bluuebunny/crossref_metadata_2025 huggingface dataset:
Mexican Federal Law for the Protection of Cultural Heritage of Indigenous and Afro-Mexican Peoples and Communities
Authors: Santamaria Hernández Esteban
Published: January 2023

The present work analyses the new Mexican Federal Law for the Protection of Cultural Heritage of Indigenous and Afro-Mexican Peoples and Communities (Mexican sui generis law) against the benchmarks provided by the literature specialized in traditional knowledge (TK), traditional cultural expressions (TCEs) and genetic resources (GE). Having identified the elements that should be taken into consideration by any sui generis law, the work examines the consistency between them and the newly approved Mexican statute.
Life after death: uses in practice in the fifteenth century
Authors: Hicks Michael
Published: January 2023

This article documents a considerable increase in the percentage of manorial lords in fifteenth-century England who had enfeoffed their lands in use (trusts). Enfeoffments to use were the principal mechanism that enabled manorial lords to resettle their lands. The recent publication of inquisitions post-mortem for 1483–5 and wills for 1479–86 reveal how uses proliferated. Long-term uses appear to have been quite rare. Panels of feoffees were diminished by deaths and were rarely replaced by new panels. The article demonstrates how the uses were employed. While evasion of feudal incidents was a prime aim, this research shows how uses enabled deceased manorial lords to spend their landed incomes for religious purposes, for the benefit of spouses, daughters and younger sons subject to their conditions, and to postpone the succession of heirs for years and even decades after the lord’s death.
No more parades? Navy Weeks, naval theatre and navalism, 1927–38
Authors: Thompson Rowan
Published: January 2023

Despite calls for ‘no more parades’ following the First World War, and while the period was supposedly inhospitable to militaristic and martial ceremony, ‘naval theatre’, navalism and cultural displays of militarism all enjoyed significant resonance in the popular civic ritual of interwar Britain. One of the most prominent forms of naval theatre in this period was the annual celebration of Navy Weeks. First staged at Portsmouth, then extended to Plymouth and Chatham the following year, Navy Weeks were held between 1927 and 1938 and allowed members of the public to be brought into direct touch with the work, life and routine of the Royal Navy. Instituted to aid naval charities, the event also provided a public platform for the admiralty to promote the navy for the preservation of nation and empire, as well as encouraging naval education among the British public. Navy Weeks represented a site of modernity, technological innovation and military prestige. However, the event equally promoted naval heritage, tradition and the long-standing significance of the Royal Navy to Britain’s status as a maritime nation.
Are ideas getting cheaper? The European evidence
Authors: Antonelli Cristiano , Fusillo Fabrizio
Published: January 2023

Recent economics of knowledge studies have highlighted the strong positive effects that the limited exhaustibility of knowledge and its cumulability exert on the recombinant generation of new technological knowledge. While existing empirical investigations primarily focus on the knowledge generation and technology production functions, the analysis of the cost of knowledge has received less attention. This paper aims to fill this gap by investigating the dynamics and determinants of patent costs in the European Union in the period 1992–2012. The analysis of patent unit costs in European countries, measured as the amount of research and development (R&D) expenditure per patent application to the European Patent Office (EPO), shows a steady decline and clear convergence toward lower levels, both in time and across countries. We find that a larger stock of patents and a higher technological variety and coherence of its composition are associated with a sharper reduction in patent costs. Our findings suggest that, in Europe, ideas have been getting cheaper.
Safety, Tolerability and Pharmacokinetics of Half-Life Extended Severe Acute Respiratory Syndrome Coronavirus 2 Neutralizing Monoclonal Antibodies AZD7442 (Tixagevimab-Cilgavimab) in Healthy Adults
Authors: Forte-Soto Pablo , Albayaty Muna , Brooks Dennis , Arends Rosalinda H , Tillinghast John , Aksyuk Anastasia A , Bouquet Jerome , Chen Cecil , Gebre Asfiha , Kubiak Robert J , Pilla Reddy Venkatesh , Seegobin Seth , Streicher Katie , Templeton Alison , Esser Mark T
Published: January 2023

Background

AZD7442 is a combination of extended half-life, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)−specific neutralizing monoclonal antibodies (tixagevimab and cilgavimab).

Methods

This phase 1, first-in-human, randomized, double-blind, placebo-controlled, dose-escalation study evaluated AZD7442 administered intramuscularly (300 mg) or intravenously (300, 1000, or 3000 mg) in healthy adults (aged 18–55 years). The primary end point was safety and tolerability. Secondary end points included pharmacokinetics and antidrug antibodies.

Results

Between 18 August and 16 October 2020, a total of 60 participants were enrolled; 50 received AZD7442, and 10 received placebo. Adverse events (all of mild or moderate intensity) occurred in 26 participants (52.0%) in the AZD7442 groups and 8 (80.0%) in the placebo group. No infusion or injection site or hypersensitivity reactions occurred. Tixagevimab and cilgavimab had mean half-lives of approximately 90 days (range, 87.0–95.3 days for tixagevimab and 79.8–­91.1 days for cilgavimab) and similar pharmacokinetic profiles over the 361-day study period. SARS-CoV-2–specific neutralizing antibody titers provided by AZD7442 were maintained above those in plasma from convalescent patients with coronavirus disease 2019 (COVID-19).

