bluuebunny/crossref_metadata_2025 huggingface dataset:
Hyperthermic intravesical chemotherapy with mitomycin‐C for the treatment of high‐risk non‐muscle‐invasive bladder cancer patients
Authors: Conroy Samantha , Pang Karl , Jubber Ibrahim , Hussain Syed A. , Rosario Derek J. , Cumberbatch Marcus G. , Catto James W. F. , Noon Aidan P.
Published: December 2022

Objectives

The objectives of the study are to explore tolerability, acceptability and oncological outcomes for patients with high‐risk non‐muscle‐invasive bladder cancer (NMIBC) treated with hyperthermic intravesical chemotherapy (HIVEC) and mitomycin‐C (MMC) at our institution.

Patients and Methods

Our single‐institution, observational study consists of consecutive high‐risk NMIBC patients treated with HIVEC and MMC. Our HIVEC protocol included six weekly instillations (induction), followed by two further cycles of three instillations (maintenance) (6 + 3 + 3) if there was cystoscopic response. Patient demographics, instillation dates and adverse events (AEs) were collected prospectively in our dedicated HIVEC clinic. Retrospective case‐note review was performed to evaluate oncological outcomes. Primary outcomes were tolerability and acceptability of HIVEC protocol; secondary outcomes were 12‐month recurrence‐free, progression‐free and overall survival.

Results

In total, 57 patients (median age 80.3 years) received HIVEC and MMC, with a median follow‐up of 18 months. Of these, 40 (70.2%) had recurrent tumours, and 29 (50.9%) had received prior Bacillus Calmette–Guérin (BCG). HIVEC induction was completed by 47 (82.5%) patients, but only 19 (33.3%) completed the full protocol. Disease recurrence (28.9%) and AEs (28.9%) were the most common reasons for incompletion of protocol; five (13.2%) patients stopped treatment due to logistical challenges. AEs occurred in 20 (35.1%) patients; the most frequently documented were rash (10.5%), urinary tract infection (8.8%) and bladder spasm (8.8%). Progression during treatment occurred in 11 (19.3%) patients, 4 (7.0%) of whom had muscle invasion and 5 (8.8%) subsequently required radical treatment. Patients who had received prior BCG were significantly more likely to progress (p = 0.04). 12‐month recurrence‐free, progression‐free and overall survival rates were 67.5%, 82.2%, and 94.7%, respectively.

Conclusions

Our single‐institution experience suggests that HIVEC and MMC are tolerable and acceptable. Oncological outcomes in this predominantly elderly, pretreated cohort are promising; however, disease progression was higher in patients pretreated with BCG. Further randomised noninferiority trials comparing HIVEC versus BCG in high‐risk NMIBC are required.
A retrospective study of cladribine and low‐dose cytarabine–based regimens for the treatment of chronic myelomonocytic leukemia and secondary acute myeloid leukemia
Authors: Bazinet Alexandre , Darbaniyan Faezeh , Kadia Tapan M. , Venugopal Sangeetha , Kanagal‐Shamanna Rashmi , DiNardo Courtney D. , Borthakur Gautam , Jabbour Elias J. , Daver Naval G. , Pemmaraju Naveen , Konopleva Marina Y. , Ravandi Farhad , Sasaki Koji , Chien Kelly S. , Hammond Danielle , Pierce Sherry A. , Kantarjian Hagop M. , Garcia‐Manero Guillermo , Montalban‐Bravo Guillermo
Published: December 2022

Background

Patients with higher risk chronic myelomonocytic leukemia (CMML) have limited therapeutic options beyond hydroxyurea and hypomethylating agents (HMAs). Regimens based on a backbone of cladribine (CLAD), low‐dose cytarabine (LDAC), and an HMA are effective low‐intensity therapies for acute myeloid leukemia (AML).

Methods

The authors conducted a retrospective chart review to evaluate the efficacy of CLAD/LDAC/HMA in CMML and secondary acute myeloid leukemia (sAML) arising from CMML. Responses were evaluated according to the 2006 International Working Group criteria for CMML and the 2017 European LeukemiaNet criteria for AML. The overall survival (OS), leukemia‐free survival (LFS), and duration of response were evaluated with the Kaplan–Meier method. Patients were stratified on the basis of prior HMA exposure.

Results

The authors identified 21 patients with CMML (eight with HMA‐naive CMML and 13 with HMA‐failure CMML) and 33 patients with sAML (11 with HMA‐naive sAML and 22 with HMA‐failure sAML) treated with CLAD/LDAC/HMA‐based regimens. The CMML cohort was enriched for high‐risk features (proliferative type, elevated blasts, and RAS/MAPK mutations). The overall response rate was 33% in CMML (50% in HMA‐naive CMML and 23% in HMA‐failure CMML) and 48% in sAML (82% in HMA‐naive sAML and 32% in HMA‐failure sAML). The median OS was 14.4, 8.8, 42.9, and 2.9 months for HMA‐naive CMML, HMA‐failure CMML, HMA‐naive sAML, and HMA‐failure sAML, respectively. The median LFS was 14.4 and 3.9 months for HMA‐naive CMML and HMA‐failure CMML, respectively.

