bluuebunny/crossref_metadata_2025 huggingface dataset:
Therapeutic Pipeline in Alcohol-Associated Liver Disease
Authors: Thakral Nimish , Deutsch-Link Sasha , Singal Ashwani K.
Published: December 2022

Alcohol-associated liver disease is a leading cause of mortality and morbidity worldwide. Patients with alcohol-associated liver disease are often diagnosed at advanced stage and disease spectrum including alcoholic hepatitis, a severe manifestation with a high short-term mortality. Corticosteroid, recommended first-line treatment for patients with alcoholic hepatitis, is a very suboptimal treatment. Although the use of early liver transplantation has increased with consistent benefit in select patients with alcoholic hepatitis, its use remains heterogeneous worldwide due to lack of uniform selection criteria. Over the last decade, several therapeutic targets have evolved of promise with ongoing clinical trials in patients with cirrhosis and alcoholic hepatitis. Even with availability of effective medical therapies for alcohol-associated liver disease, long-term outcome depends on abstinence from alcohol use in any spectrum of alcohol-associated liver disease. However, alcohol use disorder treatment remains underutilized due to several barriers even in patients with advanced disease. There is an urgent unmet need to implement and promote integrated multidisciplinary care model with hepatologists and addiction experts to provide comprehensive management for these patients. In this review, we will discuss newer therapies targeting liver disease and therapies targeting alcohol use disorder in patients with alcohol-associated liver disease.
Restricted Boltzmann Machine and Matrix Factorization-Alternating Square Algorithm for Development Tourist Recommendation System
Authors: Pratama Yohanssen , Sianturi Riyanthi Angrainy , Chandra Dedi , Lumbantoruan Kristopel , Tampubolon Indah Trivena
Published: December 2022

The rapid development of technology affects the growth of tourist attraction information in Indonesia. Therefore, an accurate recommendation system is needed in recommending tourist attractions. In this final project, we use the Collaborative Filtering method, namely the Restricted Boltzmann Machine (RBM) algorithm and the Matrix Factorization-Alternating Least Squares (MF-ALS) algorithm in recommending tourist attractions. Attraction recommendations will be generated from the type of tourist attraction available on the website and the rating that has been given by previous users who have visited the tourist attraction. We use a root mean square error (RMSE) to find the accuracy. From the results of the research and implementation of the two algorithms, it can be concluded that the RBM algorithm is more accurate than the MF-ALS algorithm. The RBM algorithm has an RMSE value of 41%, while the MF-ALS algorithm 81%.
Evaluation and Performance Analysis using ANP and TOPSIS Algorithm
Authors: Utama Dana Marsetiya , Parameswari Reza Putri , Mubin Ahmad
Published: December 2022

Suppliers play an important role in supporting the supply chain within the company. Therefore, evaluation of suppliers in the company is a problem that is studied to improve the performance of the company’s supply chain. The purpose of this study is to evaluate the performance of green suppliers using the Analytic Network Process (ANP)-Technique for order performance by similarity to ideal solution (TOPSIS). ANP is used to weigh each factor and criteria, and TOPSIS is used to evaluate the performance of green suppliers. This research is a case study on the construction industry in Indonesia. Six factors and fourteen sub-criteria are used to evaluate the performance of green suppliers. Based on the ANP method, the cost factor is the criterion that has the highest weight, which is 0.44318. The sub-criteria that has the highest weight is product price, with a weight of 0.2681. Furthermore, the order of green supplier performance based on TOPSIS shows that supplier B ranks first, followed by suppliers A, D, and C.
Rough Set: Utilizing Machine Learning for the Covid-19 Vaccine
Authors: Andini Silfia , Arminarahmah Nur , Achmad Daengs GS , Surya Sara , Afdhal Muhammad
Published: December 2022

Rough Set is a machine learning algorithm that analyses and determines important attributes based on an uncertain data set. The purpose of this study is to classify public interest in the Covid-19 vaccine. Vaccination is one of the solutions from the government that is considered the most appropriate to reduce the number of Covid-19 cases. Data collection was taken through a questionnaire distributed to the village community in Air Manik Village, Padang-West Sumatra, randomly as many as 100 respondents. The assessment attributes in this study are Vaccine Understanding (1), Environment (2), Community Education (3), Vaccine Confidence (4), and Cost (5), while the target attribute is the result that contains the community’s interest or not to participate in vaccination. The analysis process is assisted using the Rosetta application. This study resulted in 3 reductions with 58 rules based on 100 respondents. This study concludes that the Rough Set algorithm can be used to classify public interest in the Covid-19 vaccine. Based on this research, it is hoped that it can provide information and input for local governments to be more aggressive in urging and encouraging the public to be vaccinated.
A Dynamics System of Modelling for Construction Development
Authors: Sarasanty Diah , Asmorowati Erna Tri
Published: December 2022

The construction industry is one industry that contributes significantly to a country’s economic growth. A construction project is successful if the implementation meets the three components namely the cost, time and quality. Project financing is one of the important components in the construction project activities that define how much budget should be provided in a construction project activity. Cost components used for feasibility studies, design alternatives are possible, and the selection of optimal design in a construction project. Inaccuracy in analyzing construction costs can have a negative effect on the entire construction process and all parties involved. A system dynamics approach is a simulation method in solving real-world problems to describe relationships among variables in complex real systems. The expected results from this research are quantitatively in the form of reinforced concrete work costs which are influenced by direct costs and indirect costs that can be updated in real-time. From the simulation results, a graphical analysis through the model output will be obtained and all the resulting scenarios can be compared. In addition, with sensitivity analysis through model scenarios, it can accommodate all possible deviations that will occur in the future, including risk factors in the future.
Effects of chain ownership and private equity financing on quality in the English care home sector: retrospective observational study
Authors: Patwardhan Sharvari , Sutton Matthew , Morciano Marcello
Published: December 2022

Background

the structure of care homes markets in England is changing with the emergence of for-profit homes organised in chains and financed by private equity. Previous literature shows for-profit homes were rated lower quality than not-for-profit homes when inspected by the national regulator, but has not considered new forms of financing.

