bluuebunny/crossref_metadata_2025 huggingface dataset:
Polyglutamine-expanded ATXN7 alters a specific epigenetic signature underlying photoreceptor identity gene expression in SCA7 mouse retinopathy
Authors: Niewiadomska-Cimicka Anna , Hache Antoine , Le Gras Stéphanie , Keime Céline , Ye Tao , Eisenmann Aurelie , Harichane Imen , Roux Michel J. , Messaddeq Nadia , Clérin Emmanuelle , Léveillard Thierry , Trottier Yvon
Published: December 2022

Background

Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disorder that primarily affects the cerebellum and retina. SCA7 is caused by a polyglutamine expansion in the ATXN7 protein, a subunit of the transcriptional coactivator SAGA that acetylates histone H3 to deposit narrow H3K9ac mark at DNA regulatory elements of active genes. Defective histone acetylation has been presented as a possible cause for gene deregulation in SCA7 mouse models. However, the topography of acetylation defects at the whole genome level and its relationship to changes in gene expression remain to be determined.

Methods

We performed deep RNA-sequencing and chromatin immunoprecipitation coupled to high-throughput sequencing to examine the genome-wide correlation between gene deregulation and alteration of the active transcription marks,e.g.SAGA-related H3K9ac, CBP-related H3K27ac and RNA polymerase II (RNAPII), in a SCA7 mouse retinopathy model.

Results

Our analyses revealed that active transcription marks are reduced at most gene promoters in SCA7 retina, while a limited number of genes show changes in expression. We found that SCA7 retinopathy is caused by preferential downregulation of hundreds of highly expressed genes that define morphological and physiological identities of mature photoreceptors. We further uncovered that these photoreceptor genes harbor unusually broad H3K9ac profiles spanning the entire gene bodies and have a low RNAPII pausing. This broad H3K9ac signature co-occurs with other features that delineate superenhancers, including broad H3K27ac, binding sites for photoreceptor specific transcription factors and expression of enhancer-related non-coding RNAs (eRNAs). In SCA7 retina, downregulated photoreceptor genes show decreased H3K9 and H3K27 acetylation and eRNA expression as well as increased RNAPII pausing, suggesting that superenhancer-related features are altered.

Conclusions

Our study thus provides evidence that distinctive epigenetic configurations underlying high expression of cell-type specific genes are preferentially impaired in SCA7, resulting in a defect in the maintenance of identity features of mature photoreceptors. Our results also suggest that continuous SAGA-driven acetylation plays a role in preserving post-mitotic neuronal identity.
Pro-resolving and pro-inflammatory fatty acid-derived mediators in sputum of stable state bronchiectasis patients
Authors: Terranova Leonardo , Risé Patrizia , Gramegna Andrea , Pinna Christian , Agostoni Carlo , Syrén Marie-Louise , Turolo Stefano , Marchisio Paola , Amati Francesco , Aliberti Stefano , Sala Angelo , Blasi Francesco
Published: December 2022

Background

Bronchiectasis is characterized by neutrophilic inflammation and frequent exacerbations often associated with infections. Lipid mediators play critical roles in the inflammatory response, and the balance between anti-inflammatory and pro-inflammatory mediators could drive to chronic inflammation. The aim of this study was to evaluate the metabolites of docosahexaenoic acid and arachidonic acid in sputum of adults with bronchiectasis defining their associations with clinical data, bacterial load and neutrophil elastase.

Methods

An observational, cross-sectional study was conducted at the bronchiectasis program of the Policlinico Hospital in Milan, Italy, where patients were enrolled. Active neutrophil elastase was measured by enzyme-linked immunosorbent assay, pro-resolving and pro-inflammatory fatty acid-derived mediators were evaluated by mass spectrometry and respiratory pathogens were assessed by real-time PCR. Analysis were performed on sputum collected during stable state and clinical data were also collected.

Results

Levels of pro-inflammatory mediators derived from arachidonic acid metabolism showed association with neutrophil elastase, were proportional to Pseudomonas aeruginosa identifications and were linked with radiological gravity index, while the concentrations of pro-resolution mediators derived from docosahexaenoic acid were associated with a better health status, highlighted by the inverse correlation with radiological gravity index, bacterial infections and sputum volume production.

Conclusion

Pro-inflammatory mediators derived from FA metabolisms are associated with severity of bronchiectasis while DHA-derived metabolites are inversely associated with severity of the disease, which may be used for personized treatment of bronchiectasis.
Elevated circulating level of β-aminoisobutyric acid (BAIBA) in heart failure patients with type 2 diabetes receiving sodium-glucose cotransporter 2 inhibitors
Authors: Katano Satoshi , Yano Toshiyuki , Kouzu Hidemichi , Nagaoka Ryohei , Numazawa Ryo , Yamano Kotaro , Fujisawa Yusuke , Ohori Katsuhiko , Nagano Nobutaka , Fujito Takefumi , Nishikawa Ryo , Ohwada Wataru , Katayose Masaki , Sato Tatsuya , Kuno Atsushi , Furuhashi Masato
Published: December 2022

Aims

The mechanism by which a sodium-glucose cotransporter inhibitor (SGLT2i) induces favorable effects on diabetes and cardiovascular diseases including heart failure (HF) remains poorly understood. Metabolomics including amino acid profiling enables detection of alterations in whole body metabolism. The aim of this study was to determine whether plasma amino acid profiles are modulated by SGLT2i use in HF patients with type 2 diabetes mellitus (T2DM).