Conclusions

CLAD/LDAC/HMA‐based regimens are effective in a subset of patients with higher risk CMML and sAML arising from CMML who have not previously experienced HMA failure. These findings must be confirmed in prospective studies.
A Tool, an App and a Field: Fluorescent PET Sensors, Blood Electrolyte Analysis and Molecular Logic as Products of Supramolecular Photoscience from Northern Ireland and Sri Lanka
Authors: Yao Chao‐Yi , de Silva A. Prasanna
Published: December 2022

The general tool of fluorescent PET (photoinduced electron transfer) sensors/switches – a molecular design principle with engineering features – is outlined, with the aid of frontier orbital energy diagrams. Fluorophores such as anthracene, 1,3‐diaryl‐Δ2‐pyrazolines and 4‐amino‐1,8‐naphthalimides are employed within this system, alongside receptors such as amines, carboxylates, crown ethers and amino acids. This tool appealed to a multinational corporation for building a medical analyzer for electrolytes such as Na+, K+, Ca2+ and gases like CO2, which became a commercially successful application. Finally, the tool was a springboard for chemistry to cross into computer science. The field of molecular logic can elucidate how molecules inside us handle information. Molecular examples of the simplest logic gates such as YES, NOT, OR, AND are described. A case of a human‐level computation – visual edge detection – is also included.
Recontextualization of knowledge in the new Norwegian curriculum: Epistemic and non‐epistemic design in learning objectives for social studies
Authors: Bratland Erik , El Ghami Mohamed
Published: December 2022

The recent Norwegian curriculum reform for schools, called “The subject renewal”, is part of an international trend regarding knowledge‐based curricula. The Norwegian curriculum, which places decisive emphasis on subjects and subject concepts, aims to bring in‐depth learning and knowledge back to schools. This paper is based on Rata's theory, referred to as the curriculum design coherence (CDC) model, and examines the curriculum for social studies. The analysis reveals significant differences in the curriculum's goal formulations, with designs that lack connections between subject concepts and content knowledge, which sheds light on how the transition to a knowledge‐based curriculum is accompanied by several unresolved issues. The paper explains why curricula with coherent designs and epistemically structured knowledge are a prerequisite for in‐depth learning and cumulative knowledge building in schools.
iCoreDrop: A robust immune monitoring spectral cytometry assay with six open channels for biomarker flexibility
Authors: Jensen Holly A. , Kim Jeong
Published: December 2022

Recent advances in spectral cytometry have extended our ability to monitor immune cell subsets and activation status while simultaneously improving rare population detection. However, technical challenges in reference control selection and autofluorescence extraction serve as barriers to broad application of spectral flow cytometry. Furthermore, the complexity of spectral cytometry panel development limits the adaptation of established assays. Here, we describe the development of a spectral immunophenotyping assay with robust drop‐in capability to enable biomarker interrogation flexibility. The immune monitoring core (iCore), which can be used in part or total, captures broad and granular immune subsets across T cells, B cells, NK cells, monocytes, dendritic cells, and granulocytes in peripheral whole blood. Additional user‐selected biomarkers can be dropped in (Drop) using channels BV421, Alexa Fluor 488, PE, PE‐Cy7, APC, and APC‐Cy7. A comprehensive assessment of reagent and panel performance was conducted, including reference control comparison and optimal autofluorescence (AF) extraction on the 5‐laser Cytek Aurora system for healthy donor blood. Assay precision and stability analyses revealed robust intra‐assay precision, with 95% of 83 distinct population gates having <20% CV. In the presence of additional drop‐in markers in two different settings, a T cell module and a myeloid/B cell module, the drop‐in channels themselves achieved <20% CV across 12 out of 13 additionally queried population gates. Overall, establishment of optimal unmixing practices will enable widespread adoption of spectral cytometry assays.
A unique case of anaplastic thyroid carcinoma comprising of two distinct patterns osteoclastic variant and squamous cell carcinoma in separate lobe imitating collision tumor: A case report
Authors: Gupta Rakesh Kumar , John Aishwarya , Ravina Mudalsha , Arora Ripu Daman
Published: December 2022

Anaplastic thyroid carcinoma with two distinct morphologies in two lobes with no intermixing is very rare and not reported earlier. Furthermore, osteoclastic variant of anaplastic thyroid carcinoma as well as primary squamous cell carcinoma without any differentiated components are also very rare with only few reported cases describing their cytological features. Herein, we are reporting a unique and first case of anaplastic thyroid carcinoma comprising of two distinct patterns osteoclastic variant and squamous cell carcinoma in different lobes in a 55‐years‐old lady with review of literature.
Deep marine diagenesis, offshore Hawaii and Enewetak, with implications for older carbonates
Authors: Saller Arthur , Winterbottom Charlotte
Published: December 2022

Cenozoic limestones from Hawaii and Enewetak were studied to characterise diagenesis in deep sea water. Hawaii samples were from subsea outcrops of drowned Pleistocene reefs 150–1,505 m deep (maximum age 550–600 ka). Most samples had early fibrous aragonite and high‐magnesium calcite cements precipitated in shallow sea water. Partial dissolution of aragonite (including coral) and high‐magnesium calcite were significant at 412 m and increased to 1,505 m. Crusts of ‘stubby’ sparry calcite cement (2–8 mol.% MgCO3; ‘lower Mg calcite’) precipitated on early aragonite and high‐magnesium calcite cements at 473–1,358 m. Dissolution of aragonite and high‐magnesium calcite was incomplete. Aragonite and high‐magnesium calcite were not neomorphosed to low‐magnesium calcite ( <5 mol.% MgCO3). Enewetak well samples came from 3 to 1,400 m (Holocene to Upper Eocene). Lower Miocene to Upper Eocene carbonates at 380–1,380 m near the atoll margin showed pervasive dissolution of aragonite and conversion of high‐magnesium calcite fossils to low‐magnesium calcite. Their lower‐Mg calcite cements (380–820 m; mainly radiaxial) were associated with aragonite dissolution. The lower‐Mg calcite cements and bulk limestones below 500 m had geochemistry indicating precipitation or stabilisation in sea water at 10–27°C. Data indicate Enewetak dolomitisation (1,250–1,320 m) in cold sea water during burial >1,000 m. Coralline algae showed little petrographic alteration, but Mg decreased downward from 15 to 1.5 mol.% MgCO3. In both areas, aragonite dissolution, alteration of high‐magnesium calcite, and precipitation of lower‐Mg calcite cements occurred in deep sea water (>300 m) undersaturated for aragonite, but supersaturated for low‐magnesium calcite. Original high‐magnesium calcite was partially dissolved in Hawaii samples, but converted to low‐magnesium calcite in deep Enewetak cores, possibly due to gradual deepening at Enewetak. Dolomitisation and low‐magnesium calcite dissolution occurred below the calcite saturation depth (approximately 1,000 m) in Enewetak, but not deep Hawaii samples, possibly because dolomitisation is slower. Temporal variations in carbonate saturation, especially related to pCO2, are interpreted as the main control on mineralogy during marine diagenesis now and in many ancient oceans.
Phenological response to climate variation in a northern red oak plantation: Links to survival and productivity
Authors: Knott Jonathan A. , Liang Liang , Dukes Jeffrey S. , Swihart Robert K. , Fei Songlin
Published: December 2022