Conclusions

AZD7442 was well tolerated in healthy adults, showing a favorable safety profile across all doses. Depending on the SARS-CoV-2 variant, pharmacokinetic analyses suggest the AZD7442 could offer protection for ≥6 months against symptomatic COVID-19 after a single 300-mg intramuscular administration.

Clinical trials registration

NCT04507256.
Defining Variability in Evaluation and Management of Children with Chronic Osteomyelitis
Authors: Moorthy Ganga S , Boutzoukas Angelique E , Benjamin Daniel K , Polgreen Philip M , Beekmann Susan E , Bradley John S , Dehority Walter
Published: January 2023

Pediatric chronic osteomyelitis is a rare, debilitating condition lacking management guidelines. In a national survey of 162 pediatric infectious disease physicians through the Emerging Infections Network, tremendous variability in diagnostic approaches and management was noted, highlighting a need for a prospective study to better define the spectrum of pathogens and disease.
Postpartum dyspareunia: clinical evaluation, causes, and treatment outcomes
Authors: Ram-Weiner Maya , Hayman-Mendelson Anat , Allouche-Kam Hadas , Lev-Sagie Ahinoam
Published: January 2023

Background

Dyspareunia affects approximately half of postpartum women and is attributed to multiple factors. Despite its high prevalence and resultant negative effects, data are lacking regarding the causes and different pain components, the usefulness of recommended treatments, and the prognosis.

Aim

To evaluate causes of postpartum dyspareunia, targeted treatment modalities, and their effectiveness.

Methods

A retrospective observational study was conducted of women diagnosed with postpartum dyspareunia between September 2008 and January 2017 at a single designated vulvovaginal disorder clinic. The inclusion criterion was complaint of painful intercourse commencing postdelivery. The cohort was divided into 4 groups based on the causes of dyspareunia: muscle hypertonicity, scar tenderness, vestibular tenderness, and atrophy.

Outcomes

The following were assessed for each group: patient background demographics, clinical and obstetric data, physical findings, recommended therapy, adherence to the suggested treatment, level of improvement at follow-up visits, and length of time until maximal improvement.

Results

A hundred women met the inclusion criterion; the majority (n = 60) presented with >1 causative factor. The most common finding was vestibular tenderness (n = 78, 78%), which was significantly associated with atrophy (adjusted odds ratio [aOR], 15.08; 95% CI, 2.45-93.35), contraceptive usage (aOR, 4.76; 95% CI, 1.07-21.39), and primiparity (aOR, 4.89; 95% CI, 1.01-23.88). Episiotomy was the only risk factor for scar tenderness (aOR, 5.43; 95% CI, 1.20-24.53), while the existence of a spontaneous perineal tear was not. No specific correlation was found with pelvic floor muscle hypertonicity. Targeted treatment resulted in significant improvement in most patients.

Clinical Implications

A targeted diagnostic and treatment approach for postpartum dyspareunia is effective and can be beneficial for caregivers treating postpartum women.

Strengths and Limitations

A uniform and consistent protocol for patient selection and management is a major strength, which magnifies the clinical implication of our findings. The retrospective nature of the study is the primary limitation.

Conclusion

Postpartum dyspareunia is a common problem; however, many women refrain from discussing it with their providers. Therefore, it is important to assess this condition with all women during the postpartum visit as targeted diagnosis and treatment can significantly improve outcomes.
Symptoms and associated impact in pre- and postmenopausal women with sexual arousal disorder: a concept elicitation study
Authors: Symonds Tara , Kingsberg Sheryl A , Simon James A , Kroll Robin , Althof Stanley E , Parish Sharon J , Cornell Katherine A , Johnson Isabella F , Goldstein Andrew T
Published: January 2023

Background

Approximately 26% of adult women in the United States suffer from female sexual arousal disorder (FSAD), yet little has been done to compare the experience of FSAD in pre- and postmenopausal women, which is critical to enhance the current understanding of FSAD and inform the development and assessment of treatment options for these patient populations.

Aim

To explore the experience of condition-associated symptoms and the relative importance of FSAD symptoms, including their severity, bother, and impact, on participants’ health-related quality of life (HRQoL) in pre- and postmenopausal women with FSAD.

Methods

In-depth, qualitative, semistructured concept elicitation interviews were conducted with premenopausal (n = 23) and postmenopausal (n = 13) women who were clinically diagnosed with FSAD by a trained sexual medicine clinician. All interviews were audio recorded and transcribed verbatim by a professional transcription company. Thematic analysis was performed with the assistance of NVivo qualitative analysis software.

Outcomes

Outcomes included qualitative interview data about FSAD symptoms and HRQoL, as well as a comparison between pre- and postmenopausal populations.

Results

The most frequently reported symptom in both cohorts was “inability or difficulty with orgasm” (premenopausal, n = 21; postmenopausal, n = 13). The symptom that premenopausal women most desired to have treated was lubrication, and for postmenopausal women, it was a lack of lubrication or wetness and loss of feeling/sensation. In total, 21 of 23 premenopausal women and all 13 postmenopausal women reported a lack of feeling or sensation in the genitals. The most frequently reported HRQoL impact in both groups was decreased confidence.

Clinical Implications

Results from this study suggest that the manifestation and experience of FSAD are similar in pre- and postmenopausal women and that the unmet need for an FSAD treatment in the postmenopausal population is just as great as that of the premenopausal population.

Strengths and Limitations

This study involved in-depth qualitative interviews with a relatively small group of women (N = 36) recruited from only 5 study sites across the United States.