Methods

We retrospectively examined 81 HF patients with T2DM (68 ± 11 years old; 78% male). Plasma amino acid concentrations in a fasting state after stabilization of HF were determined using ultraperformance liquid chromatography. To minimize potential selection bias in the retrospective analyses, the differences in baseline characteristics between patients receiving an SGLT2i and patients not receiving an SGLT2i were controlled by using an inverse probability of treatment weighting (IPTW)-adjusted analysis.

Results

Of amino acids measurable in the present assay, plasma β﻿﻿-aminoisobutyric acid (BAIBA), an exercise-induced myokine-like molecule also known as 3-aminoisobutyric acid or 3-amino-2-methyproponic acid, was detected in 77% of all patients and the proportion of patients in whom plasma BAIBA was detected was significantly higher in patients receiving an SGLT2i than in patients not receiving an SGLT2i (93% vs. 67%, p = 0.01). Analyses in patients in whom plasma BAIBA was detected showed that plasma BAIBA concentration was significantly higher in patients receiving an SGLT2i than in patients not receiving an SGLT2i (6.76 ± 4.72 vs. 4.56 ± 2.93 nmol/ml, p = 0.03). In multivariate logistic regression analyses that were adjusted for age and sex, SGLT2i use was independently associated with BAIBA detection. The independent association between BAIBA and SGLT2i use remained after inclusion of body mass index, HF with reduced ejection fraction, ischemic etiology, renal function, NT-proBNP, albumin, hemoglobin, and HbA1c into the Cox proportional hazards model. When the differences in baseline characteristics between patients receiving an SGLT2i and patients not receiving an SGLT2i were controlled by using an IPTW-adjusted analysis, least squares mean of plasma BAIBA concentration was significantly higher in patients receiving an SGLT2i than in patients not receiving an SGLT2i.

Conclusion

SGLT2i use is closely associated with increased circulating BAIBA concentration in HF patients with T2DM.
Constitutive glucose dehydrogenase elevates intracellular NADPH levels and luciferase luminescence in Bacillus subtilis
Authors: Wu Yuzheng , Kawabata Honami , Kita Kyosuke , Ishikawa Shu , Tanaka Kan , Yoshida Ken-ichi
Published: December 2022

Background

Genetic modifications in Bacillus subtilis have allowed the conversion of myo-inositol into scyllo-inositol, which is proposed as a therapeutic agent for Alzheimer’s disease. This conversion comprises two reactions catalyzed by two distinct inositol dehydrogenases, IolG and IolW. The IolW-mediated reaction requires the intracellular regeneration of NADPH, and there appears to be a limit to the endogenous supply of NADPH, which may be one of the rate-determining factors for the conversion of inositol. The primary mechanism of NADPH regeneration in this bacterium remains unclear.

Results

The gdh gene of B. subtilis encodes a sporulation-specific glucose dehydrogenase that can use NADP+ as a cofactor. When gdh was modified to be constitutively expressed, the intracellular NADPH level was elevated, increasing the conversion of inositol. In addition, the bacterial luciferase derived from Photorhabdus luminescens became more luminescent in cells in liquid culture and colonies on culture plates.

Conclusion

The results indicated that the luminescence of luciferase was representative of intracellular NADPH levels. Luciferase can therefore be employed to screen for mutations in genes involved in NADPH regeneration in B. subtilis, and artificial manipulation to enhance NADPH regeneration can promote the production of substances such as scyllo-inositol.
Sarcopenia is associated with worse surgical complications but not relapse-free survival and overall survival in patients with retroperitoneal liposarcoma
Authors: Zhao Mingkun , Lv Minzhi , Fang Yuan , Zhuang Aobo , Wu Qian , Tong Hanxing , Lu Weiqi , Zhang Yong
Published: December 2022

Objective

This investigation aimed to explore the relationship between sarcopenia and severe postoperative complications, relapse-free survival (RFS), and overall survival (OS) in patients with retroperitoneal liposarcoma (RLPS).

Material and methods

This retrospective study included 72 RLPS patients (47 men, 25 women; mean age, 57.49 years, SD 10.92) who had abdominal CT exams. Clinical information was recorded, including RLPS characteristics (histologic subtypes, grade, size), laboratory assessment (ALB, PALB, A/G, Hb, SCr), relapse-free survival, overall survival, and postoperative complications. The relationships between those variables and RFS and OS were analyzed using Cox proportional hazard models.