In a changing climate, the future survival and productivity of species rely on individual populations to respond to shifting environmental conditions. Many tree species, including northern red oak (Quercus rubra), exhibit phenotypic plasticity, the ability to respond to changes in environmental conditions at within‐generation time scales, through varying traits such as leaf phenology. Phenotypic plasticity of phenology may vary among populations within a species' range, and it is unclear if the range of plasticity is adequate to promote fitness. Here, we used a 58‐year‐old common garden to test whether northern red oak populations differed in phenological sensitivity to changes in temperature and whether differences in phenological sensitivity were associated with differences in productivity and survival (proxies of fitness). We recorded 8 years of spring leaf emergence and autumn leaf coloration and loss in 28 distinct populations from across the species' full range. Across the 28 populations, spring leaf out consistently advanced in warmer years, but fall phenology was less responsive to changes in temperature. Southern, warm‐adapted populations had larger shifts in phenology in response to springtime warming but had lower long‐term survival. Moreover, higher phenological sensitivity to spring warming was not strongly linked to increased productivity. Instead, fitness was more closely linked to latitudinal gradients. Although springtime phenological sensitivity to climate change is common across northern red oak populations, responses of productivity and survival, which could determine longer‐term trajectories of species abundance, are more variable across the species' range.
Single‐cell fate mapping reveals widespread clonal ignorance of low‐affinity T cells exposed to systemic infection
Authors: Leube Justin , Mühlbauer Anton , Andrä Immanuel , Biggel Madleen , Busch Dirk H. , Kretschmer Lorenz , Buchholz Veit R.
Published: December 2022

T cell ignorance is a specific form of immunological tolerance. It describes the maintenance of naivety in antigen‐specific T cells in vivo despite the presence of their target antigen. It is thought to mainly play a role during the steady state, when self‐antigens are presented in absence of costimulatory signals and at low density or to T cells of low affinity. In how far antigen‐specific T cells can also remain clonally ignorant to foreign antigens, presented in the inflammatory context of systemic infection, remains unclear. Using single‐cell in vivo fate mapping and high throughput flow cytometric enrichment, we find that high‐affinity antigen‐specific CD8+ T cells are efficiently recruited upon systemic infection. In contrast, most low‐affinity antigen‐specific T cells ignore the priming antigen and persist in the naïve state while remaining fully responsive to subsequent immunization with a high‐affinity ligand. These data establish the widespread clonal ignorance of low‐affinity T cells as a major factor shaping the composition of antigen‐specific CD8+ T cell responses to systemic infection.
Quality evaluation of immunomodulatory polysaccharides from Agaricus bisporus by an integrated fingerprint technique
Authors: Yuan Qin , Liu Wen , Huang Ling , Wang Liju , Yu Juan , Wang Yitao , Wu Ding‐Tao , Wang Shengpeng
Published: December 2022

Agaricus bisporus (A. bisporus) is a rich source of polysaccharides with medical and nutraceutical interests; however, the complex structure of A. bisporus polysaccharides (ABPs) poses a challenge to its quality control. This study aims to investigate the immunomodulatory fractions of ABPs and further establish a quality control system for the detection and characterization of bioactive ABPs. Two fractions of ABPs were obtained using gradient alcohol precipitation combined ultrafiltration, followed by characterization of molecular weight, monosaccharide composition, chemical structure, and evaluation of immunomodulatory activity. Results showed that the two isolated fractions with different molecular weight, 8.95 × 106 Da (ABP17‐1) and 1.73 × 104 Da (ABP17‐2), were more homogeneous and exerted stronger immunomodulatory activity than that of ABPs. Furthermore, an integrated fingerprint technique including HPSEC‐MALL‐RID and HPLC was applied for the fingerprint analysis of ABPs from 17 batches of A. bisporus, which showed high similarity. Besides, two polysaccharide fractions, two monosaccharides (glucose and galactose), and the main cellulose hydrolysate glucose were identified as potential quality control markers of ABPs. Overall, this study could help better understand the structure–activity relationship of ABPs and serve as a guidance for the quality control of active ABPs and their related products.
A pilot randomized sham controlled trial of bilateral iTBS for depression and executive function in older adults
Authors: Cristancho Pilar , Arora Jyoti , Nishino Tomoyuki , Berger Jacinda , Carter Alexandre , Blumberger Daniel , Miller Philip , Snyder Abraham , Barch Deanna , Lenze Eric J.
Published: December 2022

Introduction

Executive function deficits (EFD) in late life depression (LLD) are associated with poor outcomes. Dysfunction of the cognitive control network (CCN) has been posited in the pathophysiology of LLD with EFD.