Objectives

to examine whether financing and organisation of care homes is associated with regulator assessments of quality.

Methods

retrospective observational study of the Care Quality Commission’s ratings of 10,803 care homes providing services to older people as of January 2020. We used generalised ordered logistic models to assess whether ratings differed between not-for-profit and for-profit homes categorised into three groups: (i) chained ownership, financed by private equity; (ii) chained ownership, not financed by private equity and (iii) independent ownership. We compared Overall and domain (caring, effective, responsive, safe, well-led) ratings adjusted for care home size, age and location.

Results

all three for-profit ownership types had lower average overall ratings than not-for-profit homes, especially independent (6.8% points (p.p.) more likely rated as ‘Requires Improvement/Inadequate’, 95% CI: 4.7–8.9) and private equity chains (6.6 p.p. more likely rated as ‘Requires Improvement/Inadequate’, 95% CI: 2.9–10.2). Independent homes scored better than private equity chains in the safe, effective and responsive domains but worst in the well-led domain.

Discussion

private equity financing and independent for-profit ownership are associated with lower quality. The consequences of the changing care homes market structure for quality of services should be monitored.
Symptom Provocation Following Post-concussion Computerized Neurocognitive Testing and Its Relationship to Other Clinical Measures of Concussion
Authors: Stephenson Katie , Womble Melissa N , Eagle Shawn , Collins Michael W , Kontos Anthony P , Elbin R J
Published: December 2022

Objective

The objective of this study was to document the prevalence of post-computerized neurocognitive test (post-CNT) increases in symptoms in athletes with sport-related concussion, and to examine the effect of post-CNT symptom increases on concussion neurocognitive and vestibular/ocular motor clinical outcomes.

Methods

This was a retrospective analysis of medical records from a concussion specialty clinic. Two hundred and three athletes (M = 16.48 ± 1.97 years; 44% [90/203] female) completed a clinical visit for concussion within 30 days of injury (M = 7.73 ± 5.54 days). Computerized neurocognitive testing (the Immediate Post-concussion Assessment and Cognitive Testing: ImPACT), the Post-Concussion Symptom Scale (PCSS), and the Vestibular Ocular Motor Screening (VOMS) were the main outcome measures for the current study.

Results

Sixty-nine percent (141/203) of the sample did not report significant increases in PCSS scores following post-concussion CNT and were classified into a No Provocation (NO PROV) group. Thirty-one percent (62/203) of participants did report a significant increase in symptoms following post-concussion CNT and were classified into a Provocation (PROV) group. Neurocognitive performance was similar between groups. However, the PROV group reported significantly higher scores on the VOMS symptom items than the NO PROV group.

Conclusions

The majority of adolescent athletes can complete a post-concussion CNT without experiencing significant increases in concussion symptoms. Individuals that report symptom increases from completing a post-concussion CNT are more likely to exhibit increased vestibular/ocular motor symptoms. These findings underscore the relationship between the clinical findings from both CNT and vestibular/ocular motor measures following concussion.
Intrinsic Job Quality Attributes and Perceived Stress Amongst Social Workers: The Mediating Role of In-Work Social Environment Factors
Authors: Achdut Netta , Schwartz Tayri Talia Meital
Published: December 2022

Social work is a highly stressful occupation, its practice requiring coping with complex situations integral to serving the most deprived populations. Professionals in this field experience varying degrees of secondary trauma, burnout and psychological distress imperiling their own well-being. This study uses the newest framework of intrinsic job attributes to examine a multidimensional model of intrinsic job quality constructs to explain perceived stress (PS) amongst national sample of social workers in Israel (N = 2,542). Based on cross-sectional data, we employed exploratory factor analysis and confirmatory factor analysis to construct intrinsic job quality index. Structural equation model (SEM) and path analyses revealed the adverse effect of workload and a poor physical working environment on social workers’ PS. Social environment factors relating to superiors’ and co-workers’ support and sense of recognition mediated the effects of workload, job autonomy, physical working environment and meaningful work on social workers’ PS through diverse pathways. These findings may inform policy measures responding to the urgent need to monitor social workers’ workload and suggest how to nurture a stress-reducing social environment in social services in order to promote social workers’ well-being and the quality of the services they provide.
Bioanalysis of Endogenous Isotretinoin in Altered and Unaltered Human Plasma by Liquid Chromatography–Tandem Mass Spectrometry Coupled with Electrospray Ionization
Authors: Soni Kanchan , Agrawal Gopal Prasad
Published: December 2022