Results

There were 8 severe postoperative complications (Clavien-Dindo grade > 2). The chi-square test showed sarcopenia was associated with severe postoperative complications (P = 0.011). In multivariate analysis, sarcopenia was not associated with relapse-free survival (P = 0.574) and overall survival (P = 0.578).

Conclusions

Sarcopenia predicts worse surgical complications but does not affect relapse-free survival and overall survival.
Insufficient HtrA2 causes meiotic defects in aging germinal vesicle oocytes
Authors: Gao Min , Qiu Yanling , Cao Tianqi , Li Dungao , Wang Jingwen , Jiao Yiren , Chen Zhiyun , Huang Junjiu
Published: December 2022

Background

High-temperature requirement protease A2 (HtrA2/Omi) is a mitochondrial chaperone that is highly conserved from bacteria to humans. It plays an important role in mitochondrial homeostasis and apoptosis. In this study, we investigated the role of HtrA2 in mouse oocyte maturation.

Methods

The role of HtrA2 in mouse oocyte maturation was investigated by employing knockdown (KD) or overexpression (OE) of HtrA2 in young or old germinal vesicle (GV) oocytes. We employed immunoblotting, immunostaining, fluorescent intensity quantification to test the HtrA2 knockdown on the GV oocyte maturation progression, spindle assembly checkpoint, mitochondrial distribution, spindle organization, chromosome alignment, actin polymerization, DNA damage and chromosome numbers and acetylated tubulin levels.

Results

We observed a significant reduction in HtrA2 protein levels in aging germinal vesicle (GV) oocytes. Young oocytes with low levels of HtrA2 due to siRNA knockdown were unable to complete meiosis and were partially blocked at metaphase I (MI). They also displayed significantly more BubR1 on kinetochores, indicating that the spindle assembly checkpoint was triggered at MI. Extrusion of the first polar body (Pb1) was significantly less frequent and oocytes with large polar bodies were observed when HtrA2 was depleted. In addition, HtrA2 knockdown induced meiotic spindle/chromosome disorganization, leading to aneuploidy at metaphase II (MII), possibly due to the elevated level of acetylated tubulin. Importantly, overexpression of HtrA2 partially rescued spindle/chromosome disorganization and reduced the rate of aneuploidy in aging GV oocytes.

Conclusions

Collectively, our data suggest that HtrA2 is a key regulator of oocyte maturation, and its deficiency with age appears to contribute to reproduction failure in females.
NLRP3 deficiency decreases alcohol intake controlling anxiety-like behavior via modification of glutamatergic transmission in corticostriatal circuits
Authors: Li Ziyi , Vidjro Olivia Ewi , Guo Gengni , Du Yanfeng , Zhou Yao , Xie Qian , Li Jiaxin , Gao Keqiang , Zhou Li , Ma Tengfei
Published: December 2022

Background

Alcohol use disorders result from repeated binge and chronic alcohol consumption followed by negative effects, such as anxiety, upon cessation. This process is associated with the activation of NLRP3 inflammasome-mediated responses. However, whether and how inhibition of the NLRP3 inflammasome alters alcohol intake and anxiety behavior remains unclear.

Methods

A combination of drinking-in-the-dark and gavage was established in NLRP3-knockout and control mice. Behavior was assessed by open-field and elevated plus maze tests. Binge alcohol drinking was measured at 2 h and 4 h. A 2 h/4 h/24 h voluntary drinking was determined by a two-bottle choice paradigm. Western blotting and ELISA were applied to examine the levels of the NLRP3 inflammasome and- inflammatory factors, such as IL-1β and TNF-α. Nissl staining was used to measure neuronal injury. The electrophysiological method was used to determine glutamatergic transmission in corticostriatal circuits. In vivo optogenetic LTP and LTD were applied to control the function of corticostriatal circuits on the behavior of mice. MCC950 was used to antagonize the NLRP3 inflammasome.

Results

The binge alcohol intake was decreased in NLRP3 KO mice compared to the control mice. During alcohol withdrawal, NLRP3 deficiency attenuated anxiety-like behavior and neuronal injury in the mPFC and striatum. Moreover, we discovered that glutamatergic transmission to striatal neurons was reduced in NLRP3 KO mice. Importantly, in vivo optogenetic induction of long-term potentiation (LTP) of corticostriatal circuits reversed the effects of NLRP3 deficiency on glutamatergic transmission and anxiety behavior. We also demonstrated that optogenetic induction of LTD decreased anxiety-like behavior and caused a reduction in glutamatergic transmission. Interestingly, NLRP3 deficiency or inhibition (MCC950 injection) attenuated the anxiety-like behavior, but it did not prevent DID + gavage paradigm-induced a persistent enhancement of drinking in a two-bottle choice at 2 and 4 days into withdrawal.