Methods

Seventeen older adults with depression and EFD were randomized to iTBS or sham for 6 weeks. Intervention was delivered bilaterally using a recognized connectivity target.

Results

A total of 89% (17/19) participants completed all study procedures. No serious adverse events occurred. Pre to post‐intervention change in mean Montgomery‐Asberg‐depression scores was not different between iTBS or sham, p = 0.33. No significant group‐by‐time interaction for Montgomery‐Asberg Depression rating scale scores (F
3, 44 = 0.51; p = 0.67) was found. No significant differences were seen in the effects of time between the two groups on executive measures: Flanker scores (F
1, 14 = 0.02, p = 0.88), Dimensional‐change‐card‐sort scores F
1, 14 = 0.25, p = 0.63, and working memory scores (F
1, 14 = 0.98, p = 0.34). The Group‐by‐time interaction effect for functional connectivity (FC) within the Fronto‐parietal‐network was not significant (F
1, 14 = 0.36, p = 0.56). No significant difference in the effect‐of‐time between the two groups was found on FC within the Cingulo‐opercular‐network (F
1, 14 = 0, p = 0.98).

Conclusion

Bilateral iTBS is feasible in LLD. Preliminary results are unsupportive of efficacy on depression, executive function or target engagement of the CCN. A future Randomized clinical trial requires a larger sample size with stratification of cognitive and executive variables and refinement in the target engagement.
System and policy‐level barriers and facilitators for timely and accurate diagnosis of young onset dementia
Authors: Burkinshaw Kirsty , Tsourtos George , Cations Monica
Published: December 2022

Objective

The multiyear diagnostic journey for young onset dementia (YOD) is fraught with clinical and personal difficulties and poses significant uncertainty for people living with YOD and their families. Most existing research has examined the personal and/or clinical barriers to a timely diagnosis of YOD, but less evidence exists regarding system level factors. The aim of this study is to investigate health professionals' insights for a timely and accurate YOD diagnosis at the system level.

Design

Grounded theory qualitative study.

Setting and Participants

Semi‐structured in‐depth interviews with 11 health professionals working across varied healthcare settings were conducted online via videoconference.

Measurements

Data were contrasted and compared within and between transcripts using the constant comparative method.

Results

Seven themes emerged about barriers and facilitators for timely and accurate diagnosis of YOD: (1) stigma and awareness of YOD; (2) mismatched policy; (3) fractured health system; (4) inadequate pathways for YOD diagnostic care; (5) effective use of General Practitioners; (6) inequitable access and fragmented service navigation; (7) diverse and marginalised groups.

Conclusion

A complex web of systemic and system level barriers contributes to the delay of accurate and timely diagnosis for YOD. Diverse and marginalised groups experience greater inequitable disadvantage regarding YOD diagnostic care. There is an urgent need to focus on YOD diagnosis facilitators at the broader health system level.
Brain functional connectivity alterations associated with neuropsychological performance 6–9 months following SARS‐CoV‐2 infection
Authors: Voruz Philippe , Cionca Alexandre , Jacot de Alcântara Isabele , Nuber‐Champier Anthony , Allali Gilles , Benzakour Lamyae , Lalive Patrice H. , Lövblad Karl O. , Braillard Olivia , Nehme Mayssam , Coen Matteo , Serratrice Jacques , Reny Jean‐Luc , Pugin Jérôme , Guessous Idris , Ptak Radek , Landis Basile N. , Adler Dan , Griffa Alessandra , Van De Ville Dimitri , Assal Frédéric , Péron Julie A.
Published: December 2022

Neuropsychological deficits and brain damage following SARS‐CoV‐2 infection are not well understood. Then, 116 patients, with either severe, moderate, or mild disease in the acute phase underwent neuropsychological and olfactory tests, as well as completed psychiatric and respiratory questionnaires at 223 ± 42 days postinfection. Additionally, a subgroup of 50 patients underwent functional magnetic resonance imaging. Patients in the severe group displayed poorer verbal episodic memory performances, and moderate patients had reduced mental flexibility. Neuroimaging revealed patterns of hypofunctional and hyperfunctional connectivities in severe patients, while only hyperconnectivity patterns were observed for moderate. The default mode, somatosensory, dorsal attention, subcortical, and cerebellar networks were implicated. Partial least squares correlations analysis confirmed specific association between memory, executive functions performances and brain functional connectivity. The severity of the infection in the acute phase is a predictor of neuropsychological performance 6–9 months following SARS‐CoV‐2 infection. SARS‐CoV‐2 infection causes long‐term memory and executive dysfunctions, related to large‐scale functional brain connectivity alterations.
Recent advances in the diagnosis and management of typhoid fever in Africa: A review
Authors: Mahmoud Ashraf , Oluyemisi Adekunbi , Uwishema Olivier , Sun Jeffrey , Jobran Afnan Waleed , David Success , Wireko Andrew Awuah , Adanur Irem , Dost Burhan , Onyeaka Helen
Published: December 2022

