bluuebunny/crossref_metadata_2025 huggingface dataset:
Caloric Restriction Intervention Alters Specific Circulating Biomarkers of the Senescence-Associated Secretome in Middle-Aged and Older Adults With Obesity and Prediabetes in an 18-Week Randomized Controlled Trial
Authors: Justice Jamie N , Leng Xiaoyan I , LeBrasseur Nathan K , Tchkonia Tamara , Kirkland James L , Mitin Natalia , Liu Yongmei , Kritchevsky Stephen B , Nicklas Barbara J , Ding Jingzhong
Published: September 2023

Cellular senescence is a biological aging process that is exacerbated by obesity and leads to inflammation and age- and obesogenic-driven chronic diseases including type 2 diabetes. Caloric restriction (CR) may improve metabolic function in part by reducing cellular senescence and the pro-inflammatory senescence-associated phenotype (SASP). We conducted an ancillary investigation of an 18-week randomized controlled trial (RCT) of CR (n = 31) or Control (n = 27) in 58 middle-aged/older adults (57.6 ± 5.8 years; 75% Women) with obesity and prediabetes. We measured mRNA expression of select senescence and apoptosis genes in blood CD3 + T cells (qRT-PCR) and a panel of 25 plasma SASP proteins (Luminex/multiplex; ELISA). Participants randomized to CR lost −10.8 ± 0.9 kg (−11.3% ± 5.4%) over 18 weeks compared with +0.5 ± 0.9 kg (+0.03% ± 3.5%) in Control group. T-cell expression of senescence biomarkers, p16INK4a and p21CIP1/WAF1, and apoptosis markers, BCL2L1 and BAK1, was not different between CR and Control groups in age, race, and sex-adjusted mixed models (p > .05, all). Iterative principal axis factor analysis was used to develop composite SASP Factors, and the Factors comprising TNFRI, TNFRII, uPAR, MMP1, GDF15, OPN, Fas, and MPO were significantly altered with CR intervention (age, sex, race-adjusted mixed model time × treatment F = 4.17, p ≤ .05) and associated with the degree of weight loss (R2 = 0.12, p ≤ .05). Our study provides evidence from an RCT that specific circulating biomarkers of senescent cell burden are changed by CR in middle-aged and older adults with obesity and prediabetes. Future studies compare tissue and circulating levels of p16INK4a and pro-inflammatory SASP biomarkers in other populations, and interventions.
Aging-Related Mitochondrial Dysfunction Is Associated With Fibrosis in Benign Prostatic Hyperplasia
Authors: Adrian Alexis E , Liu Teresa T , Pascal Laura E , Bauer Scott R , DeFranco Donald B , Ricke William A
Published: September 2023

Background

Age is the greatest risk factor for lower urinary tract symptoms attributed to benign prostatic hyperplasia (LUTS/BPH). Although LUTS/BPH can be managed with pharmacotherapy, treatment failure has been putatively attributed to numerous pathological features of BPH (eg, prostatic fibrosis, inflammation). Mitochondrial dysfunction is a hallmark of aging; however, its impact on the pathological features of BPH remains unknown.

Methods

Publicly available gene array data were analyzed. Immunohistochemistry examined mitochondrial proteins in the human prostate. The effect of complex I inhibition (rotenone) on a prostatic cell line was examined using quantitative polymerase chain reaction, immunocytochemistry, and Seahorse assays. Oleic acid (OA) was tested as a bypass of complex I inhibition. Aged mice were treated with OA to examine its effects on urinary dysfunction. Voiding was assessed longitudinally, and a critical complex I protein measured.

Results

Mitochondrial function and fibrosis genes were altered in BPH. Essential mitochondrial proteins (ie, voltage-dependent anion channels 1 and 2, PTEN-induced kinase 1, and NADH dehydrogenase [ubiquinone] iron–sulfur protein 3, mitochondrial [NDUFS3]) were significantly (p < .05) decreased in BPH. Complex I inhibition in cultured cells resulted in decreased respiration, altered NDUFS3 expression, increased collagen deposition, and gene expression. OA ameliorated these effects. OA-treated aged mice had significantly (p < .05) improved voiding function and higher prostatic NDUFS3 expression.

Conclusions

Complex I dysfunction is a potential contributor to fibrosis and lower urinary tract dysfunction in aged mice. OA partially bypasses complex I inhibition and therefore should be further investigated as a mitochondrial modulator for treatment of LUTS/BPH. Hypotheses generated in this investigation offer a heretofore unexplored cellular target of interest for the management of LUTS/BPH.
Childhood Parental Disfavoritism and Chinese Adults’ Psychological Well-Being in Middle and Later Life: The Moderating Effect of Gender
Authors: Hou Yifei , Suitor J Jill
Published: September 2023

Objectives

Parental differential treatment of children, particularly disfavoritism, has been found to detrimentally affect adult children’s psychological well-being in the United States. However, no study has investigated the long-reaching influence of parental disfavoritism in China, where there is an absence of equal treatment norms. Drawing from theories of social comparison, life course, and gender dynamics in China, we tested how perceptions of childhood parental disfavoritism affect midlife and older Chinese adults’ depressive symptoms, and how the effects differ by own and parent’s gender.

Methods

Random-intercept models were used based on a sample of 17,682 midlife and older Chinese adults, drawn from 5 waves of China Health and Retirement Longitudinal Study.