Conclusion

Our results demonstrate that NLRP3 deficiency decreases binge alcohol intake and anxiety-like behavior through downregulation of glutamatergic transmission in corticostriatal circuits, which may provide an anti-inflammatory target for treating alcohol use disorders.
Investigation of cryotherapy for pain relief after arthroscopic shoulder surgery
Authors: Uchida Rinko , Hombu Amy , Ishida Yasuyuki , Nagasawa Makoto , Chosa Etsuo
Published: December 2022

Background

Recently, cryotherapy has become a common practice for postoperative pain management. The current accepted practice in Japan is the use of cryotherapy at 5 °C after arthroscopic shoulder surgery. However, this therapy has been reported to be highly intense because the sustained low temperature causes discomfort for patients. The optimum temperature and duration of cooling required for comfortable and effective cryotherapy after arthroscopic shoulder surgery were investigated.

Methods

Because pain levels might differ depending on the condition, we selected 52 patients with rotator cuff injuries, which were the most common disorders indicated for arthroscopic shoulder surgery. Patients were treated with cryotherapy at 5 °C or 10 °C for 16 h or 24 h. The pain level was determined using the visual analogue scale, and deep shoulder joint temperatures were recorded at different time points for analysis.

Results

Pain after arthroscopic shoulder surgery was found to be related to the presence of a brachial plexus block using the interscalene approach during surgical anesthesia. To obtain effective analgesia with cryotherapy, the cooling temperature and duration of cryotherapy had to be changed based on the presence or absence of the brachial plexus block. Patients who received brachial plexus blocks had the lowest recorded pain scores after receiving cryotherapy at 5 °C for 24 h after surgery. Patients who did not receive the block had the lowest recorded pain scores when receiving cryotherapy at either 5 °C for 16 h or 10 °C for 24 h.

Conclusions

Using universal cryotherapy intensity and duration settings regardless of the use of other interventions is likely to unintentionally increase postoperative pain levels. This study revealed that cryotherapy at 5 °C for 24 h was optimal for patients who received an anesthesia block and at 5 °C for 16 h or at 10 °C for 24 h for those who did not receive the anesthesia block. These results can be used as a reference for setting the temperature and duration of cryotherapy after arthroscopic shoulder surgery.
Ginsenoside Rg1 inhibits nucleus pulposus cell apoptosis, inflammation and extracellular matrix degradation via the YAP1/TAZ pathway in rats with intervertebral disc degeneration
Authors: Yang Yong-hua , Gu Xiao-peng , Hu Hong , Hu Bin , Wan Xiang-lian , Gu Zhi-ping , Zhong Shao-jin
Published: December 2022

Purpose

Intervertebral disc degeneration (IDD) is one of the main causes of low back pain, which not only affects patients’ life quality, but also places a great burden on the public health system. Recently, ginsenoside Rg1 has been found to act in IDD; however, the mechanism is still unclear. The purpose of this study is to explore the function of ginsenoside Rg1 and its molecular mechanism in IDD.

Methods

The rat model of IDD and nucleus pulposus (NP) experimental groups treated with ginsenoside Rg1 was constructed for investing the role of ginsenoside Rg1 in IDD rats. In the in vitro and in vivo study, the histological morphological changes, motor threshold (MT), inflammatory factors, oxidative stress, apoptosis and expression of the YAP1/TAZ signaling pathway-related proteins of the intervertebral discs (IVD) were measured by histological staining, mechanical and thermal stimulation, ELISA, qRT-PCR, flow cytometry, and western blot, respectively.

Results

Ginsenoside Rg1 significantly increased the threshold for mechanical and thermal stimulation and alleviated histological changes in IDD rats. Ginsenoside Rg1 had a significant inhibitory effect on the secretion level of inflammatory factors, redox activity, extracellular matrix (ECM) degradation in IVD tissue and NP cells, and apoptosis in NP cells. Further investigation revealed that ginsenoside Rg1 significantly inhibited the expression of YAP1/TAZ signaling pathway-related proteins. Additionally, the above inhibitory effect of ginsenoside Rg1 on IDD progression was concentration-dependent, that is, the highest concentration of ginsenoside Rg1 was most effective.

Conclusion

Ginsenoside Rg1 inhibits IDD progression by suppressing the activation of YAP1/TAZ signaling pathway. This means that ginsenoside Rg1 has the potential to treat IDD.
A prospective observational study on impact of epinephrine administration route on acute myocardial infarction patients with cardiac arrest in the catheterization laboratory (iCPR study)
Authors: Aldujeli Ali , Haq Ayman , Tecson Kristen M. , Kurnickaite Zemyna , Lickunas Karolis , Bailey Som , Tatarunas Vacis , Braukyliene Rima , Baksyte Giedre , Aldujeili Montazar , Khalifeh Hussein , Briedis Kasparas , Ordiene Rasa , Unikas Ramunas , Hamadeh Anas , Brilakis Emmanouil S.
Published: December 2022

Background

Epinephrine is routinely utilized in cardiac arrest; however, it is unclear if the route of administration affects outcomes in acute myocardial infarction patients with cardiac arrest.

Objectives

To compare the efficacy of epinephrine administered via the peripheral intravenous (IV), central IV, and intracoronary (IC) routes.