Conclusion

The analysis of qualitative data from the concept elicitation interviews revealed a substantial physical and emotional burden of FSAD, underscoring the need for Food and Drug Administration–approved treatment options for pre- and postmenopausal women with FSAD.
CAFuncAPA: a knowledgebase for systematic functional annotations of APA events in human cancers
Authors: Huang Kexin , Wu Sijia , Yang Xiaotong , Wang Tiangang , Liu Xi , Zhou Xiaobo , Huang Liyu
Published: January 2023

Alternative polyadenylation (APA) is a widespread posttranscriptional regulation process. APA generates diverse mRNA isoforms with different 3’ UTR lengths, affecting mRNA expression, miRNA binding regulation and alternative splicing events. Previous studies have demonstrated the important roles of APA in tumorigenesis and cancer progression through diverse aspects. Thus, a comprehensive functional landscape of diverse APA events would aid in a better understanding of the underlying mechanisms related to APA in human cancers. Here, we built CAFuncAPA (https://relab.xidian.edu.cn/CAFuncAPA/) to systematically annotate the functions of 15478 APA events in human pan-cancers. Specifically, we first identified APA events associated with cancer survival and tumor progression. We annotated the potential downstream effects of APA on genes/isoforms expression, regulation of miRNAs, RNA binding proteins (RBPs) and alternative splicing events. Moreover, we also identified up-regulators of APA events, including the effects of genetic variants on poly(A) sites and RBPs, as well as the effect of methylation phenotypes on APA events. These findings suggested that CAFuncAPA can be a helpful resource for a better understanding of APA regulators and potential functions in cancer biology.
Cytomegalovirus DNAemia Requiring (Val)Ganciclovir Treatment for More Than 8 Weeks Is a Key Factor in the Development of Antiviral Drug Resistance
Authors: Acquier M , Taton B , Alain S , Garrigue I , Mary J , Pfirmann P , Visentin J , Hantz S , Merville P , Kaminski H , Couzi L
Published: January 2023

Background

Prolonged (val)ganciclovir [(V)GCV] exposure for ≥6 weeks is a known predisposing factor for cytomegalovirus (CMV) drug resistance. However, the selection of this threshold was based on limited data. In this study, we sought to reappraise the risk factors for the development of (V)GCV resistance through a specific focus on kidney transplant recipients (KTRs).

Methods

This single-center retrospective study included 313 consecutive KTRs treated for a first CMV episode. Adjusted Cox multivariate regression analysis was used for identifying independent risk factors.

Results

Antiviral drug resistance was identified in 20 (6%) KTRs. A cumulative (V)GCV exposure for more than 6 weeks (regardless of the viral load) was not associated with antiviral drug resistance (hazard ratio [HR] = 2.45, 95% confidence interval [CI] = 0.33–18.30, P = .38). In contrast, persistent CMV DNAemia requiring (V)GCV treatment for more than 8 weeks was the main independent risk factor for antiviral drug resistance (HR = 11.68, 95% CI = 2.62–52.01, P = .001). The (V)GCV treatment for more than 8 weeks was given to 9% and 18% of patients who had persistent or recurrent CMV DNAemia, respectively. These scenarios were associated with the occurrence of drug resistance in 39% and 12% of cases, respectively.

Conclusions

Cumulative (V)GCV exposure ≥6 weeks regardless of the viral load is not associated with antiviral drug resistance. In contrast, prolonged exposure to (V)GCV during CMV replication (with a cutoff ³8 weeks) seems to be a key factor.
Abusive Unconstitutional Constitutional Amendments: Indonesia, the Pancasila and the Spectre of Authoritarianism
Authors: Nugraha Ignatius Yordan
Published: January 2023

This article explores how an unconstitutional constitutional amendments doctrine could be abused to advance an illiberal or even authoritarian agenda, with Indonesia as a case study. In Indonesia, there is a pervasive belief that the five fundamental principles of the state (the Pancasila) are the ‘basic norm’ of the Indonesian legal order. Based on this understanding, it has been argued that all positive laws, including constitutional amendments, must be consistent with the Pancasila. At the same time, there is a danger lurking behind this idea. The four amendments to the 1945 Constitution, which have ushered in a new era of democracy, have been claimed to be repugnant to the Pancasila. Consequently, a future authoritarian president could invoke this doctrine to revert to the original 1945 Constitution, which has enabled two authoritarian regimes in the past. Nevertheless, this threat could be minimised by applying the concepts of constituent and constituted powers.
Fit for social innovation? Policy reflections for EU energy and climate policy making
Authors: Rogge Karoline S , Stadler Maria , de Geus Tessa , Hielscher Sabine , Wittmayer Julia , Broich Annalena , Kotler Adrienne , Mischkowski Niklas , Stasik Agata , Ranville Adélie , Vernay Anne-Lorène
Published: January 2023

Achieving climate-neutrality by mid-century and its intermediary reduction targets for 2030, notably the EU’s greenhouse gas emissions reduction of 55% by 2030, requires an accelerated transformation of our systems of production and consumption. In essence, such transformations are socio-technical change processes that require a combination of technological and social innovation. While it is widely acknowledged that ambitious climate and energy policies are needed to accelerate such transition processes, research and practise have largely focused on their importance for spurring technological innovation. In this research perspective, we argue that energy and climate policy making should pay more attention to social innovation as much needed additional puzzle piece for successful decarbonisation. Such social innovation is diverse, ranging from renewable energy cooperatives, to participatory incubation and experimentation, and crowdfunding as well as local electricity exchange. Based on a literature review that informed an EU policy dialogue bringing together policy makers, practitioners and researchers and followed up by a workshop with city administrations, twelve practical action points were co-created on how to better consider social innovation in energy and climate policy making in the EU (and beyond). We thereby hope to stimulate a broader discourse on the dual need for social and technological innovation for reaching climate-neutrality.
Estimating Production Functions of Multiproduct Firms
Authors: Valmari Nelli
Published: January 2023