Bioanalytical method development and validation of endogenous Isotretinoin with Isotretinoin D5 as internal standard was done as per current regulatory guidelines. The method is simple, rugged and sensitive enough to estimate endogenous Isotretinoin using the chromatography-tandem mass spectrometry technique. An alternative approach has been adopted for quantitative analysis of endogenous Isotretinoin in human plasma. Isotretinoin free matrix (surrogate matrix) was prepared and further used for the development and validation of Isotretinoin. The method was validated in altered and unaltered plasma. The chromatographic optimization was done with column (ACE C18, 100 × 4.6 mm I.D. 5 μm particle size), using a mobile phase containing 1 mM ammonium acetate, pH 3.0 as a solvent A and solvent B (1 mM ammonium acetate (pH 3.0) with acetonitrile in a ratio of 10:90). A flow rate was set at 0.75 mL/min in a binary gradient mode. The analyte was recovered by liquid–liquid extraction method with diethyl ether as an extraction solvent. Multi-reaction monitoring mode in negative polarity was implemented for the quantification of endogenous Isotretinoin in plasma. The calibration curve of Isotretinoin was linear (r2 > 0.9992) over the concentration range of 0.5–1000 ng/mL. The intra-day precision was found in a range of 2.0–3.9% CV for altered samples and 0.9–3.7% CV for unaltered samples. The inter-day precision was found 2.6–6.1% CV for altered samples and 1.3–3.8% CV for unaltered samples. The average recovery of the extraction procedure was found 64.6% for altered samples and 62.2% for unaltered samples.
Transmitted Drug Resistance to Integrase-Based First-Line Human Immunodeficiency Virus Antiretroviral Regimens in Mediterranean Europe
Authors: de Salazar Adolfo , Viñuela Laura , Fuentes Ana , Teyssou Elisa , Charpentier Charlotte , Lambert-Niclot Sidonie , Serrano-Conde Esther , Pingarilho Marta , Fabeni Lavinia , De Monte Anne , Stefic Karl , Perno Carlo Federico , Aguilera Antonio , Falces Iker , Delgado Rafael , Fernandes Sandra , Diogo Isabel , Gomes Perpetua , Paraskevis Dimitrios , Santoro Maria-Mercedes , Ceccherini-Silberstein Francesca , Marcelin Anne-Geneviève , Garcia Federico
Published: December 2022

Background

We evaluated the prevalence of transmitted drug resistance (TDR) to integrase strand-transfer inhibitors (INSTIs) and nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and of clinically relevant resistance (CRR) in newly diagnosed people with human immunodeficiency virus (HIV; PWH) naive to antiretroviral therapy (ART) in Europe.

Methods

MeditRes is a consortium that includes ART-naive PWH newly diagnosed in France, Greece, Italy, Portugal, and Spain during 2018–2021. Reverse transcriptase and INSTI sequences were provided by participating centers. To evaluate the prevalence of surveillance drug resistance mutations (SDRM), we used the calibrated population resistance tools from the Stanford HIV website. To evaluate CRR, defined as any resistance level ≥3, we used the Stanford HIV Drug Resistance Database v.9.1 algorithm.

Results

We included 2705 PWH, 72% men, median age of 37 years (interquartile range, 30–48); 43.7% were infected by non-B subtypes. The prevalence of INSTI-SDRMs was 0.30% (T66I, T66A, E92Q, E138T, E138K, Y143R, S147G, R263K; all n=1) and the prevalence of NRTI-SDRMs was 5.77% (M184V: 0.85%; M184I: 0.18%; K65R/N: 0.11%; K70E: 0.07%; L74V/I: 0.18%; any thymidine analog mutations: 4.36%). INSTI-CRR was 2.33% (0.15% dolutegravir/bictegravir, 2.29% raltegravir/elvitegravir) and 1.74% to first-line NRTIs (0.89% tenofovir/tenofovir alafenamide, 1.74% abacavir, 1.07% lamivudine/emtricitabine).

Conclusions

We present the most recent data on TDR to integrase-based first-line regimens in Europe. Given the low prevalence of CRR to second-generation integrase inhibitors and to first-line NRTIs during 2018–2021, it is unlikely that newly diagnosed PWH in MeditRes countries would present with baseline resistance to a first-line regimen based on second-generation integrase inhibitors.
Global myocardial oedema in resuscitated out-of-hospital cardiac arrest patients assessed by cardiac magnetic resonance: a pilot study
Authors: Klein Anika , Grand Johannes , Meyer Martin Abild Stengaard , Wiberg Sebastian , Mogelvang Rasmus , Vejlstrup Niels , Schousboe Birgitte , Gjedsted Jakob , Oestergaard Morten , Wanscher Michael , Kjaergaard Jesper , Hassager Christian
Published: December 2022

Aims

Myocardial dysfunction is well described after out-of-hospital cardiac arrest (OHCA); however, the underlying mechanisms are not yet understood. We hypothesized that this dysfunction is associated to a global myocardial oedema. Using cardiac magnetic resonance (CMR), we assessed the presence of such oedema early after successful resuscitation from OHCA.

Methods and results

Comatose patients resuscitated from OHCA and admitted to the cardiac intensive care unit were consecutively included and underwent CMR in general anaesthesia within 36 h after cardiac arrest with anaesthetic support. To assess global myocardial oedema, T1 and T2 segmented maps were generated from three representative short-axis slices, and values from each segment were then used to determine a mean global T1 and T2 time for each patient. Healthy subjects were used as controls. CMR was obtained in 16 patients and compared with nine controls. The OHCA patients were 60 ± 9 years old, and acute myocardial infarction (MI) was diagnosed in six cases. On admission, left ventricular ejection fraction assessed by transthoracic echocardiography was 35 ± 15%, and this improved significantly to 43 ± 14% during hospitalization (P < 0.05). Mean global T1 and T2 time was significantly higher in OHCA patients compared with the control group (1071 ms vs. 999 ms, P = 0.002, and 52 ms vs. 46 ms, P < 0.001, respectively), and this difference remained significant when segments involved in the MI were excluded.