Methods

Prospective two-center pilot cohort study of acute myocardial infarction patients who suffered cardiac arrest in the cardiac catheterization laboratory during percutaneous coronary intervention. We compared the outcomes of patients who received epinephrine via peripheral IV, central IV, or IC.

Results

158 participants were enrolled, 48 (30.4%), 50 (31.6%), and 60 (38.0%) in the central IV, IC, and peripheral IV arms, respectively. Peripheral IV epinephrine administration route was associated with lower odds of achieving return of spontaneous circulation (ROSC, odds ratio = 0.14, 95% confidence interval = 0.05–0.36, p < 0.0001) compared with central IV and IC administration. (There was no difference between central IV and IC routes; p = 0.9343.) The odds of stent thrombosis were significantly higher with the IC route (IC vs. peripheral IV OR = 4.6, 95% CI = 1.5–14.3, p = 0.0094; IC vs. central IV OR = 6.0, 95% CI = 1.9–19.2, p = 0.0025). Post-ROSC neurologic outcomes were better for central IV and IC routes when compared with peripheral IV.

Conclusion

Epinephrine administration via central IV and IC routes was associated with a higher rate of ROSC and better neurologic outcomes compared with peripheral IV administration. IC administration was associated with a higher risk of stent thrombosis.

Trial registration This trial is registered at NCT05253937.

Graphical Abstract
Development and validation of an AI-enabled digital breast cancer assay to predict early-stage breast cancer recurrence within 6 years
Authors: Fernandez Gerardo , Prastawa Marcel , Madduri Abishek Sainath , Scott Richard , Marami Bahram , Shpalensky Nina , Cascetta Krystal , Sawyer Mary , Chan Monica , Koll Giovanni , Shtabsky Alexander , Feliz Aaron , Hansen Thomas , Veremis Brandon , Cordon-Cardo Carlos , Zeineh Jack , Donovan Michael J.
Published: December 2022

Background

Breast cancer (BC) grading plays a critical role in patient management despite the considerable inter- and intra-observer variability, highlighting the need for decision support tools to improve reproducibility and prognostic accuracy for use in clinical practice. The objective was to evaluate the ability of a digital artificial intelligence (AI) assay (PDxBr) to enrich BC grading and improve risk categorization for predicting recurrence.

Methods

In our population-based longitudinal clinical development and validation study, we enrolled 2075 patients from Mount Sinai Hospital with infiltrating ductal carcinoma of the breast. With 3:1 balanced training and validation cohorts, patients were retrospectively followed for a median of 6 years. The main outcome was to validate an automated BC phenotyping system combined with clinical features to produce a binomial risk score predicting BC recurrence at diagnosis.

Results

The PDxBr training model (n = 1559 patients) had a C-index of 0.78 (95% CI, 0.76–0.81) versus clinical 0.71 (95% CI, 0.67–0.74) and image feature models 0.72 (95% CI, 0.70–0.74). A risk score of 58 (scale 0–100) stratified patients as low or high risk, hazard ratio (HR) 5.5 (95% CI 4.19–7.2, p < 0.001), with a sensitivity 0.71, specificity 0.77, NPV 0.95, and PPV 0.32 for predicting BC recurrence within 6 years. In the validation cohort (n = 516), the C-index was 0.75 (95% CI, 0.72–0.79) versus clinical 0.71 (95% CI 0.66–0.75) versus image feature models 0.67 (95% CI, 0.63–071). The validation cohort had an HR of 4.4 (95% CI 2.7–7.1, p < 0.001), sensitivity of 0.60, specificity 0.77, NPV 0.94, and PPV 0.24 for predicting BC recurrence within 6 years. PDxBr also improved Oncotype Recurrence Score (RS) performance: RS 31 cutoff, C-index of 0.36 (95% CI 0.26–0.45), sensitivity 37%, specificity 48%, HR 0.48, p = 0.04 versus Oncotype RS plus AI-grade C-index 0.72 (95% CI 0.67–0.79), sensitivity 78%, specificity 49%, HR 4.6, p < 0.001 versus Oncotype RS plus PDxBr, C-index 0.76 (95% CI 0.70–0.82), sensitivity 67%, specificity 80%, HR 6.1, p < 0.001.

Conclusions

PDxBr is a digital BC test combining automated AI-BC prognostic grade with clinical–pathologic features to predict the risk of early-stage BC recurrence. With future validation studies, we anticipate the PDxBr model will enrich current gene expression assays and enhance treatment decision-making.
Canalization of genome-wide transcriptional activity in Arabidopsis thaliana accessions by MET1-dependent CG methylation
Authors: Srikant Thanvi , Yuan Wei , Berendzen Kenneth Wayne , Contreras-Garrido Adrián , Drost Hajk-Georg , Schwab Rebecca , Weigel Detlef
Published: December 2022

Background

Despite its conserved role on gene expression and transposable element (TE) silencing, genome-wide CG methylation differs substantially between wild Arabidopsis thaliana accessions.