Multiproduct firms constitute a considerable share of firms and account for an even greater share of production. Nevertheless, the vast majority of production function estimates are based on the assumption that firms are single-product manufacturers. This assumption is due to a lack of data on how firms allocate their inputs across their various product lines. I provide a strategy for estimating product-specific input allocations and production functions of multiproduct firms involved in monopolistic competition. The strategy is based on using firms’ product prices and output demand in solving for product-level input allocations.
Survey of patients and physicians on shared decision-making in treatment selection in relapsed/refractory multiple myeloma
Authors: Bylund Carma L , Eggly Susan , LeBlanc Thomas W , Kurtin Sandra , Gandee Marianne , Medhekar Rohan , Fu Alan , Khurana Monica , Delaney Kara , Divita Alecia , McNamara Michelle , Baile Walter F
Published: January 2023

Shared decision-making (SDM) is a key component of patient-centered healthcare. SDM is particularly pertinent in the relapsed and/or refractory multiple myeloma (RRMM) setting, in which numerous treatment options can present challenges for identifying optimal care. However, few studies have assessed the extent and relevance of SDM and patient-centered communication (PCC) in RRMM. To describe treatment decision-making patterns between physicians and patients in the RRMM setting, we conducted online surveys of patients and physicians in the USA to compare their perspectives on the process of treatment decision-making. We analyzed the surveys descriptively. Two hundred hematologists/oncologists and 200 patients with RRMM receiving second-line (n = 89), third-line (n = 65), and fourth-line (n = 46) therapy participated. Top treatment goals for physicians and patients included extending overall survival (among 76% and 83% of physicians and patients, respectively) and progression-free survival (among 54% and 77% of physicians and patients, respectively), regardless of the number of prior relapses. Thirty percent of physicians believed patients preferred a shared approach to treatment decision-making, while 40% of patients reported most often preferring a shared role in treatment decision-making. One-fourth of patients most often preferred physicians to make the final treatment decision after seriously considering their opinion. Thirty-two percent of physicians and 16% of patients recalled ≥3 treatment options presented at first relapse. Efficacy was a primary treatment goal for patients and physicians. Discrepancies in their perceptions during RRMM treatment decision-making exist, indicating that communication tools are needed to facilitate SDM and PCC.
Recommendations to bolster adherence in cognitive behavioral therapy for insomnia: a self-efficacy approach
Authors: Fretz Katherine M
Published: January 2023

Lay Summary

The safest and most effective treatment for chronic insomnia is Cognitive Behavioural Therapy for Insomnia (CBT-I). People sometimes struggle to adhere to, or follow the steps, involved in CBT-I because they are challenging (i.e., restricting time in bed to induce sleepiness, getting out of bed when not sleeping). These steps are based on sleep science and research shows that more closely adhering to them relates to better sleep improvements. One way that clinicians can help patients completing CBT-I improve their adherence to the difficult treatment steps is to promote their self-efficacy, or belief that they can effectively complete the treatment steps. Inspired by tried-and-true health promotion techniques rooted in Social Cognitive Theory, this paper describes concrete recommendations that clinicians can use to improve their patients’ self-efficacy when completing CBT-I. These recommendations include suggestions such as setting positive treatment expectations, discussing with patients how to set up for success when completing the treatment steps at home, and how to work with potential barriers to treatment. If clinicians can help boost patients’ self-efficacy, they may be able to carry out the treatment steps of CBT-I more effectively, and ultimately experience more benefits.
A literature review of schistosomiasis in Ghana: a reference for bridging the research and control gap
Authors: Boateng Enoch Mensah , Dvorak Jan , Ayi Irene , Chanova Marta
Published: January 2023

Schistosomiasis is endemic in most sub-Saharan African countries, including Ghana, where the need for effective control involving preventive chemotherapy was indicated by the WHO. Mass drug administration commenced in 2008 and has continued since then in Ghana, but the country remains highly endemic. Here, we review the literature on schistosomiasis to identify research and knowledge gaps potentially affecting disease control. A total of 100 Ghana-related schistosomiasis literature sources were reviewed, showing that most studies were conducted on epidemiology, control of transmission and diagnosis. By contrast, many aspects of this disease remain neglected, including livestock schistosomiasis and its zoonotic potential, recent distribution of disease vectors or widely overlooked genital schistosomiasis. Stratified by region, the highest number of studies focus on Greater Accra, while studies are limited or absent for several other regions. Although this review shows apparent progress in terms of schistosomiasis research and control, a considerable amount of work remains to achieve at least a reduction in the prevalence of the disease, which affects a significant proportion of the population. National epidemiological data based on a nationwide survey, integrated control and improved monitoring and evaluation must be ensured.
Training Resource for Improvement of Visual Assessment of Field Crop Disease and Insect Defoliation Severity
Authors: Sisson Adam J. , Mueller Daren S.
Published: January 2023

The Field Crop Disease and Insect Defoliation Severity Training Tool is an interactive online resource designed to help crop scouts and researchers to increase visual assessment skills for disease symptom and insect defoliation severity on plant leaves or other tissue. With two training options, it is widely available for any type of computer, tablet, or smartphone through common web browsers. The Field Crop Disease and Insect Defoliation Severity Training Tool is accessible through the Crop Protection Network website ( www.cropprotectionnetwork.org ). The training tool was designed to be updated for additional crops and tissue types, as well as for different disease lesions. Accurate assessment of severity is useful for making informed decisions regarding pest management, assessing research treatments, and assessing crop losses caused by injury.