Conclusion

Assessed with CMR, we for the first time document an early global myocardial oedema in patients successfully resuscitated from OHCA.
A systematic review and evidence assessment of monogenic gene–disease relationships in human female infertility and differences in sex development
Authors: Van Der Kelen Annelore , Okutman Özlem , Javey Elodie , Serdarogullari Münevver , Janssens Charlotte , Ghosh Manjusha S , Dequeker Bart J H , Perold Florence , Kastner Claire , Kieffer Emmanuelle , Segers Ingrid , Gheldof Alexander , Hes Frederik J , Sermon Karen , Verpoest Willem , Viville Stéphane
Published: December 2022

BACKGROUND

As in other domains of medicine, high-throughput sequencing methods have led to the identification of an ever-increasing number of gene variants in the fields of both male and female infertility. The increasing number of recently identified genes allows an accurate diagnosis for previously idiopathic cases of female infertility and more appropriate patient care. However, robust evidence of the gene–disease relationships (GDR) allowing the proper translation to clinical application is still missing in many cases.

OBJECTIVE AND RATIONALE

An evidence-based curation of currently identified genes involved in female infertility and differences in sex development (DSD) would significantly improve both diagnostic performance and genetic research. We therefore performed a systematic review to summarize current knowledge and assess the available GDR.

SEARCH METHODS

PRISMA guidelines were applied to curate all available information from PubMed and Web of Science on genetics of human female infertility and DSD leading to infertility, from 1 January 1988 to 1 November 2021. The reviewed pathologies include non-syndromic as well as syndromic female infertility, and endocrine and reproductive system disorders. The evidence that an identified phenotype is caused by pathogenic variants in a specific gene was assessed according to a standardized scoring system. A final score (no evidence, limited, moderate, strong, or definitive) was assigned to every GDR.

OUTCOMES

A total of 45 271 publications were identified and screened for inclusion of which 1078 were selected for gene and variant extraction. We have identified 395 genes and validated 466 GDRs covering all reported monogenic causes of female infertility and DSD. Furthermore, we present a genetic diagnostic flowchart including 105 genes with at least moderate evidence for female infertility and suggest recommendations for future research. The study did not take into account associated genetic risk factor(s) or oligogenic/polygenic causes of female infertility.

WIDER IMPLICATIONS

We have comprehensively reviewed the existing research on the genetics of female infertility and DSD, which will enable the development of diagnostic panels using validated genes. Whole genome analysis is shifting from predominantly research to clinical application, increasing its diagnostic potential. These new diagnostic possibilities will not only decrease the number of idiopathic cases but will also render genetic counselling more effective for infertile patients and their families.
Gradient discretization of a 3D-2D-1D mixed-dimensional diffusive model with resolved interface, application to the drying of a fractured porous medium
Authors: Brenner K , Chave Florent , Masson R
Published: December 2022

We consider a 3D-2D-1D mixed-dimensional diffusive model in a fractured porous medium coupling the 1D model along the centerline skeleton of a tubular network, the 2D model on a network of planar fractures and the 3D model in the surrounding matrix domain. The transmission conditions are based on a potential continuity assumption at matrix fracture interfaces, and on Robin type conditions at the resolved interfaces between the tubular network and the matrix and fracture network domains. The discretization of this mixed-dimensional model is formulated in the gradient discretization framework (Droniou, J., Eymard, R. & Herbin, R. (2016) Gradient schemes: generic tools for the numerical analysis of diffusion equations. ESAIM Math. Model. Numer. Anal., 50, 749–781), which covers a large class of conforming and nonconforming schemes and provides stability and error estimates based on general coercivity, consistency and limit-conformity properties. As an example of discretization fitting this framework, the mixed-dimensional version of the vertex approximate gradient (VAG) scheme is developed. It is designed to allow nonconforming meshes at the interface between the 1D and 3D-2D domains, to provide a conservative formulation with local flux expressions and to be asymptotic preserving in the limit of high transfer coefficients. Numerical experiments are provided on analytical solutions for simplified geometries, which confirm the theoretical results. Using its equivalent finite volume formulation, the VAG discretization is extended to a drying mixed-dimensional model coupling the Richards equation in a fractured porous medium and the convection diffusion of the vapor molar fraction along the 1D domain. It is applied to simulate the drying process between an operating tunnel and a radioactive waste storage rock with explicit representation of the fractures in the excavated damaged zone.
The effects of a Nutritional Packet (live yeast, vitamins C and B1, and electrolytes) offered during the final phase of feedlot steers on growth performance, nutrient digestion, and feeding behavior
Authors: Nardi Kaue T , Sarturi Jhones O , Huerta-Leidenz Nelson , Henry Darren D , Woerner Dale R , Ciriaco Francine M , Sánchez-Escalante Armida , Torrescano-Urrutia Gastón R , Silva Kaliu G S , Favero Igor G
Published: December 2022