Results

Recollections of childhood parental disfavoritism were associated with higher depressive symptoms among Chinese adults. Perceptions of paternal disfavoritism predicted both men’s and women’s depressive symptoms, whereas perceptions of maternal disfavoritism predicted women’s depressive symptoms only. Paternal disfavoritism was more detrimental than maternal disfavoritism, but only for men. Maternal disfavoritism was more detrimental for women than men.

Discussion

These findings shed light on the universality of the long-reaching detrimental effect of perceptions of parental disfavoritism across cultures as well as the unique gendered patterns in China shaped by patriarchy. Findings suggest that the implementation of Three-Child Policy in China should be accompanied with parental education programs involving fathers on equal treatment of children.
Sarcopenia Transitions and Influencing Factors Among Chinese Older Adults With Multistate Markov Model
Authors: Sun Boran , Li Shatao , Wang Yanbo , Xiao Wenbo , Zhao Han , Liu Xuewei , Liu Yang , Lu Xinlin , Gao Bei , Zhou Jiangtao , Wang Bingyi , Wang Yuan , Chen Yongjie , Lu Wenli
Published: September 2023

Background and Objectives

Little is known about the sarcopenia transition process across different stages among Chinese community-dwelling older adults. We aimed to explore dynamic transitions of sarcopenia and its influencing factors in Chinese older adults.

Research Design and Methods

Data were derived from the China Health and Retirement Longitudinal Study. A total of 2856 older adults with complete data in the 2011, 2013, and 2015 waves were included in our study. Participants were categorized into 3 states: no sarcopenia, possible sarcopenia, and sarcopenia according to the Asian Working Group for Sarcopenia 2019 (AWGS 2019) criteria. Continuous-time multistate Markov model was performed to estimate the 1-year transition probabilities and the associated factors of sarcopenia transitions. The association strength was expressed as hazard ratio and 95% confidence interval.

Results

The progression and reversion rates between no sarcopenia and sarcopenia state were 6.01 and 9.20 per 100 person-years, respectively. The 1-year progression probability to possible sarcopenia was higher compared with the likelihood of moving to the sarcopenia state (0.127 vs 0.034). The reversion probability to no sarcopenia was also higher among those with possible sarcopenia (0.281 vs 0.157). Older age, rural living, worse cognition status, higher chronic disease numbers, and lower nutrition status measured by body mass index accelerated the sarcopenia progression. Cognition status and body mass index level were related to higher chances of reverting.

Discussion and Implications

Possible sarcopenia might be a critical time window to promote sarcopenia reversion. Timely interventions aimed at delaying the progression and facilitating sarcopenia recovery should focus on improving cognitive function and nutrition levels.
4. The regulation of the legal profession
Authors: Herring Jonathan
Published: September 2023

This chapter considers who is allowed to become a solicitor or a barrister. It also considers what training they must have completed. The profession of solicitor has recently undertaken some radical, and controversial, changes in relation to training. The chapter goes on to examine the nature of the ethical guidance issued by the profession through its Codes of Practice. It sets out the general principles which underpin the guidance for solicitors and barristers. There is discussion of the different ways in which the legal professions are regulated. The work of the Solicitors Regulatory Authority (SRA) and the Bar Standards Board (BSB) is explained.
5. The lawyer–client relationship
Authors: Herring Jonathan
Published: September 2023

This chapter explores the nature of the relationship between a lawyer and a client. It discusses how the professional codes regulate that relationship. It also looks at three standard conceptions from an ethical perspective: partisanship, neutrality, and non-accountability. The differences between these turn on the extent to which the interests of the client should be the sole primary concern of a lawyer. It goes on to discuss the advertising of legal services, the ‘cab-rank rule’, solicitors and client choice, and ending a relationship with a client. It considers how lawyers should balance their duties to their clients and to others. The chapter also discusses the nature of the contract between solicitors and their clients.
7. Conflicts of interests
Authors: Herring Jonathan
Published: September 2023

This chapter discusses the ‘conflicts of interest’ principle. It explains the principles that underpin the no conflict rule. While generally lawyers are required to avoid being in a position in which there is a conflict between their own interests and the interest of a client, or indeed between the interests of two clients, sometimes this is unavoidable. The chapter consider the obligations under the professional codes of conduct for the rule. The chapter also explores the ethical basis for the principle and exceptions to it. The chapter looks too at some of the case law on how lawyers should avoid conflicts of interest.
8. Fees
Authors: Herring Jonathan
Published: September 2023

This chapter focuses on legal fees. It discusses the ways in which lawyers charge fees and the different ways of funding legal costs. A common way of assessing fees is using the ‘billable’ hour, by which a client is charged for each hour (or part of an hour) a lawyer works in their case. This has both advantages and disadvantages, as explored in this chapter. The chapter goes on to consider the ethical aspects of fees. The chapter covers conditional fee arrangements (CFAs) and speculative fees, legal expense insurance, hourly fees, and legal proceedings to recover fees. It also discusses legal aid.
10. Litigation
Authors: Herring Jonathan
Published: September 2023

This chapter explores the ethical issues that arise around litigation. It discusses theories of litigation, including disputes over whether litigation is ‘good’. The attitude that anything that helps a client to win in litigation is justified is rarely accepted these days, and there is a need for lawyers to weigh up their duties to the court and to their clients. The chapter covers the adversarial system of litigation in England and Wales, and inquisitorial adjudication. This can create tensions for lawyers between their duties to their clients and their duties the justice system and to the general public. The chapter also covers both criminal and civil litigation proceedings. In addition, the chapter considers advocacy services and the duties that litigators owe to the court.
15. Applying ethical theories
Authors: Herring Jonathan
Published: September 2023