Typhoid fever, a classical disease of enteric origin caused by Salmonella species of bacteria, is among the most important diseases threatening public health in Africa. The African continent is a marker for both low resources within the healthcare system and poor disease control policy formulations in managing endemic infectious diseases. Since the colonial era, the Widal serological test has been used to confirm typhoid fever in Africa, however recent studies recommend blood culture, and when blood culture cannot be obtained, clinical findings, laboratory Widal test confirmation, and ruling out other febrile illnesses as confirmatory pathway to diagnose typhoid fever in Africa. Managing typhoid fever relies on antimicrobials. In 1980s chloramphenicol was the medication of choice. Years later, amoxicillin and co‐trimoxazole were adopted. However, the instantaneous rise of resistant strains of Salmonella enterica confers an important challenge to treat the burdensome enteric fever. The current treatment algorithm of typhoid fever in Africa relies significantly on the use of fluoroquinolones, macrolides, and cephalosporins. Developed nations have successfully addressed and controlled typhoid fever via improvement in accessing safe water and food, better sanitary and hygienic behaviours, and vaccines development. Nevertheless, there is significant evidence to infer improvement in the diagnosis management of typhoid fever over the last few decades, and efforts are underway to control the disease spread in Africa. This review aims to provide an overview of the latest developments in typhoid fever diagnosis and management in Africa and provide key recommendations for a coordinated approach to mitigate typhoid in the continent.
Gene Therapy Using Recombinant AAV Type 8 Vector Encoding TNAP‐D10 Improves the Skeletal Phenotypes in Murine Models of Osteomalacia
Authors: Amadeu de Oliveira Flavia , Mohamed Fatma F. , Kinoshita Yuka , Narisawa Sonoko , Farquharson Colin , Miyake Koichi , Foster Brian L , Millan Jose Luis
Published: December 2022

Hypophosphatasia (HPP), caused by loss‐of‐function mutations in the ALPL gene encoding tissue‐nonspecific alkaline phosphatase (TNAP), is characterized by skeletal and dental hypomineralization that can vary in severity from life‐threatening to milder manifestations only in adulthood. PHOSPHO1 deficiency leads to early‐onset scoliosis, osteomalacia, and fractures that mimic pseudo‐HPP. Asfotase alfa, a life‐saving enzyme replacement therapy approved for pediatric‐onset HPP, requires subcutaneous injections 3 to 6 times per week. We recently showed that a single injection of an adeno‐associated virus vector serotype 8 harboring TNAP‐D10 (AAV8‐TNAP‐D10) effectively prevented skeletal disease and prolonged life in Alpl−/− mice phenocopying infantile HPP. Here, we aimed to determine the efficacy of AAV8‐TNAP‐D10 in improving the skeletal and dental phenotype in the AlplPrx1/Prx1 and Phospho1−/− mouse models of late‐onset (adult) HPP and pseudo‐HPP, respectively. A single dose of 3 × 1011 vector genomes per body (vg/b) was injected intramuscularly into 8‐week‐old AlplPrx1/Prx1 and wild‐type (WT) littermates, or into 3‐day‐old Phospho1−/− and WT mice, and treatment efficacy was evaluated after 60 days for late‐onset HPP mice and after 90 days for Phospho1−/− mice. Biochemical analysis showed sustained serum alkaline phosphatase activity and reduced plasma PPi levels, and radiographic images, micro‐computed tomography (micro‐CT) analysis, and hematoxylin and eosin (H&E) staining showed improvements in the long bones in the late‐onset HPP mice and corrected scoliosis in the Phospho1−/− mice. Micro‐CT analysis of the dentoalveolar complex did not reveal significant changes in the phenotype of late‐onset HPP and pseudo‐HPP models. Moreover, alizarin red staining analysis showed that AAV8‐TNAP‐D10 treatment did not promote ectopic calcification of soft organs in adult HPP mice after 60 days of treatment, even after inducing chronic kidney disease. Overall, the AAV8‐TNAP‐D10 treatment improved the skeletal phenotype in both the adult HPP and pseudo‐HPP mouse models. This preclinical study will contribute to the advancement of gene therapy for the improvement of skeletal disease in patients with heritable forms of osteomalacia. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
Molecular Dissection of Somatic Skeletal Disease in Neurofibromatosis Type 1
Authors: Paria Nandina , Khalid Aysha , Shen Bo , Lemoine Ben , Chan Jinyan , Kidane Yared H , Oxendine Ila , Cornelia Reuel , Wise Carol A , Rios Jonathan J
Published: December 2022

Neurofibromatosis type 1 (NF1) is a tumor predisposition syndrome caused by heterozygous NF1 gene mutations. Patients with NF1 present with pleiotropic somatic secondary manifestations, including development of bone pseudarthrosis after fracture. Somatic NF1 gene mutations were reproducibly identified in patient-derived pseudarthrosis specimens, suggesting a local mosaic cell population including somatic pathologic cells. The somatic cellular pathogenesis of NF1 pseudarthroses remains unclear, though defects in osteogenesis have been posited. Here, we applied time-series single-cell RNA-sequencing (scRNA-seq) to patient-matched control and pseudarthrosis-derived primary bone stromal cells (BSCs). We show that osteogenic specification to an osteoblast progenitor cell population was evident for control bone-derived cells and haploinsufficient pseudarthrosis-derived cells. Similar results were observed for somatic patient fracture-derived NF1−/− cells; however, expression of genetic pathways associated with skeletal mineralization were significantly reduced in NF1−/− cells compared with fracture-derived NF1+/− cells. In mice, we show that Nf1 expressed in bone marrow osteoprogenitors is required for the maintenance of the adult skeleton. Results from our study implicate impaired Clec11a-Itga11-Wnt signaling in the pathogenesis of NF1-associated skeletal disease. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Application of lncRNA–miRNA–mRNA ceRNA network analysis in the treatment of androgenic alopecia
Authors: Wei Hanxiao , Yi Tian , Li Qiang , Guo Yanping , Shen Caiqi , Jin Peisheng
Published: December 2022

Background

Long noncoding RNAs (lncRNAs) can be used as competitive endogenous RNAs (ceRNAs) to bind to microRNAs (miRNAs) to regulate gene expression. Previous studies have demonstrated that ceRNAs play an important role in the development of tumors. However, it is not clear whether the lncRNA–miRNA–mRNA ceRNA network plays a role in androgenic alopecia (AGA).