The effects of a Nutritional Packet offered to beef steers during the final 64 d of the feedlot-finishing phase on growth performance, carcass characteristics, nutrient digestibility, and feeding behavior were evaluated. Angus-crossbred steers (N = 120; initial body weight = 544 ± 52 kg) were assigned to 30 pens (4 steers per pen; 15 pens per treatment) in a randomized complete block design where pen was the experimental unit. A steam-flaked corn-based finishing diet was offered to ad libitum, and the treatments were as follows: 1) control and 2) 30 g per steer-daily (dry matter basis) of the Nutritional Packet. The Nutritional Packet was formulated to provide 1.7 × 1010 CFU per steer-daily of Saccharomyces cerevisiae, 162 mg per steer-daily of vitamin C; 400 mg per steer-daily of vitamin B1; 2.4 g per steer-daily of NaCl, and 2.4 g per steer-daily of KCl. Data were analyzed using the GLIMMIX procedure of SAS with the fixed effect of treatment and the random effect of block. The average daily gain (P = 0.89), dry matter intake (P = 0.57), and gain efficiency (P = 0.82) were not affected by the inclusion of the Nutritional Packet. Digestibility of dry and organic matter, and neutral and acid detergent fiber increased (P ≤ 0.02) for steers offered the Nutritional Packet, while a trend for the same response was observed for hemicellulose (P = 0.08). The 12th rib backfat thickness increased (P = 0.02) for carcasses of steers offered the Nutritional Packet, followed by a greater (P = 0.03) calculated yield grade, whereas other carcass traits were not affected (P ≥ 0.32). While the steers under the control diet decreased behavior activities on day 63, a consistent pattern of feeding behavior measurements (activity min/d and min/kg of dry and organic matter, fiber fractions, and digestible nutrients) were observed for steers consuming the Nutritional Packet during both feeding behavior assessment periods (treatment × period interactions, P ≤ 0.03). Overall time (min/d) spent on rumination, drinking, active, chewing, and resting were not affected (P ≥ 0.28) by treatments. The Nutritional Packet offered to steers during the final 64 d on feed induced an improvement in apparent digestibility of nutrients and carcass fat deposition, without affecting growth performance or other carcass quality indices. Such effects associated with the more consistent feeding behavior of steers receiving the Nutritional Packet may warrant a shorter time on feed during the final portion of the finishing phase.
To go or not to go: variable density-dependent dispersal in small mammals
Authors: Rutherford Kate L , Cottenie Karl , Denomme-Brown Simon T
Published: December 2022

Population density has been widely understood to be a key influencer of dispersal behavior; however, the generality of density-dependent (DD) dispersal in vertebrates is unclear. We conducted a review of the available empirical data on small mammal DD dispersal, distinguishing between the three dispersal stages: emigration, immigration, and transience (dispersal distance). We focused on small mammals because they are a well-studied, functionally similar group of vertebrates, with a distinct ecological importance. We also examined the effect of season, body mass, study length, and study type on the strength and direction of DD dispersal. The majority of emigration and dispersal distance studies reported negative density dependence, while immigration was mostly independent of density. No correlative patterns were detected; however, interpretation of the available data was hindered by inconsistencies in experimental and analytical approach across studies. Our results suggest that the three phases of the dispersal process may be influenced differently by density and highlight the importance of distinguishing between emigration, immigration, and transience when considering the effects of density dependence. As well, our study identifies several limitations with the current available data which limit the ability to compare DD dispersal behavior across systems, and calls for future investigations that consider all three phases of dispersal in the same system.
A case of extrapulmonary tuberculosis after use of baricitinib
Authors: Shimada Tetsuro , Maeyama Akira , Hagio Tomonobu , Muraoka Kunihide , Shibata Terufumi , Yamasaki Yutaro , Oda Taiga , Hamasaki Makoto , Yamamoto Takuaki
Published: December 2022

Extrapulmonary tuberculosis (TB) can occur in patients treated with Janus kinase (JAK) inhibitors. We present a case of rheumatoid arthritis complicated by extrapulmonary TB following baricitinib treatment. A 45-year-old Japanese woman was diagnosed with rheumatoid arthritis at another hospital, and she subsequently started treatment with methotrexate (MTX) at 6.0 mg/week and prednisolone at 3.0 mg/day at our institute. The MTX dose was increased to 10 mg/week, and clinical remission was achieved; however, the disease activity flared up 6 months after the initial visit. Isoniazid (INH) prophylaxis was started following positive T-SPOT® screening for TB, and baricitinib (Olumiant®) was introduced 3 weeks later because of an insufficient response to MTX. INH prophylaxis was continued for 6 months. Ten months after starting INH treatment, a painless mass was observed on the left side of the patient’s neck. Magnetic resonance imaging showed enlarged lymph nodes with calcification. A subsequent biopsy and pathologic examination led to a diagnosis of tuberculous lymphadenitis, and the patient was started on anti-TB therapy. Ten months later, the patient was still in remission and doing well. Extrapulmonary TB can be difficult to diagnose because of inconsistent physical and laboratory findings. When treating patients with JAK inhibitors, physicians should be cognisant of the potential for extrapulmonary TB to develop.
Mitotic count is prognostic in IDH mutant astrocytoma without homozygous deletion of CDKN2A/B. Results of consensus panel review of EORTC trial 26053 (CATNON) and EORTC trial 22033-26033
Authors: Kros Johan M , Rushing Elisabeth , Uwimana Aimé L , Hernández-Laín Aurelio , Michotte Alex , Al-Hussaini Maysa , Bielle Franck , Mawrin Christian , Marucci Gianluca , Tesileanu C Mircea S , Stupp Roger , Baumert Brigitta , van den Bent Martin , French Pim J , Gorlia Thierry
Published: December 2022

Background

Gliomas with IDH1/2 mutations without 1p19q codeletion have been identified as the distinct diagnostic entity of IDH mutant astrocytoma (IDHmut astrocytoma). Homozygous deletion of Cyclin-dependent kinase 4 inhibitor A/B (CDKN2A/B) has recently been incorporated in the grading of these tumors. The question of whether histologic parameters still contribute to prognostic information on top of the molecular classification, remains unanswered. Here we evaluated consensus histologic parameters for providing additional prognostic value in IDHmut astrocytomas.