This chapter explores the application of the principles discussed in the preceding chapters to specific cases. It imagines how four lawyers might respond to three different scenarios. The first is taken from criminal law. The other two are taken from commercial law and family law. The four lawyers represent different schools of thought on lawyers’ ethics. This gives readers the chance to think through how taking a different general ethical approach might impact on their response to a particular scenario. It also might help readers more clearly identify which broad ethical theory they support. It shows how ethical disputes can have considerable practical significance.
Environmental DNA complements scientific trawling in surveys of marine fish biodiversity
Authors: Veron Pierre , Rozanski Romane , Marques Virginie , Joost Stéphane , Deschez Marie Emilie , Trenkel Verena M , Lorance Pascal , Valentini Alice , Polanco F. Andrea , Pellissier Loïc , Eme David , Albouy Camille
Published: September 2023

Environmental DNA (eDNA) metabarcoding is a method to detect taxa from environmental samples. It is increasingly used for marine biodiversity surveys. As it only requires water collection, eDNA metabarcoding is less invasive than scientific trawling and might be more cost effective. Here, we analysed data from both sampling methods applied in the same scientific survey targeting Northeast Atlantic fish in the Bay of Biscay. We compared the methods regarding the distribution of taxonomic, phylogenetic, and functional diversity. We found that eDNA captured more taxonomic and phylogenetic richness than bottom trawling and more functional richness at the local scale. eDNA was less selective than trawling and detected species in local communities spanning larger phylogenetic and functional breadths, especially as it detected large pelagic species that escaped the trawl, even though trawling detected more flat fish. eDNA indicated differences in fish community composition that were comparable to those based on trawling. However, consistency between abundance estimates provided by eDNA metabarcoding and trawl catches was low, even after accounting for allometric scaling in eDNA production. We conclude that eDNA metabarcoding is a promising method that can complement scientific trawling for multi-component biodiversity monitoring based on presence/absence, but not yet for abundance.
A non-contractual approach to smart contracts
Authors: Gamper Florian
Published: September 2023

This article adds to the debate on what, legally speaking, smart contracts are and what they should be. Currently, much of this debate focuses on the relationship between smart contracts and legal contracts, overlooking that other legal categories may also be appropriate. This article suggests that the concept of abandonment can be fruitfully applied to smart contracts. Using the concept of abandonment has the advantage of allowing smart contracts, as close as legally possible, to be utilized as machines (or using the terminology suggested by Vitalik Buterin, founder of Etherium, as a ‘persistent script’). It would also make other issues, like the interpretation of smart contracts, easier to deal with. The argument is not that smart contracts can never be legal contracts; rather, it is suggested that, prima facie, users should have the choice of utilizing smart contracts as legal contracts or as machines.
Nodal Sets of Eigenfunctions of Sub-Laplacians
Authors: Eswarathasan Suresh , Letrouit Cyril
Published: September 2023

Nodal sets of eigenfunctions of elliptic operators on compact manifolds have been studied extensively over the past decades. In this note, we initiate the study of nodal sets of eigenfunctions of hypoelliptic operators on compact manifolds, focusing on sub-Laplacians. A standard example is the sum of squares of bracket-generating vector fields on compact quotients of the Heisenberg group. Our results show that nodal sets behave in an anisotropic way, which can be analyzed with standard tools from sub-Riemannian geometry such as sub-Riemannian dilations, nilpotent approximation, and desingularization at singular points. Furthermore, we provide a simple example demonstrating that for sub-Laplacians, the Hausdorff measure of nodal sets of eigenfunctions cannot be bounded above by $\sqrt \lambda $, which is the bound conjectured by Yau for Laplace–Beltrami operators on smooth manifolds.
An Eigenvalue Problem for Prescribed Curvature Equations
Authors: Lee Taehun
Published: September 2023

We study an eigenvalue problem for prescribed $\sigma _{k}$-curvature equations of star-shaped, $k$-convex, closed hypersurfaces. We establish the existence of a unique eigenvalue and its associated hypersurface, which is also unique, provided that the given data is even. Moreover, we show that the hypersurface must be strictly convex. A crucial aspect of our proof involves deriving uniform estimates in $p$ for $L_{p}$-type prescribed curvature equations.
Impact of COVID-19 pandemic on accredited programs and graduates who sat for the American Society for Clinical Pathology–Board of Certification Examination: program directors’ perspective
Authors: Duzan Dana , Fong Karen , Freeman Vicki S , Goodyear Nancy , Nadder Teresa S , Spiczka Amy , Taff Teresa , Tanabe Patricia
Published: September 2023

Objective

Health professions education programs were severely affected by the COVID-19 pandemic at clinical and didactic training levels. The purpose for this American Society for Clinical Pathology–Board of Certification (BOC) study was to determine the impact of the COVID-19 pandemic on the graduates who sat for BOC certification in their respective professional disciplines from the perspective of program directors (PDs). A separate article will be published on the graduates’ perspective.

Methods

A survey was sent to all PDs from the National Accrediting Agency for Clinical Laboratory Science, Accrediting Bureau of Health Education Schools, and Commission on Accreditation of Allied Health Education Programs, accredited programs whose graduates are certified by the BOC, to determine the impact of COVID-19 on healthcare graduates and education programs during the pandemic.

Results

A total of 201 PDs responded. All programs consistently reported that the pandemic had a negative impact on their students’ BOC pass rate and scores. When asked what educational formats were used, all groups used virtual live lectures and recorded lectures. University programs were found to use more online student laboratories and simulation laboratory sessions than the hospital programs, affecting the psychomotor skills of their students.