Results

To test our hypothesis that global reduction of CG methylation would reduce epigenomic, transcriptomic, and phenotypic diversity in A. thaliana accessions, we knock out MET1, which is required for CG methylation, in 18 early-flowering accessions. Homozygous met1 mutants in all accessions suffer from common developmental defects such as dwarfism and delayed flowering, in addition to accession-specific abnormalities in rosette leaf architecture, silique morphology, and fertility. Integrated analysis of genome-wide methylation, chromatin accessibility, and transcriptomes confirms that MET1 inactivation greatly reduces CG methylation and alters chromatin accessibility at thousands of loci. While the effects on TE activation are similarly drastic in all accessions, the quantitative effects on non-TE genes vary greatly. The global expression profiles of accessions become considerably more divergent from each other after genome-wide removal of CG methylation, although a few genes with diverse expression profiles across wild-type accessions tend to become more similar in mutants. Most differentially expressed genes do not exhibit altered chromatin accessibility or CG methylation in cis, suggesting that absence of MET1 can have profound indirect effects on gene expression and that these effects vary substantially between accessions.

Conclusions

Systematic analysis of MET1 requirement in different A. thaliana accessions reveals a dual role for CG methylation: for many genes, CG methylation appears to canalize expression levels, with methylation masking regulatory divergence. However, for a smaller subset of genes, CG methylation increases expression diversity beyond genetically encoded differences.
Peritoneal antiseptic irrigation to prevent surgical site infection after laparotomy for hepatobiliary or gastrointestinal surgery (PAISI)—protocol for a randomized controlled study
Authors: Mueller Tara , Kehl Victoria , Egert-Schwender Silvia , Friess Helmut , Novotny Alexander , Reim Daniel
Published: December 2022

Background

Postoperative surgical site infections (SSIs) remain common after laparotomy for resections of the gastrointestinal or hepatobiliary tract. Especially organ/space infections (CDC class III SSI) can be life-threatening, require relaparotomy, intensive care or interventional drainage of intraabdominal abscesses. The PAISI study aims to investigate whether the use of prophylactic peritoneal irrigation with NaOCl/HOCl solution can reduce the SSI rates following laparotomy for resections of the gastrointestinal or hepatobiliary tract, compared to standard irrigation with physiological electrolyte solution (Ringer’s solution). Secondarily, to evaluate whether the use of prophylactic peritoneal irrigation with NaOCl/HOCl solution can reduce postoperative morbidity and mortality as well as the rate of re-operations and length of hospital stay.

Methods

PAISI is a prospective, randomized, observer- and patient-blinded, monocentric, two-arm surgical study in an adaptive parallel groups design, comparing peritoneal and wound irrigation with NaOCl/HOCl (50/50ppm) solution to irrigation with Ringer’s solution. The primary endpoint of the study is the SSI rate within 30 days postoperatively. Since there is no data on incidence rates from randomized clinical trials, the rates for sample size calculation were estimated according to the clinical experience at our institution. Therefore, the study design includes one unblinded look at the data by a second statistician, which will be performed after half of the patients reached the primary endpoint. This interim information will be used to check the assumptions and if needed, the sample size will be adjusted. The O’Brien-Fleming spending function is used to determine the efficacy test boundary and the non-binding futility boundary. The one-sided z-test (Group sequential test of two proportions) at the 2.5% significance level with a total of two looks at the data will have overall 80% power.

Discussion

The results of this study will provide high-level evidence for future research and clinical recommendations regarding the use of NaOCl/HOCl solution in abdominal surgery and provide the participating patients the opportunity of a potentially improved treatment.

Trial registration

German Clinical Trials Register (DRKS) DRKS00028037. Registered on 27 May 2022.
Sanfu herbal patch applied at acupoints in patients with bronchial asthma: statistical analysis plan for a randomised controlled trial
Authors: Xu Danghan , Li Jialing , Di Anqi , Yang Peidan , Xie Xiaoyan , Xu Yiming , He Jun
Published: December 2022

Background

Sanfu herbal patch (SHP) is widely used in the prevention and treatment of bronchial asthma in China, but its efficacy and mechanism of action are not completely clear. This trial aims to determine the efficacy of SHP and the underlying mechanism.

Methods/design

We will conduct a multi-centre parallel randomised controlled trial consisting of 72 participants with bronchial asthma recruited and randomly allocated at a ratio of 1:1 into two groups. The patients in one group will receive three courses of SHP treatment, and the patients in the other group will receive placebo treatment, with 24 weeks of follow-up evaluation for both groups. The primary outcome, i.e. forced expiratory volume in the first second (FEV1), which refers to the change in FEV1 from the beginning of the baseline to the end of 3 treatment sessions (TSs), will be assessed and compared via Student’s t test or the Mann–Whitney U test. Other outcomes will include questionnaire surveys and laboratory indicators. Detailed and complete statistical analyses in a double-blinded fashion will be provided for evaluating this trial.