[Formula: see text] Copyright © 2023 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .
Treatment of neurofibromatosis type II with anlotinib: a case report and literature review
Authors: Zhao Rugang , Zou Wen , Zhao Xiangfei
Published: January 2023

Patients with neurofibromatosis type II (NF2) usually require surgical treatment, but the probability of tumor recurrence remains high after surgical resection. Moreover, because most of NF2 lesions involve the facial nerve, the risk of facial nerve injury during the surgery is high. Stereotactic radiotherapy can be used to treat some cases of NF2. However, it is not recommended for treatment of multiple or large tumors, and surgical resection may be more difficult after radiotherapy. Few systemic treatments are available. At present, bevacizumab is considered the first-line drug treatment for fast-growing NF2. However, bevacizumab requires long-term administration, and tumor growth will resume after drug withdrawal. Here, we present a case of NF2 that developed exacerbations after multiple treatments with gamma knife and surgery, and achieved good results after later treatment with anlotinib. Accordingly, we propose that anlotinib may be a valuable treatment option for NF2.
HER2-positive breast cancer progresses rapidly after pyrotinib resistance: acquired RET gene fusion and TP53 gene mutation are potential reasons
Authors: Jiang Fengxian , Lai Jingjiang , Zhuo Xiaoli , Liu Lei , Yang Yucheng , Zhang Junlei , Zhao Jing , Xu Wei , Wang Jingliang , Wang Cuiyan , Fu Guobin
Published: January 2023

Approximately 15–20% of the patients with breast cancer overexpress human epidermal growth factor receptor 2 (HER2). HER2-positive breast cancer is highly aggressive and has a high relapse rate, suggesting that it is prone to and progresses rapidly after drug resistance. Pyrotinib resistance and changes in patients’ conditions after drug resistance are challenging clinical issues and require medical attention. Recently, there are few clinical reports on changes in patients’ conditions after pyrotinib resistance. We report a case of a 46-year-old patient with HER2-positive breast cancer who developed resistance to pyrotinib and rapidly progressed to uncontrolled liver failure in less than a week. To elucidate the cause of the rapid progression, we collected samples of the patient’s ascites and performed next-generation sequencing (NGS). On the basis of the NGS results, we speculated that the rapid progression after pyrotinib resistance might be due to RET gene fusion and TP53 gene mutations. Therefore, this case report aims to alert oncologists that patients with HER2-positive breast cancer, who are resistant to pyrotinib or other targeted drugs, could experience rapid or even flare-up progression and that RET gene fusion and TP53 gene mutations might be potential causes.
Immunogenicity of Homologous Heart Valves: Mechanisms and Future Considerations
Authors: Vogel Andrew D. , Kwon Jennie H. , Mitta Alekhya , Sherard Curry , Brockbank Kelvin G. M. , Rajab Taufiek Konrad
Published: January 2023

Pediatric valvar heart disease continues to be a topic of interest due to the common and severe clinical manifestations. Problems with heart valve replacement, including lack of adaptive valve growth and accelerated structural valve degeneration, mandate morbid reoperations to serially replace valve implants. Homologous or homograft heart valves are a compelling option for valve replacement in the pediatric population but are susceptible to structural valve degeneration. The immunogenicity of homologous heart valves is not fully understood, and mechanisms explaining how implanted heart valves are attacked are unclear. It has been demonstrated that preservation methods determine homograft cell viability and there may be a direct correlation between increased cellular viability and a higher immune response. This consists of an early increase in human leukocyte antigen (HLA)-class I and II antibodies over days to months posthomograft implantation, followed by the sustained increase in HLA-class II antibodies for years after implantation. Cytotoxic T lymphocytes and T-helper lymphocytes specific to both HLA classes can infiltrate tissue almost immediately after implantation. Furthermore, increased HLA-class II mismatches result in an increased cell-mediated response and an accelerated rate of structural valve degeneration especially in younger patients. Further long-term clinical studies should be completed investigating the immunological mechanisms of heart valve rejection and their relation to structural valve degeneration as well as testing of immunosuppressant therapies to determine the needed immunosuppression for homologous heart valve implantation.
Enhanced mitophagy driven by ADAR1-GLI1 editing supports the self-renewal of cancer stem cells in HCC
Authors: Luo Jie , Gong Lanqi , Yang Yuma , Zhang Yu , Liu Qin , Bai Lu , Fang Xiaona , Zhang Baifeng , Huang Jiao , Liu Ming , Liu Beilei , Tang Ying , Wong Ching Ngar , Huang Jinlin , Liu Shan , Li Shanshan , Ding Tao , Man Kwan , Lee Victor Ho-Fun , Li Yan , Ma Stephanie , Guan Xin-Yuan
Published: January 2023

Background and Aims:

Deregulation of adenosine-to-inosine editing by adenosine deaminase acting on RNA 1 (ADAR1) leads to tumor-specific transcriptome diversity with prognostic values for HCC. However, ADAR1 editase-dependent mechanisms governing liver cancer stem cell (LCSC) generation and maintenance have remained elusive.