Conclusion

The results indicated that the effects from the COVID-19 pandemic were related to the inherent differences between hospital and university programs. This study revealed that the pandemic affected university programs more than hospital programs.
Oxford to Prague: Orthodox Insular Texts in Bohemia
Authors: Hanna Ralph
Published: September 2023

Owing to protracted investigations of heresy, much of John Wyclif’s oeuvre is now available, not in insular, but only in Bohemian manuscripts. However, the mechanisms of such transmission have remained murky, in spite of Anne Hudson’s magisterial investigations in Czech libraries. This essay looks at evidence for an analogous, yet orthodox, transmission, earlier and, before 1407, considerably more prolific than the Wycliffite example. This involves Oxonian texts written for preachers; these had a lively and early Bohemian circulation, dating back to the foundations of the Charles University, Prague.
Underlying causes for prevalent false positives and false negatives in STARR-seq data
Authors: Ni Pengyu , Wu Siwen , Su Zhengchang
Published: September 2023

Self-transcribing active regulatory region sequencing (STARR-seq) and its variants have been widely used to characterize enhancers. However, it has been reported that up to 87% of STARR-seq peaks are located in repressive chromatin and are not functional in the tested cells. While some of the STARR-seq peaks in repressive chromatin might be active in other cell/tissue types, some others might be false positives. Meanwhile, many active enhancers may not be identified by the current STARR-seq methods. Although methods have been proposed to mitigate systematic errors caused by the use of plasmid vectors, the artifacts due to the intrinsic limitations of current STARR-seq methods are still prevalent and the underlying causes are not fully understood. Based on predicted cis-regulatory modules (CRMs) and non-CRMs in the human genome as well as predicted active CRMs and non-active CRMs in a few human cell lines/tissues with STARR-seq data available, we reveal prevalent false positives and false negatives in STARR-seq peaks generated by major variants of STARR-seq methods and possible underlying causes. Our results will help design strategies to improve STARR-seq methods and interpret the results.
Magnitude, Patterns, and Associated Predictors of Cardiovascular Events in Tetanus: A 2-Year, Single-Center, Ambidirectional Cohort Study Involving 572 Patients
Authors: Pham Oanh Kieu Nguyet , Tran Bao Nhu , Duong Minh Cuong , Do Thi Cam Nhung , Pham Thi Lieu , Lam Minh Yen , Thwaites Louise , Nguyen Van Hao
Published: September 2023

Background

Cardiovascular events (CEs) remain the leading cause of death in patients with tetanus. We examined the incidence, patterns, and associated predictors of CEs among patients with tetanus in Vietnam.

Methods

An ambidirectional cohort study was conducted on hospitalized adult patients with tetanus at the Hospital for Tropical Diseases between 2019 and 2020. Information on demographics, tetanus disease, CEs and outcomes were collected.

Results

Among all 572 included patients, CEs accounted for 10.8% (95%CI 8.6–13.7%) and included Takotsubo cardiomyopathy (40.3%, 95%CI 29.0–52.8%), arrhythmia (19.4%, 95%CI 11.4–30.9%), sudden cardiac arrest (16.1%, 95%CI 9.0–27.2%), myocardial infarction (11.3%, 95%CI 5.6–21.5%), heart failure (6.5%, 95%CI 2.5–15.4%) and pulmonary embolism (6.5%, 95%CI 2.5–15.4%). CEs occurred from day 5 to 20 of illness. Among 62 CE patients, 21% (95%CI 12.7–32.6%) died and 61.3% (95%CI 48.9–72.4%) developed autonomic nervous system dysfunction (ANSD). Three-fourths (24/32) of patients with Takotsubo cardiomyopathy or myocardial infarction had ANSD. CEs were significantly associated with modified Ablett scores (AOR = 2.42, 95%CI 1.1–5.6, P = .04), underlying diseases (AOR = 2.7, 95%CI 1.1–6.8, P = .04) and overweight (AOR = 0.18, 95%CI .04–.8, P = .02).

Conclusions

CEs are not rare and associated with high mortality. The most common CE is Takotsubo cardiomyopathy. CEs can occur at any stage of illness, with or without ANSD. To prevent mortality, it is pivotal to screen CEs in patients with tetanus, especially those with underlying diseases, high modified Ablett scores, and a normal or low BMI. More studies are needed to fully elucidate the impact of ANSD on the cardiovascular function and the CE associated mortality in tetanus.
Remdesivir Is Associated With Reduced Mortality in COVID-19 Patients Requiring Supplemental Oxygen Including Invasive Mechanical Ventilation Across SARS-CoV-2 Variants
Authors: Mozaffari Essy , Chandak Aastha , Gottlieb Robert L , Chima-Melton Chidinma , Read Stephanie H , Lee EunYoung , Der-Torossian Celine , Gupta Rikisha , Berry Mark , Hollemeersch Stijn , Kalil Andre C
Published: September 2023

Background

This comparative effectiveness study investigated the effect of remdesivir on in-hospital mortality among patients hospitalized for coronavirus disease 2019 (COVID-19) requiring supplemental oxygen including low-flow oxygen (LFO), high-flow oxygen/noninvasive ventilation (HFO/NIV), or invasive mechanical ventilation/extracorporeal membrane oxygenation (IMV/ECMO) across variant of concern (VOC) periods.