Discussion

The data we obtain will be examined based on the above statistical analysis, which will help to reduce the risk of external reporting bias and data-driven results.

Trial registration

Chinese Clinical Trial Registry (http://www.chictr.org.cn), ChiCTR1900024616. Registered on 19 July 2019.
Evaluating the impact of Community-Based Sociotherapy on social dignity in post-genocide Rwanda: study protocol for a cluster randomized controlled trial
Authors: Jansen Stefan , Niyonsenga Japhet , Ingabire Chantal Marie , Jansen Angela , Nzabonimpa Emmanuel , Ingabire Noella , Kangabe Jeannette , Sarabwe Emmanuel , Richters Annemiek , Rutayisire Theoneste , Nsabimana Epaphrodite
Published: December 2022

Background

Community-Based Sociotherapy (CBS) is an approach that was introduced in Rwanda in 2005, with the aim of improving psychosocial well-being among its participants and facilitating reconciliation processes. Over the years, CBS has been adapted contextually and the effectiveness of the approach has been measured in different ways, using qualitative and quantitative study designs. This study specifically assesses the effectiveness of CBS in terms of fostering the social dignity of participants as the primary outcome.

Methods/design

A cluster randomized controlled trial design with person-level outcomes whereas the CBS treatment is delivered at the cluster level. A total of 1200 eligible participants will be randomly assigned to two groups in a 1:1 ratio. Participants in the intervention group will receive the CBS intervention, while the control group will be waitlisted. The primary outcome measure is a self-designed and psychometrically validated Social Dignity Scale. The secondary outcome measures will be the WHO (Five) Well-Being Index (WHO-5), the Multidimensional Scale of Perceived Social Support (MSPSS), the Posttraumatic Stress Disorder Checklist for DSM-5 (PCL-5), the Self-reporting Questionnaire (SRQ-20), and the perceived parental self-efficacy scale. The primary analysis will be performed following an intention to treat analysis, using generalized estimating equation modeling.

Discussion

We expect this cluster randomized controlled trial to provide insight into the effectiveness of CBS on social dignity and secondary psychosocial outcomes among its group participants, who have different socio-historical backgrounds including genocide survivors, perpetrators, bystanders and their descendants, people in conflicts (family/community), and local leaders. This study will inform CBS implementers, policymakers, practitioners, and other stakeholders on the role of social dignity in interventions that focus on psychosocial healing.

Trial registration

ISRCTN ISRCTN11199072. It was registered on 2 April 2022.
A comprehensive transfer program from pediatrics to adult care for parents of adolescents with chronic illness (ParTNerSTEPs): study protocol for a randomized controlled trial
Authors: Thomsen Ena Lindhart , Boisen Kirsten Arntz , Hanghøj Signe , Hansson Helena , Grabow Scheelhardt Heidi-Christina V. , Christensen Susanne Thing , Esbensen Bente Appel
Published: December 2022

Background

Previous research shows that adolescents with a chronic illness have more successful transfers to adult care if their parents are involved during the transition. However, there is a lack of structured and evaluated transfer programs for parents. Our aim will be to test a comprehensive transfer program for parents of adolescents with chronic illness during the transfer from pediatric to adult care and to evaluate the program’s effectiveness, acceptability, and costs.

Methods

The overall design for this protocol will be a randomized controlled trial. A total of 62 dyads consisting of an adolescent (age 16.5–17.5) and at least one parent will be recruited from one of four pediatric outpatient clinics (nephrology, hepatology, neurology, or rheumatology) at Copenhagen University Hospital - Rigshospitalet, Denmark. The dyads will be randomized to receive the transfer program in addition to usual care or to receive usual care only. The program includes an informative website, bi-annual online educational events, and transfer consultations across pediatric and adult care. Outcome measures will include transition readiness, allocation of responsibility, parental uncertainty level, and transfer satisfaction. Data will be collected from participants at baseline, every 6 months until transfer, at transfer, and 3 months after transfer. The parents’ acceptance of and satisfaction with the program will be explored through semi-structured interviews. Cost, barriers, and facilitators affecting future implementation will be identified in interviews with health care professionals, using the Normalization Process Theory as a framework for the process analysis.

Discussion

To our knowledge, this transfer program is one of the first interventions for parents of adolescents with a chronic illness during their child’s transfer to adult care. Our trial will include parental and adolescent measures allowing us to examine whether a transfer program for parents will improve transfer to adult care for both parents and adolescents. We believe that results from our trial will be helpful in forming recommendations to ensure better involvement of parents in transitional care.