Methods

The hair follicles of three AGA patients and three healthy individuals were collected for high‐throughput whole transcriptome sequencing to screen for differentially expressed lncRNAs. Differentially expressed lncRNA target genes were subjected to databases to predict miRNA–mRNA and lncRNA–miRNA relationship pairs, and a ceRNA network was constructed using Cytoscape software. Relative expression was verified by real‐time quantitative reverse transcription–polymerase chain reaction (qRT‐PCR).

Results

84 lncRNAs were significantly differentially expressed between the hair follicles of AGA patients and those of healthy individuals; 30 were upregulated, and 54 were downregulated. The top 10 upregulated lncRNAs were ENST00000501520, ENST00000448179, ENST00000318291, ENST00000568280, ENST00000561121, ENST00000376609, ENST00000602414, ENST00000573866, ENST00000513358, and ENST00000564194. The top 10 downregulated lncRNAs were ENST00000566804, ENST00000561973, ENST00000587680, ENST00000569927, ENST00000340444, ENST00000424345, ENST00000589787, NR_024344, NR_073026, and NR_110001. The qRT‐PCR validation results and receiver‐operating characteristic curve analysis indicated that one upregulated lncRNA, LOXL1‐AS1 (ENST00000564194), had the most significant clinical diagnostic potential. After further analysis, it was concluded that LOXL1‐AS1 could be used as a sponge to target hsa‐miR‐5193, thereby regulating TP53 expression.

Conclusion

The ceRNA network‐regulating AGA was constructed through high‐throughput sequencing. Our study also identified a key lncRNA that is possibly related to the AGA pathological process.
Personalized Dosing of Infliximab in Patients With Inflammatory Bowel Disease Using a Bayesian Approach: A Next Step in Therapeutic Drug Monitoring
Authors: Desai Devendra C. , Dherai Alpa J. , Strik Anne , Mould Diane R.
Published: December 2022

Although biological agents have revolutionized the management of inflammatory bowel diseases (IBDs), a significant proportion of patients show primary non‐response or develop secondary loss of response. Therapeutic drug monitoring (TDM) is advocated to maintain the efficacy of biologic agents. Reactive TDM can rationalize the management of primary non‐response and secondary loss of response and has shown to be more cost‐effective compared with empiric dose escalation. Proactive TDM is shown to increase clinical remission and the durability of the response to a biologic agent. However, the efficacy of proactive and reactive TDM has been questioned in recent studies and meta‐analyses. Hence, we need a different approach to TDM, which addresses inflammatory burden, the individual patient, and disease factors. Bayesian approaches, which use population pharmacokinetic models, enable clinicians to make better use of TDM for dose adjustment. With rapid improvement in computer technology, these Bayesian model‐based software packages are now available for clinical use. Bayesian dashboard systems allow clinicians to apply model‐based dosing to understand an individual's pharmacokinetics and achieve a target serum drug concentration. The model is updated using previously measured drug concentrations and relevant patient factors, such as body weight, C‐reactive protein, and serum albumin concentration, to maintain effective drug concentrations in the serum. Initial studies have found utility for the Bayesian approach in induction and maintenance, in adult and pediatric patients, in clinical trials, and in real‐life situations for patients with IBD treated with infliximab. This needs confirmation in larger studies. This article reviews the Bayesian approach to therapeutic drug monitoring in IBD.
Central pancreatectomy prevents postoperative diabetes
Authors: Klotz Rosa , Schilling Constanze , Kuner Charlotte , Hinz Ulf , Klaiber Ulla , Holze Magdalena , Tjaden Christine , Loos Martin , Büchler Markus W. , Hackert Thilo
Published: December 2022

Background

Central pancreatectomy (CP) can be performed as an alternative surgical approach to distal pancreatectomy (DP) in the treatment of benign or low‐grade malignant lesions located in the neck and body of the pancreas, aiming to reduce loss of parenchyma and therefore organ failure. The objective of this study was to evaluate the short‐ and long‐term outcome of CP in comparison to DP.

Methods

Patients who received CP in a large tertiary care pancreatic surgery center between 2001 and 2020 were identified from a prospectively maintained database and compared via propensity score matching with patients receiving DP during the same time period. Perioperative rate of complications and long‐term outcome of pancreatic endocrine and exocrine function were evaluated.

Results

One hundred and seven patients undergoing open CP were compared to 107 patients with open DP. No significant difference in rates or severity of most surgical complications could be found including postoperative pancreatic fistula, intraabdominal fluid collection, delayed gastric emptying and wound infection. However, patients receiving CP had a significantly higher risk of grade C postpancreatectomy hemorrhage (PPH) (CP: 10 patients, 9.3% versus DP: 1 patient, 0.9%; p = .0019). Perioperative mortality was comparable. Long‐term follow‐up of 60 matched pairs revealed significantly less patients with new‐onset diabetes after CP (eight patients, 13.3%) compared to DP (22 patients, 36.7%, p = .0056).

Conclusion

CP offers an improved endocrine long‐term outcome at the expense of a higher risk of PPH without increased perioperative mortality. As evidence on this parenchyma sparing surgical technique is sparse, more prospective data are needed.
Early postoperative complications following tracheotomy: Does suturing technique influence outcomes?
Authors: Silva‐Nash Jennifer , Campbell Jessica B. , Gardner James Reed , Daigle Olivia , King Deanne , Moreno Mauricio , Vural Emre , Tulunay‐Ugur Ozlem E.
Published: December 2022

Introduction

Tracheotomy is one of the most commonly performed procedure by otolaryngologists, but no consensus exists on the effect of suturing techniques on postoperative complications. Stay sutures and Bjork flaps are utilized frequently for securing the tracheal incision to the neck skin in order to create a tract for recannulation.