Methods

Patients hospitalized for COVID-19 between December 2020 and April 2022 and administered remdesivir upon admission were 1:1 propensity score matched to patients not administered remdesivir during their COVID-19 hospitalization. Analyses were stratified by supplemental oxygen requirement upon admission and VOC period. Cox proportional hazards models were used to derive adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for 14- and 28-day mortality.

Results

Patients treated with remdesivir (67 582 LFO, 34 857 HFO/NIV, and 4164 IMV/ECMO) were matched to non-remdesivir patients. Unadjusted mortality rates were significantly lower for remdesivir-treated patients at 14 days (LFO: 6.4% vs. 8.8%; HFO/NIV: 16.8% vs. 19.4%; IMV/ECMO: 27.8% vs. 35.3%) and 28 days (LFO: 9.8% vs. 12.3%; HFO/NIV: 25.8% vs. 28.3%; IMV/ECMO: 41.4% vs. 50.6%). After adjustment, remdesivir treatment was associated with a statistically significant reduction in in-hospital mortality at 14 days (LFO: aHR, 0.72; 95% CI, 0.66–0.79; HFO/NIV: aHR, 0.83; 95% CI, 0.77–0.89; IMV/ECMO: aHR, 0.73; 95% CI, 0.65–0.82) and 28 days (LFO: aHR, 0.79; 95% CI, 0.73–0.85; HFO/NIV: aHR, 0.88; 95% CI, 0.82–0.93; IMV/ECMO: aHR, 0.74; 95% CI, 0.67–0.82) compared with non-remdesivir treatment. Lower risk of mortality among remdesivir-treated patients was observed across VOC periods.

Conclusions

Remdesivir treatment is associated with significantly reduced mortality among patients hospitalized for COVID-19 requiring supplemental oxygen upon admission, including those requiring HFO/NIV or IMV/ECMO with severe or critical disease, across VOC periods.
Inequality in uptake of bowel cancer screening by deprivation, ethnicity and smoking status: cross-sectional study in 86 850 citizens
Authors: Creavin Alexandra , Creavin Sam , Kenward Charlie , Sterne Jonathan , Williams Jo
Published: September 2023

Background

Survival from colorectal cancer depends on stage at detection. In England, bowel cancer mortality has historically been highest in deprived areas. During the initial stages of the COVID-19 pandemic, it was necessary to temporarily halt many screening programmes, which may have led to inequalities in uptake since screening restarted.

Methods

Cross-sectional data from the Bristol, North Somerset and South Gloucestershire Systemwide Dataset were analyzed. Associations of baseline characteristics with uptake of bowel screening were examined using logistic regression.

Results

Amongst 86 850 eligible adults aged 60–74 years, 5261 had no screening record. There was little evidence of association between no screening and sex (adjusted odds ratio 0.95 (95% confidence interval 0.90, 1.02)). Absence of screening record was associated with deprivation (1.26 (1.14, 1.40) for the most compared with the least deprived groups), smoking (1.11 (1.04, 1.18)) compared with no smoking record and black (1.36 (1.09, 1.70)) and mixed (1.08 (1.01, 1.15)) ethnicity compared with white ethnicity.

Conclusions

In a data set covering a whole NHS Integrated Care Board, there was evidence of lower uptake of bowel cancer screening in adults living in more deprived areas, of minority ethnic groups and who smoked. These findings may help focus community engagement work and inform research aimed at reducing inequalities.
Further evaluation of inflammatory and non-inflammatory aspects of pain in rheumatoid arthritis patients
Authors: Jansen Niels , ten Klooster Peter M , Vonkeman Harald E , van den Berg Boudewijn , Buitenweg Jan R
Published: September 2023

Objective

A high discrepancy between the number of tender and swollen joints (e.g. ΔTSJ ≥ 7) has previously been used as an indication for the presence of changes in central mechanisms in patients with moderate-to-high disease activity. In this study, we explored whether the ΔTSJ can also be used to obtain insights into the underlying pain mechanisms in patients with on average well-controlled disease activity.

Methods

A 2 year retrospective analysis of routinely obtained 28-joint DAS (DAS28) components was performed on 45 patients with low inflammatory activity at the group level. All patients underwent pressure pain threshold (PPT) and electrical pain threshold (EPT) measurements and completed four self-report questionnaires [short-form 36 (SF-36v2); central sensitization inventory (CSI); generalized pain questionnaire (GPQ); and the pain catastrophizing scale (PCS)].

Results

Patients with a ΔTSJ ≥ 3 at least once in the past 2 years showed significantly lower EPT and PPT values and higher levels of pain and disability on the SF-36v2 compared with the ΔTSJ < 3 group. Furthermore, GPQ scores were significantly higher in those with ΔTSJ ≥ 3, while CSI and PCS scores were similar.

Conclusion

These findings suggest that in patients in the ΔTSJ ≥ 3 group, mechanisms other than inflammation (only) underlie the pain. Moreover, our findings suggest that among the multiple potential underlying psychological mechanisms, pain catastrophizing (as measured by the PCS) and psychological hypervigilance (as measured by the CSI) do not play an important role. These findings could be useful in the clinical management of the patient. Depending on the dominant mechanism underlying the (persistent) pain, patients might respond differently to treatment.
Plating versus Intramedullary Nailing of OTA/AO 43C1 and C2 Intra-articular Distal Tibia Fractures: A Propensity Score and Multivariate Analysis
Authors: Jang Yohan , Wilson Nathaniel , Jones Jenna , Alcaide Doriann , Szatkowski Jan , Sorkin Anthony , Slaven James E , Natoli Roman
Published: September 2023

Objective:

To compare rates of loss of reduction, nonunion, and infection in intra-articular distal tibia fractures (IADTF) treated with limited open reduction internal fixation and intramedullary nailing (IMN) as compared to open reduction internal fixation with plate and screws (PF).