Methods

An international panel of seven neuropathologists scored 13 well-defined histologic features in virtual microscopy images of 192 IDHmut astrocytomas from EORTC trial 22033-26033 (low-grade gliomas) and 263 from EORTC 26053 (CATNON) (1p19q non-codeleted anaplastic glioma). For 192 gliomas the CDKN2A/B status was known. Consensus (agreement ≥ 4/7 panelists) histologic features were tested together with homozygous deletion (HD) of CDKN2A/B for independent prognostic power.

Results

Among consensus histologic parameters, the mitotic count (cut-off of 2 mitoses per 10 high power fields standardized to a field diameter of 0.55 mm and an area of 0.24 mm2) significantly influences PFS (P = .0098) and marginally the OS (P = .07). Mitotic count also significantly affects the PFS of tumors with HD CDKN2A/B, but not the OS, possibly due to limited follow-up data.

Conclusion

The mitotic index (cut-off 2 per 10 40× HPF) is of prognostic significance in IDHmut astrocytomas without HD CDKN2A/B. Therefore, the mitotic index may direct the therapeutic approach for patients with IDHmut astrocytomas with native CDKN2A/B status.
Back to the Future, II
Authors: Bates Susan E
Published: December 2022

This editorial reflects on the vision and focus of The Oncologist, both historically and with a look toward the future.
Endoplasmic reticulum calnexins participate in the primary root growth response to phosphate deficiency
Authors: Montpetit Jonatan , Clúa Joaquín , Hsieh Yi-Fang , Vogiatzaki Evangelia , Müller Jens , Abel Steffen , Strasser Richard , Poirier Yves
Published: December 2022

Accumulation of incompletely folded proteins in the endoplasmic reticulum (ER) leads to ER stress, activates ER protein degradation pathways, and upregulates genes involved in protein folding. This process is known as the unfolded protein response (UPR). The role of ER protein folding in plant responses to nutrient deficiencies is unclear. We analyzed Arabidopsis (Arabidopsis thaliana) mutants affected in ER protein quality control and established that both CALNEXIN (CNX) genes function in the primary root response to phosphate (Pi) deficiency. CNX1 and CNX2 are homologous ER lectins promoting protein folding of N-glycosylated proteins via the recognition of the GlcMan9GlcNAc2 glycan. Growth of cnx1-1 and cnx2-2 single mutants was similar to that of the wild type under high and low Pi conditions, but the cnx1-1 cnx2-2 double mutant showed decreased primary root growth under low Pi conditions due to reduced meristematic cell division. This phenotype was specific to Pi deficiency; the double mutant responded normally to osmotic and salt stress. Expression of CNX2 mutated in amino acids involved in binding the GlcMan9GlcNAc2 glycan failed to complement the cnx1-1 cnx2-2 mutant. The root growth phenotype was Fe-dependent and was associated with root apoplastic Fe accumulation. Two genes involved in Fe-dependent inhibition of primary root growth under Pi deficiency, the ferroxidase LOW PHOSPHATE 1 (LPR1) and P5-type ATPase PLEIOTROPIC DRUG RESISTANCE 2 (PDR2) were epistatic to CNX1/CNX2. Overexpressing PDR2 failed to complement the cnx1-1 cnx2-2 root phenotype. The cnx1-1 cnx2-2 mutant showed no evidence of UPR activation, indicating a limited effect on ER protein folding. CNX might process a set of N-glycosylated proteins specifically involved in the response to Pi deficiency.
Direct computation of nth-order correlations of the solution of a non-linear stochastic equation
Authors: Saïdi Abdelkader , Dušek Jan
Published: December 2022

A system of nonlinear stochastic equations excited by a Gaussian random term leading to a statistically stationary solution is considered. The Carleman linearization is used to handle the nonlinearity and the statistical characterization of the solution is formulated in terms of a sequence of correlations of increasing order. Truncated in a finite but arbitrary order, the problem leads to a linear system of equations yielding directly the correlations. It is demonstrated in two examples that, if the excitation is not too strong, the solution converges as a function of the truncation order and provides an alternative to the Monte Carlo approach consisting in ensemble averaging a large number of time-dependent random solutions. For a low-dimensional system, it is shown that replacing the tensor indexing by a numbering accounting for redundancies makes it possible to keep the total problem dimension within reasonable limits even if relatively high-order correlations are accounted for. A model reduction based on the singular value decomposition of the second-order correlation matrix is tested with success for a case of a partial differential equation (Burgers’ equation), showing that the method can be potentially applied even to high-dimensional systems originating in partial differential equations.
Sleep and neurocognitive outcome in primary school children with Robin Sequence
Authors: Wiechers Cornelia , Uhlig Simone , Poets Anette , Weise Christina , Naros Andreas , Krimmel Michael , Koos Bernd , Poets Christian F , Quante Mirja
Published: December 2022

Study objectives

To investigate neurocognitive and behavioral outcomes at primary school age in relation to obstructive sleep apnea (OSA) in children with Robin sequence (RS) treated with the Tuebingen palatal plate in infancy and to assess the impact of OSA in these patients.