Methods

Retrospective cohort study of tracheotomies performed by Otolaryngology‐Head and Neck Surgery providers (May 2014 to August 2020) was conducted to determine the effect of suturing technique on postoperative complications and patient outcomes. Patient demographics, medical comorbidities, indication for tracheostomy, and postoperative complications were analyzed with a statistical alpha set of .05.

Results

Out of 1395 total tracheostomies performed at our institution during the study period, 518 met inclusion criteria for this study. Three hundred and seventeen tracheostomies were secured by utilizing a Bjork flap, while 201 were secured with up and down stay sutures. Neither technique was noted to be more commonly associated with tracheal bleeding, infection, mucus plugging, pneumothorax, or false passage of the tracheostomy tube. One mortality was noted following decannulation during the study period.

Conclusion

Though various techniques exist; adverse outcomes are not associated with the manner in which a new tracheostomy stoma is secured. Medical comorbidities and the indications for tracheostomy likely play a more significant role in postoperative outcomes and complications.

Level of evidence

Level 3.
Recent Advances on Mn2+‐Doping in Diverse Metal Halide Perovskites
Authors: Yun Rui , Yang Huanxin , Sun Wenda , Zhang Libing , Liu Xiaowang , Zhang Xiaodan , Li Xiyan
Published: December 2022

Mn2+ dopants introduce a new emission center in semiconductor luminescent materials, endowing them promising photoluminescence (PL) properties, such as a wide color tuning range, reversible color change, reduced self‐absorption etc. Recently, rapid development of Mn2+ doped metal halide perovskites (MHPs) promote their promising applications in displays, photovoltaics, scintillators, etc. The emission color, luminous efficiency, and energy transfer pathway of doped perovskites are affected by condition of host lattice that accommodates Mn2+ ions. In this review, the optical properties determined by host materials with diverse geometries involving perovskite nanocrystals and perovskite derivatives is focused on, and the possible energy transfer routes in different doping systems are analyzed. An overview of recent advances of different doped systems with assigned emission channels together with the influence factors, strategies to enhance PL intensity and finally potential applications are summarized. To the end, the underlying challenges and possible solutions for further research in Mn doped perovskites are proposed.
Gelation Kinetics and Mechanical Properties of Thiol‐Tetrazole Methylsulfone Hydrogels Designed for Cell Encapsulation
Authors: de Miguel‐Jiménez Adrián , Ebeling Bastian , Paez Julieta I. , Fink‐Straube Claudia , Pearson Samuel , del Campo Aránzazu
Published: December 2022

Hydrogel precursors that crosslink within minutes are essential for the development of cell encapsulation matrices and their implementation in automated systems. Such timescales allow sufficient mixing of cells and hydrogel precursors under low shear forces and the achievement of homogeneous networks and cell distributions in the 3D cell culture. The previous work showed that the thiol‐tetrazole methylsulfone (TzMS) reaction crosslinks star‐poly(ethylene glycol) (PEG) hydrogels within minutes at around physiological pH and can be accelerated or slowed down with small pH changes. The resulting hydrogels are cytocompatible and stable in cell culture conditions. Here, the gelation kinetics and mechanical properties of PEG‐based hydrogels formed by thiol‐TzMS crosslinking as a function of buffer, crosslinker structure and degree of TzMS functionality are reported. Crosslinkers of different architecture, length and chemical nature (PEG versus peptide) are tested, and degree of TzMS functionality is modified by inclusion of RGD cell‐adhesive ligand, all at concentration ranges typically used in cell culture. These studies corroborate that thiol/PEG‐4TzMS hydrogels show gelation times and stiffnesses that are suitable for 3D cell encapsulation and tunable through changes in hydrogel composition. The results of this study guide formulation of encapsulating hydrogels for manual and automated 3D cell culture.
Distribution of intra‐host variations and mutations in the genomes of SARS‐CoV‐2 and their implications on detection and therapeutics
Authors: Xiong Dongyan , Zhang Xiaoxu , Yu Junping , Wei Hongping
Published: December 2022

The ongoing circulation of SARS‐CoV‐2 variants of concern (VOCs) has caused global concerns, because VOCs could escape current vaccines, antiviral drugs, and diagnosis. Analyzing mutations and intra‐host diversities in different and widespread VOCs can provide important insights to virus adaptive evolution and validity of vaccines, antiviral drugs, and diagnosis. In this study, by analyzing 1744 high‐throughput sequencing data for intra‐host single‐nucleotide variations (iSNVs) and 3,668,205 genome sequences for mutations in different VOCs, it was found that Omicron variant is still evolving at high speed, especially having high iSNVs frequency in its S and N genes. The efficacies of antibodies or detection primers targeting these two genes are at high risks to be invalid. Instead, highly conserved regions such as NSP8 gene could be better therapeutic and detection targets. Furthermore, mutations in later VOCs could be traced to the minor alleles in the previous variant samples such as Alpha and Delta in different countries. Finally, it was found that mutations C14408T in RdRp and A18163G in NSP14 gene might be associated with the higher genetic diversity in Omicron. Our findings not only contribute to understanding the adaptive evolution of SARS‐CoV‐2 VOCs, but also provide useful information for both drugs and diagnostic kits development.
The Relationship between PDQ‐8 and Costs in Parkinson's Disease—A Swedish Register‐Based Study
Authors: Kellerborg Klas , Norlin Jenny M. , Odin Per
Published: December 2022

Background

Parkinson's disease (PD) is a progressive neurodegenerative disorder associated with substantial costs which increase with progression state. However, few studies have investigated the association between costs and health related quality of life.

Objectives

To estimate the relationship between costs and health related quality of life, measured by the Parkinson's disease Quality of Life Questionnaire (PDQ)‐8 from a societal perspective, partial societal perspective (excluding productivity loss), and a health care perspective.