Approach and Results:

RNA-seq profiling identified ADAR1-responsive recoding editing events in HCC and showed editing frequency of GLI1, rather than transcript abundance was clinically relevant. Functional differences in LCSC self-renewal and tumor aggressiveness between wild-type (GLI1wt) and edited GLI1 (GLI1edit) were elucidated. We showed that overediting of GLI1 induced an arginine-to-glycine (R701G) substitution, augmenting tumor-initiating potential and exhibiting a more aggressive phenotype. GLI1R701G harbored weak affinity to SUFU, which in turn, promoted its cytoplasmic-to-nuclear translocation to support LCSC self-renewal by increased pluripotency gene expression. Moreover, editing predisposed to stabilize GLI1 by abrogating β-TrCP-GLI1 interaction. Integrative analysis of single-cell transcriptome further revealed hyperactivated mitophagy in ADAR1-enriched LCSCs. GLI1 editing promoted a metabolic switch to oxidative phosphorylation to control stress and stem-like state through PINK1-Parkin-mediated mitophagy in HCC, thereby conferring exclusive metastatic and sorafenib-resistant capacities.

Conclusions:

Our findings demonstrate a novel role of ADAR1 as an active regulator for LCSCs properties through editing GLI1 in the highly heterogeneous HCC.
Chimeric Antigen Receptor T-cell Therapy in Hematologic Malignancies and Patient-reported Outcomes: A Scoping Review
Authors: Efficace Fabio , Cannella Laura , Sparano Francesco , Giesinger Johannes M. , Vignetti Marco , Baron Frédéric , Bruera Eduardo , Luppi Mario , Platzbecker Uwe
Published: January 2023

The inclusion of patient-reported outcome (PRO) measures in chimeric antigen receptor (CAR) T-cell therapy research is critical for understanding the impact of this novel approach from a unique patient standpoint. We performed a scoping review to map the available literature on the use of PRO measures in CAR T-cell therapy studies of patients with hematologic malignancies published between January 2015 and July 2022. Fourteen studies were identified, of which 7 (50%) were investigational early-phase trials, 6 (42.9%) were observational studies, and 1 (7.1%) was a pilot study. The EQ-5D and the PROMIS-29 were the 2 most frequently used PRO measures, being included in 6 (42.9%) and 5 (35.7%) studies, respectively. Despite differences in study designs, there seems to be evidence of improvements over time since CAR T-cell infusion in important domains such as physical functioning and fatigue, at least in patients who respond to therapy. Overall, the studies identified in our review have shown the added value of PRO assessment in CAR T-cell therapy research by providing novel information that complements the knowledge on safety and efficacy. However, there are several questions which remain to be answered in future research. For example, limited evidence exists regarding patient experience during important phases of the disease trajectory as only 4 (28.6%) and 5 (35.7%) studies provided information on PROs during the first 2 weeks from CAR T-cell infusion and after the first year, respectively. Time is ripe for a more systematic implementation of high-quality PRO assessment in future clinical trials and in real-life settings of patients treated with CAR T-cell therapy.
First-line Treatment With Bendamustine and Rituximab for Old and Frail Patients With Aggressive Lymphoma: Results of the B-R-ENDA Trial
Authors: Braulke Friederike , Zettl Florian , Ziepert Marita , Viardot Andreas , Kahl Christoph , Prange-Krex Gabriele , Korfel Agnieszka , Dreyling Martin , Bott Alexander , Wedding Ulrich , Reichert Dietmar , de Wit Maike , Hartmann Frank , Poeschel Viola , Schmitz Norbert , Witzens-Harig Mathias , Klapper Wolfram , Rosenwald Andreas , Wulf Gerald , Altmann Bettina , Trümper Lorenz
Published: January 2023

The incidence of aggressive B-cell lymphomas increases with age, but for elderly or frail patients not eligible for doxorubicin-containing treatment standard therapy remains to be defined. In this prospective, multicenter, phase-2 B-R-ENDA trial, we investigated the feasibility, toxicity, and efficacy of 8 cycles rituximab combined with 6 cycles bendamustine (BR) in elderly or frail aggressive B-cell lymphoma patients: 39 patients aged >80 years and 29 patients aged 61–80 years with elevated Cumulative Illness Rating Scalescore >6 were included. Progression-free survival (PFS) and overall survival (OS) at 2 years were 45% (95% confidence interval [CI], 28%-61%) and 46% (28%-63%) for the patients age >80, as well 32% (13%-51%) and 37% (17%-57%) for frail patients age 64–80, respectively. In a preplanned retrospective analysis, we found no significant differences in PFS and OS comparing the outcome of the 39 patients age >80 years with 40 patients aged 76–80 years treated with 6xR-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) and 2 x rituximab in the RICOVER-60 trial (DSHNHL 1999-1, NCT00052936, EU-20243), yet we detected lower rates of infections and treatment-related deaths in the BR-treated patients. We demonstrate that older and frail patients with aggressive B-cell lymphoma who are not able to receive standard CHOP-based therapy can benefit from anthracycline-free therapy as a feasible and effective therapeutic option.
Gender Differences in Adolescents' Affective Symptoms and Behavioral Disorders After Mild Traumatic Brain Injury
Authors: Veliz Philip T. , Berryhill Marian E.
Published: January 2023

Objective:

Mild traumatic brain injuries (mTBI) are considered self-limiting and full recovery is expected. Recent studies identify deficits persisting years after mTBI. Large-scale prospective data permit testing the hypothesis that mTBI increases incidence of affective and behavioral symptoms after new, past, or new and past mTBI.