Methods

Forty-two primary school-aged children (n = 21 with RS, n = 21 age- and sex-matched controls) underwent polysomnography, intelligence testing (“Wechsler Intelligence Scale for Children—Fifth Edition” [WISC-V]), and anthropometrics. Families completed a 7-day sleep diary and questionnaires on sleep and behavior (Children’s Sleep Habits Questionnaire [CSHQ] and the Child Behavior Checklist [CBCL]).

Results

In children with RS (17 non-syndromic, four syndromic; median age 9.7 [8.5–10.8] years), the obstructive apnea-hypopnea index (OAHI) was significantly higher than in controls (1.3 [0.4–2.7]/h vs. 0.4 [0.1–0.6]/h). Two syndromic children with RS were already on nocturnal respiratory support for OSA prior to our study, and one non-syndromic child was diagnosed with severe OSA (OAHI 57/h) despite an unremarkable medical history and questionnaire. The overall intelligence quotient in children with RS was within the normal range and did not differ between children with RS and healthy peers (102 vs. 108, p = .05). However, children with RS had values in the at-risk clinical range for externalizing behavior.

Conclusions

These children with RS showed an increased risk of OSA and behavioral problems, suggesting regular screening for OSA throughout childhood. Neurocognitive scores in children with RS were within the normal range after adequate treatment of OSA during infancy.
Managing sanctions risk in the fiduciary industry—a view from Guernsey
Authors: Arstall Laila
Published: December 2022

In recent years, successive waves of economic, political and environmental challenges have caused profound disruption to our personal and professional lives. Businesses have been required to assess and reassess their ability to meet the evolving realities posed by these external risks and to take stock of the people, processes and systems that protect their vulnerabilities whilst building operational resilience to meet future challenges. In this article, Laila Arstall examines the foundational blocks for trust practitioners looking to manage sanctions risk under Guernsey’s Fiduciaries Law. She highlights recent experiences in Guernsey when dealing with sanctions introduced earlier this year in response to Russia’s aggression towards Ukraine to provide some practical insights into how Guernsey trustees are tackling sanctions risks from a legal perspective.
Toxic mechanism of the Mongolian medicine “Hunqile-7” based on metabonomics and the metabolism of intestinal flora
Authors: Wang Xiye , Bao Leer , Jiang Mingyang , Li Dan , Xu Liang , Bai Meirong
Published: December 2022

The traditional Mongolian medicine Hunqile-7 (HQL-7), which is mainly used to relieve pain in clinic, has certain toxicity. Therefore, toxicological investigation of HQL-7 is of great significance to its safety assessment. In this study, the toxic mechanism of HQL-7 was explored based on a combination of metabolomics and intestinal flora metabolism. UHPLC-MS was used to analyze the serum, liver and kidney samples of rats after intragastric administration of HQL-7. The decision tree and K Nearest Neighbor (KNN) model were established based on the bootstrap aggregation (bagging) algorithm to classify the omics data. After samples were extracted from rat feces, the high-throughput sequencing platform was used to analyze the 16s rRNA V3-V4 region of bacteria. The experimental results confirm that the bagging algorithm improved the classification accuracy. The toxic dose, toxic intensity, and toxic target organ of HQL-7 were determined in toxicity tests. Seventeen biomarkers were identified and the metabolism dysregulation of these biomarkers may be responsible for the toxicity of HQL-7 in vivo. Several kinds of bacteria was demonstrated to be closely related to the physiological indices of renal and liver function, indicating liver and kidney damage induced by HQL-7 may be related to the disturbance of these intestinal bacteria. Overall, the toxic mechanism of HQL-7 was revealed in vivo, which not only provides a scientific basis for the safe and rational clinical use of HQL-7, but also opens up a new field of research on big data for Mongolian medicine.
Heparin Conjugate Pretreatment of Kidneys From Deceased Donors Before Transplantation: Results From the First-in-human Randomized Phase I Trial
Authors: Sedigh Amir , Lundgren Torbjörn , Lindnér Per , Nordström Johan , Magnusson Peetra , Jönsson Janniz , Carlsson Fredrik , Ploeg Rutger , Lorant Tomas
Published: December 2022

Background.

Pretreating porcine kidneys with Corline Heparin Conjugate (CHC) during hypothermic machine perfusion (HMP) has been shown to reduce preservation injury and improve early kidney function. In this first-in-human phase I study, the safety and tolerability of transplanting CHC-pretreated kidneys were evaluated.

Methods.

CHC or placebo was added to the preservation solution during HMP of donated kidneys from deceased donors for at least 3 h before transplantation into adult patients. The primary safety endpoint was the number and severity of adverse events (AEs) and serious AEs (SAEs) during the first 30 d after transplantation.

Results.

In the first 30 d, 66 AEs were reported in 8 patients who received CHC-pretreated kidneys with 39 AEs in 8 patients who received placebo-pretreated kidneys (P = 0.1 in post hoc analysis). The most common AEs were hypertension (CHC, n = 5; placebo, n = 2) and anemia (CHC, n = 5; placebo, n = 2). Most AEs were assessed as mild (58%) or moderate (39%) and not related to treatment (95%). There were 2 SAEs reported in each group. One SAE, considered possibly related to CHC treatment, was a case of severe postprocedural hemorrhage that required reoperation. No patients needed dialysis. There were no observed rejections and no patient deaths.

Conclusions.