Design:

Retrospective Review

Setting:

Level-I academic trauma center

Patients:

110 patients, age ≥ 18 with operatively treated OTA/AO 43C1 and C2 IADTF between 2013-2021

Primary outcome measurement:

Loss of reduction, surgical site infection (SSI), nonunion, and patient-reported outcomes (PROs)

Results:

110 patients met the inclusion criteria (IMN 33, PF 77). There was no loss of reduction reported. 17 nonunions (15% overall; IMN 4/33, PF 13/77) and 13 SSIs (12% overall; IMN 2/33, PF11/77) were identified. Despite several risk factors being identified for nonunion and SSI in bivariate analysis, only open fracture remained significant as a risk factor for both nonunion (OR 0.09 for closed fracture, 95% CI 0.02-0.56, p=0.009) and SSI (OR 0.07 for closed fracture, 95% CI 0.06-0.26, p=0.012) in the multivariate model. Propensity scoring based on presurgical variables was significantly different between patients that received IMN vs PF (p=0.03); however, logistic regression incorporating the propensity score revealed no significant association with nonunion and SSI. Adjusting for the propensity score, there remained no association comparing IMN versus PF with nonunion and SSI (p=0.54 and p=0.17, respectively). There was also no difference in PROs between IMN and PF (Physical function: p=0.25, Pain interference: p=0.21).

Conclusion:

Overall nonunion and SSI prevalence in our cohort was 15% and 12%, respectively, in operatively treated OTA/AO 43C1 and C2 IADTF. An open fracture is a significant risk factor for nonunion and SSI. Metaphyseal fixation via IMN or PF in IADTF did not affect the loss of reduction, nonunion, SSI, and PROs.

Level of Evidence:

Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.
Diagnostic value of 18F-fluoro-2-deoxyglucose positron emission tomography/computed tomography imaging in acral melanoma–predominant Asian patients
Authors: Chen Kuan-Cheng , Chu Po-Yu , Li Cheng-Yuan , Wang Tien-Hsiang , Chiu Yu-Jen
Published: September 2023

Background:

Tumor staging is crucial for melanoma, of which acral melanoma is the predominant subtype in Asians. 18F-fluoro-2-deoxyglucose (FDG) positron emission tomography (PET) and 18F-FDG-PET/computed tomography (18F-FDG-PET/CT) serve as noninvasive imaging tools for tumor staging. However, the literature is scarce on the diagnostic value of PET for acral melanoma.

Methods:

From January 1, 2006 to November 30, 2022, a total of 352 patients were diagnosed with melanoma at our hospital. Of them, 90 were diagnosed with cutaneous melanoma and underwent preoperative PET/CT for staging and sentinel lymph node biopsy or complete lymph node dissection. Staging of PET/CT was confirmed by histopathology or following imaging. The lymph node biopsy, distant metastasis status, and PET/CT imaging results were analyzed.

Results:

Of all the 90 patients with cutaneous melanoma, 72 of them were diagnosed as acral melanoma (80.0%). Compared with the histopathologic results, the lymph nodes were true-positive, true-negative, false-positive, and false-negative in 12, 54, 7, and 17 cases, respectively. The sensitivity of PET/CT for local lymph nodes was 41.4% (95% CI, 23.5%-61.1%), whereas its specificity was 88.5% (95% CI, 77.8%-95.3%). As for the detection of distal metastasis, the PET results were true-positive, true-negative, false-positive, and false-negative in 6, 65, 15, and 4 cases, respectively. The sensitivity of PET for distal metastasis detection was 60.0% (95% CI, 26.2%-87.8%), whereas its specificity was 81.3% (95% CI, 71.0%-89.1%).

Conclusion:

Although noninvasive, PET/CT has relatively low sensitivity in regional lymph node evaluations, and fair sensitivity in distal metastasis detection in Asian patients with acral melanoma. Thus, PET/CT may be more useful in patients with clinically palpable nodes or more advanced disease stages.
A Novel Type of IDH-wildtype Glioma Characterized by Gliomatosis Cerebri-like Growth Pattern, TERT Promoter Mutation, and Distinct Epigenetic Profile
Authors: Muench Amos , Teichmann Daniel , Spille Dorothee , Kuzman Peter , Perez Eilis , May Sven-Axel , Mueller Wolf C. , Kombos Theodoros , Nazari-Dehkordi Shokufe , Onken Julia , Vajkoczy Peter , Ntoulias Georgios , Bettencourt Conceição , von Deimling Andreas , Paulus Werner , Heppner Frank L. , Koch Arend , Capper David , Kaul David , Thomas Christian , Schweizer Leonille
Published: September 2023