Methods

The Swedish Parkinson's Disease registry was linked to health care data registries to estimate annual costs. A generalized linear model was used to assess the relationship between instrument items and costs.

Results

The results suggest that PDQ‐8 captures the increase of costs by PD severity, particularly for costs within the broader societal perspective. From the best to worst PDQ‐8 quartile, we observed approximately 7‐fold increases within the societal perspective (39,400 to 274,300 SEK) and the partial societal perspective (31,800 to 219,400 SEK), and the increase within the health care perspective more than doubled (21,900 to 49,700 SEK). The PDQ‐8 dimensions “mobility,” “activities of daily living” and “social support” were associated with high costs in all perspectives.

Conclusion

Using a disease‐specific measure reflecting the patient's perspective, we found an increase of costs with worsening severity of PD, particularly for costs within the broader societal perspective. High costs were associated with not only motor symptoms, but also the dimension “Social support.”
Comparison of TROPOMI NO2, CO, HCHO, and SO2 data against ground‐level measurements in close proximity to large anthropogenic emission sources in the example of Ukraine
Authors: Savenets Mykhailo , Dvoretska Iryna , Nadtochii Lyudmila , Zhemera Natalia
Published: December 2022

The TROPOspheric Monitoring Instrument (TROPOMI) significantly improved the quality of air pollution monitoring. The comparison against other data sources showed acceptable results and good correlation. However, highly polluted areas remain the reason for large uncertainties. In our study, we compared TROPOMI NO2, CO, HCHO, and SO2 data against ground‐level measurements from Ukrainian monitoring sites, which could be considered rather unusual due to their close location to large anthropogenic emission sources. These sites were established in the former USSR to reflect the maximal air pollution levels. TROPOMI detected all cities with huge anthropogenic emissions in 2019–2020 and qualitatively reflected air pollution in Ukraine. However, direct comparison against individual monitoring sites showed mainly insignificant correlation, which was not much improved with cloudiness filtering, spatial averaging, and considering boundary layer height. We show that on an hour‐to‐daily scale, differences appear when remote sensing at a particular time cannot catch the elevated pollution levels in the boundary layer after air mass transportation. On a seasonal scale, the correlation decreases because of the differences in seasonality between near‐surface and column pollutants' content. We discuss that the relationship between TROPOMI and ground‐level measurements depends on the season, the continuance of industrial emissions, and the features of individual emission sources.
A novel X‐Ray and γ‐Ray combination strategy for potential dose escalation in patients with locally advanced pancreatic cancer
Authors: Liu Xia , Tao Yinjie , Yang Bo , Pang Tingtian , Yu Lang , Li Wenbo , Feng Siqi , Liu Renqing , Li Jinsheng , Liu Zhikai , Qiu Jie
Published: December 2022

Background

Treatment of locally advanced pancreatic cancer (LAPC) has long been calling for advances in technology of radiotherapy. Patients who received radiotherapy still had high risks of local recurrence, while suffering from gastrointestinal side effects. Based on the inherent characteristics of the x‐ray and γ‐Ray radiation techniques, here we proposed and investigated an unexplored radiation therapy.

Purpose

To investigate the potential clinical benefit of a novel x‐ray and γ‐Ray combination radiation technique in patients with LAPC.

Methods

Retrospective intensity‐modulated radiotherapy (IMRT) treatment plans of 10 LAPC patients were randomly selected to compare with dual‐modality plans. The prescribed dose to PGTV was 60.2 Gy. The PGTV dose was further escalated in dual‐modality plan while maintaining clinically tolerable dose to organs at risk (OARs). Dosimetric comparisons were made and analyzed for three treatment plans (tomotherapy, standard dual‐modality plan, escalated dual‐modality plan) to assess the ability to increase dose to target volume while minimizing dose in adjacent OARs. Finally, radiobiological models were utilized for comparison.

Results

All strategies resulted in dosimetrically acceptable plans. Dual‐modality plans were present with similar conformity index (CI) and significantly lower gradient index (GI) compared with tomotherapy (3.64 ± 0.37 vs. 4.14 ± 0.61, p = 0.002; 3.64 ± 0.42 vs. 4.14 ± 0.61, p = 0.003). Dmean of PGTV (65.46 ± 3.13 vs. 61.56 ± 1.00, p = 0.009; 77.98 ± 5.86 vs. 61.56 ± 1.00, p < 0.001) and PCTV (55.04 ± 2.14 vs. 53.93 ± 1.67, p = 0.016; 58.24 ± 3.24 vs. 53.93 ± 1.67, p = 0.001) were significantly higher, while Dmean of the stomach was reduced in both dual‐modality plans (17.98 ± 10.23 vs. 19.34 ± 9.75, p = 0.024; 17.62 ± 9.92 vs. 19.34 ± 9.75, p = 0.040). The lower V30Gy in the liver (4.83 ± 5.87 vs. 6.23 ± 6.68, p = 0.015; 4.90 ± 5.93 vs. 6.23 ± 6.68, p = 0.016) and lower V45Gy of the small intestine (3.35 ± 3.30 vs. 4.06 ± 3.87, p = 0.052) were found in dual‐modality plans. Meanwhile, radiobiological models demonstrated higher probability of tumor control (29.27% ± 9.61% vs. 18.34% ± 4.70%, p < 0.001; 44.67% ± 18.16% vs. 18.34% ± 4.70%, p = 0.001) and lower probability of small intestine complication (2.16% ± 2.30% vs. 1.25% ± 2.72%, p = 0.048) in favor of dual‐modality strategy.

Conclusions

A novel dual‐modality strategy of x‐ray and γ‐Ray combination radiation appears reliable for target dose escalation and normal tissue dose reduction. This strategy might be beneficial for local tumor control and the protection of normal organs in patients with LAPC.