Setting:

The study involved secondary analyses of survey responses from the Adolescent Brain Cognitive Development (ABCD) Study.

Participants:

Adolescents in the ABCD Study (n = 11 869; Wave 1, aged 9-10 years; Wave 2, aged 11-12 years) whose parents reported a new (n = 157), past (n = 1318), or new and past (n = 50) mTBI on the Ohio State University Traumatic Brain Injury Identification Method short form were compared with controls who had no history of mTBI (n = 9,667).

Design:

Multivariable binary logistic regression models examined associations between a new, past, or new and past mTBI and current affective (aggression, depression, anxiety) and behavioral (somatic, thought, social, attention, attention deficit hyperactivity disorder, conduct) disorders while controlling for demographic factors and baseline symptoms.

Main Measures:

The primary measure was parental reports of psychiatric and behavioral symptoms on the Child Behavior Checklist.

Results:

Girls exhibited no significant effects after a new mTBI, although a past mTBI increased anxiety (adjusted odds ratios [aOR] = 1.83, 95% confidence interval [CI: 1.15-2.90]) and attention (1.89 [1.09-3.28]) problems. Girls with new and past mTBIs reported elevated anxiety (17.90 [4.67-68.7]), aggression (7.37 [1.49-36.3]), social (9.07 [2.47-33.30]), thought (7.58 [2.24-25.60]), and conduct (6.39 [1.25-32.50]) disorders. In boys, new mTBI increased aggression (aOR = 3.83, 95% CI [1.42-10.30]), whereas past mTBI heightened anxiety (1.91 [1.42-2.95]), but new and past mTBIs had no significant effects.

Conclusion:

Adolescents are at greater risk of affective and behavioral symptoms after an mTBI. These effects differ as a function of gender and time of injury. Extended screening for mTBI history and monitoring of affective and behavioral disorders after mTBI in adolescents are warranted.
Gram-Negative Rod Breast Wound Infections After Postcancer Reconstructive Surgery
Authors: Vasiloudes Kritos P. , Pate Donna M. , Greene John N.
Published: January 2023

Background

After mastectomy, breast reconstructive surgeries using breast tissue expander (BTE) placement have a particularly high risk of infection. Whereas previous studies showed these infections to consist of primarily gram-positive organisms, gram-negative rods consist of up to 26% of the microorganisms isolated in some studies. Here we highlight the prevalence of gram-negative rods, particularly Pseudomonas aeruginosa, in BTE infections.

Methods

We used a retrospective chart review at a comprehensive cancer center to identify BTE infections caused by gram-negative rods over a 2-yearperiod. We collected data on the organism from wound cultures and antimicrobial susceptibilities.

Results

During this period, we isolated 38 gram-negative rod infections from BTE surgeries from a sample size of 215 organisms. The most common gram-negative rod was P. aeruginosa (44.7%), followed by Serratia marcescens (15.7%) and Klebsiella pneumoniae (7.9%). All Pseudomonas and Klebsiella isolates were susceptible to all antibiotics tested; Serratia isolates were resistant to cefazolin and cefoxitin. Significant resistance to ampicillin, cefazolin, cefoxitin, and ceftazidime was found in the organisms tested. Antipseudomonal antimicrobials, notably cefepime, piperacillin/tazobactam, ciprofloxacin, tobramycin, and gentamicin, had activity against all organisms tested.

Conclusions

Perioperative antimicrobial prophylaxis consisting of cefazolin often does not have activity against gram-negative rods. In addition, postoperative antibiotics often do not have activity against Pseudomonas. In our study sample, all antibiotics tested had activity against Pseudomonas. Empiric antibiotics used to treat postsurgical BTE infections should include activity against Pseudomonas.
Physiologic considerations of pig-to-human kidney xenotransplantation
Authors: Tatapudi Vasishta S. , Griesemer Adam D.
Published: January 2023

Purpose of review

The greatest challenge facing end-stage kidney disease (ESKD) patients is the scarcity of transplantable organs. Advances in genetic engineering that mitigate xenogeneic immune responses have made transplantation across species a potentially viable solution to this unmet need. Preclinical studies and recent reports of pig-to-human decedent renal xenotransplantation signify that clinical trials are on the horizon. Here, we review the physiologic differences between porcine and human kidneys that could impede xenograft survival. Topics addressed include porcine renin and sodium handling, xenograft water handling, calcium, phosphate and acid-base balance, responses to porcine erythropoietin and xenograft growth.

Recent findings

Studies in nonhuman primates (NHPs) have demonstrated that genetically modified pig kidneys can survive for an extended period when transplanted into baboons. In recent studies conducted by our group and others, hyperacute rejection did not occur in pig kidneys lacking the α1,3Gal epitope transplanted into brain-dead human recipients. These experimental trials did not study potential clinical abnormalities arising from idiosyncratic xenograft responses to human physiologic stimuli due to the brief duration of observation this model entails.