Diffuse gliomas in adults encompass a heterogenous group of central nervous system neoplasms. In recent years, extensive (epi-)genomic profiling has identified several glioma subgroups characterized by distinct molecular characteristics, most importantly IDH1/2 and histone H3 mutations. A group of 16 diffuse gliomas classified as “adult-type diffuse high-grade glioma, IDH-wildtype, subtype F (HGG-F)” was identified by the DKFZ v12.5 Brain Tumor Classifier. Histopathologic characterization, exome sequencing, and review of clinical data was performed in all cases. Based on unsupervised t-distributed stochastic neighbor embedding and clustering analysis of genome-wide DNA methylation data, HGG-F shows distinct epigenetic profiles separate from established central nervous system tumors. Exome sequencing demonstrated frequent TERT promoter (12/15 cases), PIK3R1 (11/16), and TP53 mutations (5/16). Radiologic characteristics were reminiscent of gliomatosis cerebri in 9/14 cases (64%). Histopathologically, most cases were classified as diffuse gliomas (7/16, 44%) or were suspicious for the infiltration zone of a diffuse glioma (5/16, 31%). None of the cases demonstrated microvascular proliferation or necrosis. Outcome of 14 patients with follow-up data was better compared to IDH-wildtype glioblastomas with a median progression-free survival of 58 months and overall survival of 74 months (both P<0.0001). Our series represents a novel type of adult-type diffuse glioma with distinct molecular and clinical features. Importantly, we provide evidence that TERT promoter mutations in diffuse gliomas without further morphologic or molecular signs of high-grade glioma should be interpreted in the context of the clinicoradiologic presentation as well as epigenetic profile and may not be suitable as a standalone marker for glioblastoma, IDH-wildtype.
Spiradenoma With Adenoid Cystic Carcinoma–like Changes
Authors: Plaza Jose A. , Kastnerova Liubov , Gru Alejandro A. , Dulmage Brittany , Sangueza Martin J. , Kazakov Dmitry V.
Published: September 2023

Spiradenomas are benign cutaneous adnexal neoplasms with sweat gland differentiation that can manifest a broad spectrum of histomorphologic appearances. While they show a characteristic histopathologic phenotype and clinical management involves surgical excision with a low risk of recurrence, there have been unusual histopathologic variants of spiradenoma reported, including cases with adenoid cystic carcinoma (ACC)-like changes. Primary cutaneous ACC is a low-grade malignancy presenting as a subcutaneous mass with the potential for local invasion, perineural invasion, and high rates of local recurrence after excision. The diagnosis of spiradenomas with ACC-like features can be challenging, especially when only the ACC-like component is present for evaluation. A retrospective analysis of 21 cases of spiradenoma with ACC-like changes were obtained from large academic institutions, was performed, and summarized below. All cases showed background of conventional spiradenoma, and the ACC-like areas represented a component in all lesions. The percentage of ACC-like component ranged from 5% to 40% in all cases. The ACC-like component was multifocal and without pleomorphism, perineural and/or vascular invasion, necrosis, or increased mitotic activity. MYB translocation and protein expression was studied in 16 cases by fluorescence in situ hybridization, polymerase chain reaction, and immunohistochemistry. All studied cases were negative for MYB/NFIB, MYBL1, and MYBF by fluorescence in situ hybridization and polymerase chain reaction and 3 cases were positive for MYB expression by immunohistochemistry. Our study expands on spiradenomas with ACC-like features that ought to be considered in the differential diagnosis of cutaneous neoplasms such as primary cutaneous ACC. Our results indicate that a thorough histopathologic inspection and strict application of well-defined histologic criteria are necessary to support the diagnosis of this unusual histopathologic variant. These tumors can be difficult to diagnose, and awareness of their histomorphologic spectrum will facilitate definitive diagnosis and avoid misdiagnosis with other conditions.
Risk factors for acquiring Acinetobacter baumannii infection in the intensive care unit: experience from a Moroccan hospital
Authors: Benaissa Elmostafa , Belouad Elmehdi , Maleb Adil , Elouennass Mostafa
Published: September 2023

Introduction.

Acinetobacter

species are non-fermenting and ubiquitous Gram-negative coccobacilli, which in recent years have become the leading cause of healthcare-associated infections worldwide. Our objective here was to study the epidemiology and risk factors associated with

Acinetobacter baumannii

infections in the intensive care unit (ICU).

Methods. This retrospective case-control study was conducted collaboratively between the Medical Bacteriology Department and the two ICUs of the Military Hospital of Instruction Mohammed V-Rabat over a 3 month period.

Results. We included 180 patients, of whom 60 had

A. baumannii

infection. We observed a male predominance in both matched groups, with a sex ratio of 1.6. The median age was 67 years [interquartile range (IQR) 59.5–77]. The median length of stay in the ICU before infection was 8.5 days (IQR 5–14). Multivariate logistic regression analysis identified the risk factors statistically associated with

A. baumannii

infection at the ICU level as follows: duration of invasive procedures >7 days [odds ratio (OR)=1.02], parenteral nutrition (OR=3.514), mechanical ventilation (OR=3.024), imipenem (OR=18.72), colistin (OR=5.645), probabilistic antibiotic therapy >4 days (OR=9.063) and neoplastic pathology (OR=5.727).

Conclusion. Based on our results, it can be inferred that shortening the duration of stay in the resuscitation setting, implementing rational use of medical devices and optimizing antibiotic therapy could decrease the incidence of these infections.
Novosphingobium cyanobacteriorum sp. nov., isolated from a eutrophic reservoir during the Microcystis bloom period
Authors: Kang Mingyeong , Van Le Ve , Ko So-Ra , Lee Sang-Ah , Choi Dong-Yun , Oh Hee-Mock , Ahn Chi-Yong
Published: September 2023

A novel Gram-stain-negative, aerobic and rod-shaped bacterial strain, HBC54T, was isolated from periphyton during a

Microcystis

bloom. Based on the results of the 16S rRNA gene sequence analysis, strain HBC54T was closely related to