Pretreatment of kidneys with CHC before transplantation was considered safe and tolerable. Efficacy studies are now planned to investigate if CHC can reduce early ischemia-reperfusion injury in humans.
Value of Renal Histology in Predicting Cardiorenal Outcomes in Heart Transplant–listed Patients
Authors: Barua Sumita , Yang Tao , Conte Sean , Bragg Christopher , Sevastos Jacob , Macdonald Peter S. , Muthiah Kavitha , Hayward Christopher S.
Published: December 2022

Background.

Cardiorenal syndrome (CRS) contributes significantly to morbidity and mortality in patients requiring mechanical circulatory support and transplantation. There are no validated markers to predict major adverse kidney events (MAKEs), for which simultaneous heart-kidney transplant (SHKT) could offer improved survival. We evaluate renal histology in predicting MAKEs in transplant-listed patients.

Methods.

We identified 18 patients with renal histology consistent with CRS from 655 consecutive heart transplant-listed patients between 2010 and 2019. Biopsies were analyzed for glomerular, tubular, interstitial, and arteriolar changes tallied to give a biopsy chronicity score. The primary outcome, MAKE, was a composite of death, need for renal replacement therapy (RRT), or estimated glomerular filtration rate decline >50%. These were evaluated at 2 time points: before and following the transplant. Secondary outcomes included the individual components of the composite outcomes and the need for short-term RRT following the transplant.

Results.

The mean age was 52.3 y, 22% were female. Five patients did not survive to transplant. One patient underwent successful SHKT. MAKE occurred in 8 of 18 before the transplant and in 8 of 13 following the transplant. Neither outcome was predicted by baseline biochemistry. The biopsy chronicity score was significantly higher in patients with MAKE before transplant (4.3 versus 1.7, P = 0.024) and numerically higher in patients requiring short-term RRT following transplant (3.2 versus 0.7, P = 0.075). Contrary to limited previous literature, interstitial fibrosis did not predict any outcome, whereas tubular atrophy and arteriosclerosis were associated with MAKE before transplant.

Conclusions.

A higher biopsy chronicity score was associated with adverse kidney endpoints, raising its potential utility over standard biochemistry in considering SHKT referral.
Perceptions and Early Outcomes of the Acuity Circles Allocation Policy Among Liver Transplant Centers in the United States
Authors: Pawlak Natalie , Song, Cherilyn , Alvi Saba , Schuster, Kimberly , Segalini Nicole , Kwon, Yong K. , Akoad Mohamed E. , Rauf M. Ameen , Mulligan David , Aziz, Hassan
Published: December 2022

Background.

Recently, a new liver allocation policy called the acuity circles (AC) framework was implemented to decrease geographic disparities in transplant metrics across donor service areas. Early analyses have examined the changes in outcomes because of the AC policy. However, perceptions among transplant surgeons and staff regarding the new policy remain unknown.

Methods.

A 28-item survey was sent to division chiefs and surgical directors of liver transplantation across the United States. Questions assessed the respondents’ perceptions regarding center-level metrics and staff satisfaction. We used Organ Procurement and Transplantation Network data to study differences in allocation between the pre-AC implementation period (2019) and the post-AC implementation period (2020–2021).

Results.

A total of 40 participants completed this ongoing survey study. Most responses were from region 8 (13%), region 10 (15%), and region 11 (13%). Sixty-three percent of respondents stated that the wait time for a suitable offer for recipients with model of end-stage liver disease score <30 has decreased, whereas 50% stated that wait time for a suitable offer for recipients with model of end-stage liver disease score >30 has increased. However, most respondents (75%) felt that the average cost per transplant had increased and that the rate of surgical complications and 1-y graft survival had remained the same. In most states, an observable decrease in in-state liver transplantations occurred each year between 2019 and 2021. In addition, most allocation regions reported an increase in donations after circulatory deaths between 2019 and 2021.

Conclusions.

Perceptions of the new AC policy among liver transplant surgeons in the United States remain mixed, highlighting the potential strengths and concerns regarding its future impact. Further studies should assess the effects of the AC policy on clinical outcomes and liver transplantation access.
Phaeohyphomycosis in Kidney Transplant Recipients: Highlighting the Importance of Early Recognition and Surgical Debridement
Authors: Singla Animesh A. , Garg, Priya , Chui, Juanita N. , Pham, David , Webb-Harvey, Zachary J. , Halliday, Catriona L. , De Silva, Ramesh , Hameed, Ahmer , Nulend, Rowan Klein , Lee Taina , Wong Germaine , Pleass, Henry
Published: December 2022

Background.

Fungal infections are a recognized complication of immunosuppression in solid organ transplant recipients. Phaeohyphomycoses are fungal infections caused by a diverse group of dematiaceous fungi.

Methods.

We share the learning points from 2 Australian cases of phaeohyphomycosis secondary to Phaeacreomonium species (spp). A literature review was performed using Medline, Embase, and Google Scholar to identify this condition among kidney transplant recipients.

Results.

With the 2 cases reported in this article, a total of 17 cases were identified in the literature. Phaeacremonium spp is ubiquitous in humid and temperate flora, including Australia. Minor trauma is likely the source of inoculation in most cases and diagnosis is often delayed. Presently, no guidelines for management exist given the rarity of this condition. Most known cases have been treated with surgical debulking combined with long-course antifungal therapy.

Conclusion.

This paper describes 2 Australian cases of phaeohyphomycosis in kidney transplant recipients. A high index of suspicion, especially in the immunosuppressed, is essential for timely diagnosis in kidney transplant recipients. There are several diagnostic and therapeutic challenges that remain with this condition.