Progress in biotechnology is heralding an era of xenotransplantation. We highlight the physiologic considerations for xenogeneic grafts to succeed.
The lupus nephritis classification: lost in translation
Authors: Whittier William L.
Published: January 2023

Purpose of review

The ISN/RPS lupus nephritis classification is in the process of undergoing a revision. It has lost its way and morphed from a classification based on pathophysiology of disease into a staging system based on the extent of spread and prognosis.

Recent findings

There are multiple different pathophysiologic processes that contribute to lupus nephritis. The current classification is inadequate, as it does not highlight these differences and thus squanders the opportunity to develop targeted therapies. Its focus is on the extent of disease as opposed to the pattern of injury, which defines the disease. To delineate the cause, we must include immunofluorescent and electron microscopy, which will help define the pattern of injury.

To determine eventual targeted treatments for lupus nephritis, we must first classify the disease according to the available pathophysiologic mechanisms. In the upcoming revision, including the immunofluorescence and electron microscopy and eliminating the overemphasis on extent of disease are the first steps to categorizing the lupus nephritis classes accurately.
Novel therapeutic and diagnostic approaches for preeclampsia
Authors: Vatish Manu , Powys Veronica R. , Cerdeira Ana Sofia
Published: January 2023

Purpose of review

This review will summarize recent findings relating to the diagnostic approach to preeclampsia and current avenues of research aimed at modifying the underlying disease process.

Recent findings

Growing international consensus supports a broad preeclampsia definition that incorporates maternal end-organ and uteroplacental dysfunction. Recent evidence demonstrates that this definition better identifies women and babies at risk of adverse outcomes compared to the traditional definition of hypertension and proteinuria. Multiple studies have demonstrated the usefulness and cost-effectiveness of angiogenic biomarkers such as soluble fms-like tyrosine kinase-1 and placental growth factor as a clinical adjunct to diagnose and predict severity of preeclampsia associated outcomes. Current novel therapeutic approaches to preeclampsia target pathogenic pathways (e.g. antiangiogenesis) or downstream effects such as oxidative stress and nitric oxide. Recent findings relating to these promising candidates are discussed. Multicenter clinical trials are needed to evaluate their effectiveness and ability to improve fetal and maternal outcomes.

We provide an updated framework of the current approaches to define and diagnose preeclampsia. Disease modifying therapies (in particular, targeting the angiogenic pathway) are being developed for the first time and promise to revolutionize the way we manage preeclampsia.
Obesity Education May Not Be Sufficient in US Dietetic Internship Programs
Authors: Childress Allison , Klobodu Seth S. , Chrisman Matthew , Bailey Dylan , Kerin Allison , Benavides Marqui L.
Published: January 2023

This study aimed to determine the breadth to which obesity education is included in US dietetic internships, how it is prioritized, and the perceived barriers to providing optimal obesity curricula in dietetic internships. A 27-item, cross-sectional survey was emailed to 335 dietetic internship program administrators in the United States and Puerto Rico. Data were analyzed using general descriptive statistics. A total of 83 administrators (25%) participated. Only 26 dietetic internship programs (34%) reported their interns were “very prepared” to manage patients with obesity. Thirty-six percent had no obesity education programs in place, and 65% noted obesity education is not taught as a specific clinical rotation. Forty percent of administrators believed obesity education to be a specific competency for dietetic internships, and 33% viewed expansion of obesity education as a low priority. Lack of room in the current curriculum was the predominant barrier (22%) to integrating obesity education, whereas lack of interest was not (74%). Administrators reported their interns generally had “some to great extent” of knowledge on comorbidities of obesity (60%), but knowledge of obesity etiology and assessment was low (33%). Fifty-eight percent of dietetic internship programs did not provide weight bias training. Despite the expectation that registered dietitian nutritionists are primary educators in obesity management, US dietetic internships may not be adequately preparing their students to manage patients with obesity. Contributing factors to this disconnect should be recognized, and barriers minimized, so that optimal obesity training is provided in dietetic internships.
Lifestyle and Quality of Life Among Overweight University Employees
Authors: García-Pérez-de-Sevilla Guillermo
Published: January 2023

Lifestyle is an environmental factor responsible for 60% of epigenetic factors related to the appearance of noncommunicable diseases, with a high impact on health-related quality of life (HrQoL). This observational study aimed to analyze the lifestyle and its impact on HrQoL in overweight/obese university employees. The following variables were analyzed in overweight/obese employees: lifestyle, physical activity, sedentary behavior, diet, body composition, and HrQoL. To analyze the associations between these variables, the Spearman and Pearson correlation tests were carried out. A total of 36 participants (69% female; aged 43.88 ± 7.14 years; body mass index 27.45 ± 2.99 kg/m2) were analyzed. The Mediterranean Diet Adherence Screener score was 6.83 ± 1.38. Physical activity levels were 213.33 ± 251.97 metabolic equivalent tasks–minutes per week, and sitting time was 561.67 ± 188.19 minutes per day. Health-related quality-of-life levels were very poor, according to the Short-Form 36 Health Survey Questionnaire v2. Nutrition and stress management showed moderate positive correlations with HrQoL, whereas negative moderate correlations were found between sitting time and HrQoL. Finally, waist circumference and body mass index showed negative large-moderate correlations with physical function. These findings highlight the need to promote healthy lifestyle habits in the workplace to prevent noncommunicable diseases and improve HrQoL. Physical exercise and nutrition interventions should be performed within the workplace, especially among overweight/obese employees.