab as a standard of care for patients from Asia with MSI‐H/dMMR mCRC. ClinicalTrials.gov identifier: NCT02563002.
Selection bias due to delayed comprehensive genomic profiling in Japan
Authors: Tamura Taichi , Ikegami Masachika , Kanemasa Yusuke , Yomota Makiko , Furusawa Akiko , Otani Ryohei , Saita Chiaki , Yonese Ichiro , Onishi Tomoko , Kobayashi Hiroshi , Akiyama Toru , Shimoyama Tatsu , Aruga Tomoyuki , Yamaguchi Tatsuro
Published: November 2022

Patients with advanced cancer undergo comprehensive genomic profiling in Japan only after treatment options have been exhausted. Patients with a very poor prognosis were not able to undergo profiling tests, resulting in a selection bias called length bias, which makes accurate survival analysis impossible. The actual impact of length bias on the overall survival of patients who have undergone profiling tests is unclear, yet appropriate methods for adjusting for length bias have not been developed. To assess the length bias in overall survival, we established a simulation‐based model for length bias adjustment. This study utilized clinicogenomic data of 8813 patients with advanced cancer who underwent profiling tests at hospitals throughout Japan between June 2019 and April 2022. Length bias was estimated by the conditional Kendall τ statistics and was significantly positive for 13 of the 15 cancer subtypes, suggesting a worse prognosis for patients who underwent profiling tests in early timing. The median overall survival time in colorectal, breast, and pancreatic cancer from the initial survival‐prolonging chemotherapy with adjustment for length bias was 937 (886–991), 1225 (1152–1368), and 585 (553–617) days, respectively (median; 95% credible interval). Adjusting for length bias made it possible to analyze the prognostic relevance of oncogenic mutations and treatments. In total, 12 tumor‐specific oncogenic mutations correlating with poor survival were detected after adjustment. There was no difference in survival between FOLFIRINOX (leucovorin, fluorouracil, irinotecan, and oxaliplatin) or gemcitabine with nab‐paclitaxel‐treated groups as first‐line chemotherapy for pancreatic cancer. Adjusting for length bias is an essential part of utilizing real‐world clinicogenomic data.
“Trying to be positive in the face of the storm”: The experiences of independent college students during the COVID‐19 pandemic
Authors: Sapiro Beth , Shpiegel Svetlana , Ventola Marissa , Quiroz Silvia Ramirez , Nwankwo Oomi Helen , Munyereyi Tariro
Published: November 2022

The COVID‐19 pandemic created multiple stressors for college students, particularly for young adults experiencing multiple forms of disadvantage. Little is known about the pandemic experiences of independent college students, many of whom are emancipated minors, former wards of the state, and other students who lack familial financial and practical support as they pursue higher education. Twenty‐three independent students, ages 18–23, from one northeastern university were interviewed to understand how independent students were affected by the COVID‐19 pandemic, and their needs for support from the university during this time. Most participants were identified as Black or Latinx, and two thirds were first‐generation college students. Participants reported an overall lack of support from their families prior to the pandemic. During the pandemic, they experienced compounding academic, economic, and mental health‐related stressors. Students responded to these stressors in resilient and resourceful ways, by adapting to their new realities, expressing gratitude, and finding opportunities for self‐growth. Participants recommend that institutions of higher education support independent students during periods of emergency through providing financial assistance, offering opportunities for connection with both adults and peers, and demonstrating administrative flexibility and understanding of their unique needs.
Drilling‐ and withdrawing‐related thermal effects of implant site preparation for ceramic and stainless steel twist drills in standardized bovine bone
Authors: Tur Dino , Giannis Katharina , Unger Ewald , Mittlböck Martina , Rausch‐Fan Xiaohui , Strbac Georg D.
Published: November 2022

Introduction

Excessive surgical trauma is believed to be among the most important causes for early implant losses. As thermal injury to the bone is not only dependent on the amount of generated heat but also on the tissue exposure time, and the greatest temperature increase was found within the withdrawing period, the entire osteotomy procedure with the parameters contributing to thermal damage is of particular clinical relevance. The aim of this study was to investigate the thermal performance of metal‐based and ceramic implant drills regarding the temperature exposure time during the whole osteotomy process.

Materials and Methods

This investigation consisted of 240 individual preparations in total, comprising two different drilling depths (10 and 16 mm), two irrigation methods (external and without irrigation), two implant drill materials (stainless steel and zirconia), and three consecutive drill diameters per material (2.0/2.2, 2.8, and 3.5 mm) with 10 identical repetitions. Real‐time multichannel temperature measurement was conducted during automated drilling procedures in standardized bovine bone specimens.

Results

The maximum temperature changes were highly associated with the time period of passive drill withdrawing (p ≤ 0.05), irrespective of drill material, drilling depth, or drill diameter. Statistically significant differences in temperature generation between stainless steel and ceramic drills were observed in irrigated testing sites at both drilling depths with smaller drill diameters (2.0/2.2 and 2.8 mm, p ≤ 0.05).

Conclusion

Results of this in vitro study could demonstrate a strong association between the highest temperature increase and the passive withdrawing time period in both investigated drill materials. Considering these findings and the resulting thermal bone damage due to the whole surgical procedure, high overall temperatures in combination with a prolonged heat exposure time may impact the future osseointegration process.