Novosphingobium aerophilum

4Y4T (98.36 %),

Novosphingobium aromaticivorans

DSM 12444T (98.08 %),

Novosphingobium huizhouense

c7T (97.94 %),

Novosphingobium percolationis

c1T (97.65 %),

Novosphingobium subterraneum

DSM 12447T (97.58 %),

Novosphingobium olei

TW-4T (97.58 %) and

Novosphingobium flavum

UCT-28T (97.37 %). The average nucleotide identity and digital DNA–DNA hybridization values between HBC54T and its related type stains were below 78.97 and 23.7 %, which are lower than the threshold values for species delineation. The major fatty acids (>10.0 %) were identified as C14 : 0 2-OH, summed feature 3 (C16 : 1
 ω7c and/or C16 : 1
 ω6c) and summed feature 8 (C18 : 1
 ω7c and/or C18 : 1
 ω6c) and the respiratory quinone was ubiquinone Q-10. The main polar lipids detected in the strain were phosphatidylethanolamine, phosphatidylglycerol, phosphatidylcholine, diphosphatidylglycerol and three unidentified phospholipids. The genomic DNA G+C content was 64.8 mol%. Strain HBC54T is considered to represent a novel species within the genus

Novosphingobium

, for which the name Novosphingobium cyanobacteriorum sp. nov. is proposed. The type strain is HBC54T (=KCTC 92033T=LMG 32427T).
Low-input and single-cell methods for Infinium DNA methylation BeadChips
Authors: Lee Sol Moe , Loo Christian E. , Prasasya Rexxi D. , Bartolomei Marisa S. , Kohli Rahul M. , Zhou Wanding
Published: September 2023

The Infinium BeadChip is the most widely used DNA methylome assay technology for population-scale epigenome profiling. However, the standard workflow requires over 200 ng of input DNA, hindering its application to small cell-number samples, such as primordial germ cells. We developed experimental and analysis workflows to extend this technology to suboptimal input DNA conditions, including ultra-low input down to single cells. DNA preamplification significantly enhanced detection rates to over 50% in five-cell samples and ∼25% in single cells. Enzymatic conversion also substantially improved data quality. Computationally, we developed a method to model the background signal’s influence on the DNA methylation level readings. The modified detectionp-values calculation achieved higher sensitivities for low-input datasets and was validated in over 100,000 public datasets with diverse methylation profiles. We employed the optimized workflow to query the demethylation dynamics in mouse primordial germ cells available at low cell numbers. Our data revealed nuanced chromatin states, sex disparities, and the role of DNA methylation in transposable element regulation during germ cell development. Collectively, we present comprehensive experimental and computational solutions to extend this widely used methylation assay technology to applications with limited DNA.
Intronic miR342 is a master regulator of cellular glycolysis in Foxp3+regulatory CD4 T cells
Authors: Yu Rongzhen , Li Silei , Kim Sohee , Kim Giha , Lu Li-Fan , Kim Dongkyun , Min Booki
Published: September 2023

Foxp3+regulatory T (Treg) cells are a subset of CD4 T cells that play a potent and indispensable role in regulating immunity and tolerance. The precise mechanisms by which Treg cells mediate such functions have extensively been explored, and there are many cellular and molecular factors that are instrumental for adequate Treg cell functions. miRNAs, small non-coding RNA molecules, are one of the factors capable of controlling Treg cell functions. In this study, we report that miR-342 is essential for Treg cells to mitigate autoimmune inflammation in the central nervous system. Utilizing novel mouse models with Treg cell-specific miR-342 deficiency or overexpression, we demonstrate that miR-342 expression in Treg cells, while dispensable for immune homeostasis at steady-state conditions, is necessary for Treg cells to control inflammatory responses. Mechanistically, we found that Treg cells deficient in miR-342 display dysregulated metabolic profiles, elevated glycolysis and decreased oxidative phosphorylation, a metabolic phenotype associated with functionally defective Treg cells. Interestingly, miR-342-dependent metabolic dysregulation was observed in Treg but not in Th1 type cells. In support, miR-342-mediated Rictor targeting was found in Treg but not in Th1 type cells. Collectively, our findings uncover that miR-342 may serve a master regulator specific for metabolism and functions in Treg cells.
Genome-wide distribution of 5-hydroxymethyluracil and chromatin accessibility in theBreviolum minutumgenome
Authors: Marinov Georgi K. , Chen Xinyi , Swaffer Matthew P. , Xiang Tingting , Grossman Arthur R. , Greenleaf William J.
Published: September 2023

In dinoflagellates, a unique and extremely divergent genomic and nuclear organization has evolved. The highly unusual features of dinoflagellate nuclei and genomes include permanently condensed liquid crystalline chromosomes, primarily packaged by proteins other than histones, genes organized in very long unidirectional gene arrays, a general absence of transcriptional regulation, high abundance of the otherwise very rare DNA modification 5-hydroxymethyluracil (5-hmU), and many others. While most of these fascinating properties were originally identified in the 1970s and 1980s, they have not yet been investigated using modern genomic tools. In this work, we address some of the outstanding questions regarding dinoflagellate genome organization by mapping the genome-wide distribution of 5-hmU (using both immunoprecipitation-based and basepair-resolution chemical mapping approaches) and of chromatin accessibility in the genome of the Symbiodiniaceae dinoflagellateBreviolum minutum. We find that the 5-hmU modification is preferentially enriched over certain classes of repetitive elements, often coincides with the boundaries between gene arrays, and is generally correlated with decreased chromatin accessibility, the latter otherwise being largely uniform along the genome. We discuss the potential roles of 5-hmU in the functional organization of dinoflagellate genomes and its relationship to the transcriptional landscape of gene arrays.