Trial registration

ClinicalTrials.gov NCT04969328. Retrospectively registered on 20 July 2021.
Interpolated daily temperature and precipitation data for Level II ICP Forests plots in Germany
Authors: Rukh Shah , Schad Tobias , Strer Maximilian , Natkhin Marco , Krüger Inken , Raspe Stephan , Eickenscheidt Nadine , Hentschel Rainer , Hölscher Andrea , Reiter Philipp , Sanders Tanja G. M.
Published: December 2022

Key message: A harmonized, comprehensive meteorological time series for 78 German intensive forest monitoring plots (Level II) has been made available from 1961 to 2019. The used hybrid spatial interpolation routine using simple linear regression and inverse distance weighting allows for gap filling of missing data and also for extrapolation outside measurement period to analyze long-term effects of climate on forest ecosystems. The dataset is available at https://www.openagrar.de/receive/openagrar_mods_00079174. The associated metadata are available at: https://metadata-afs.nancy.inra.fr/geonetwork/srv/fre/catalog.search#/metadata/433a028f-dfc8-4a7c-82af-b8d7efafd724.
COVID-19 mortality in Brazil, 2020-21: consequences of the pandemic inadequate management
Authors: Szwarcwald Célia Landmann , Boccolini Cristiano Siqueira , da Silva de Almeida Wanessa , Soares Filho Adauto Martins , Malta Deborah Carvalho
Published: December 2022

Background

The COVID-19 pandemic brought countless challenges to public health and highlighted the Brazilian health system vulnerabilities in facing the emergency. In this article, we analyze data on COVID-19-related deaths in 2020-21 to show the epidemic consequences in Brazil.

Methods

The Mortality Information System and the Live Birth Information System were the primary information sources. We used population estimates in 2020-21 to calculate COVID-19 specific mortality rates by age, sex, and educational level. Considering the total number of COVID-19 deaths in 2020-21, the COVID-19 proportional mortality (%) was estimated for each age group and sex. A graph of the daily number of deaths from January 2020 to December 2021 by sex was elaborated to show the temporal evolution of COVID-19 deaths in Brazil. In addition, four indicators related to COVID-19 mortality were estimated: infant mortality rate (IMR); maternal mortality ratio (MMR); number and rate of orphans due to mother’s COVID-19 death; the average number of years lost.

Results

The overall COVID-19 mortality rate was 14.8 (/10,000). The mortality rates increase with age and show a decreasing gradient with higher schooling. The rate among illiterate people was 38.8/10,000, three times higher than a college education. Male mortality was 31% higher than female mortality. COVID-19 deaths represented 19.1% of all deaths, with the highest proportions in the age group of 40-59 years. The average number of years lost due to COVID-19 was 19 years. The MMR due to COVID-19 was 35.7 per 100,000 live births (LB), representing 37.4% of the overall MMR. Regarding the number of orphans due to COVID-19, we estimated that 40,830 children under 18 lost their mothers during the epidemic, with an orphans’ rate of 7.5/10,000 children aged 0-17 years. The IMR was 11.7 per 1000 LB, with 0.2 caused by COVID-19. The peak of COVID-19 deaths occurred in March 2021, reaching almost 4000 COVID-19 deaths per day, higher than the average number of deaths per day from all causes in 2019.

Conclusions

The delay in adopting public health measures necessary to control the epidemic has exacerbated the spread of the disease, resulting in several avoidable deaths.
Decreasing Burnout and Improving Work Environment: The Impact of Firgun on a Pediatric Hematopoietic Cell Transplant Team
Authors: Stein Jerry , Madni Arshia , Moody Karen , Kramer Deborah , Vaughn Dagny , Bhatia Shalini , Sellers Janet , Snyder Angela , Lu Zhaohua , Baker Justin N. , Levine Deena R.
Published: December 2022

PURPOSE:

Oncology teams are challenged by BO, which may be alleviated by meaningful recognition. In this study, firgun—altruistic acknowledgment—was implemented on a pediatric hematopoietic cell transplant unit to evaluate its impact on staff and work environment.

METHODS:

In this longitudinal, mixed-methods pilot study, interdisciplinary inpatient hematopoietic cell transplant providers received web-based firgun education. Electronic administration of validated surveys occurred at baseline and 8 weeks, including Perceived Stress Scale, Professional Quality of Life Scale, Maslach Burnout Inventory, Workplace Civility Index, Areas of Work Life Survey, and WHO-5. Weekly e-mails reminded participants to practice and log firgun. Wilcoxon signed test for paired data compared pre/post results. Interviews conducted at project completion were coded using MaxQDA software.

RESULTS:

Forty-two participants enrolled; 25 completed pre/post surveys; eight were interviewed. At study end, participants reported feeling less nervous and stressed ( P = .008), and less difficulty coping ( P = .01; Perceived Stress Scale), while noting increased acknowledgment of others' work ( P = .04) and seeking constructive feedback ( P = .04; Workplace Civility Index). Marked BO was not evident overall on the Maslach Burnout Inventory; however, emotional exhaustion subscale mean (SD) scores improved from pre (19.4 [8.6]) to post (16 [6.3; P = .02]) and individual items illustrated decreased fatigue ( P = .008), frustration ( P = .04), and feeling “at the end of my rope” ( P = .001). Postintervention participants noted increased receipt of recognition ( P = .02; Areas of Work Life Survey), decreased feeling “bogged down” ( P = .02), decreased affective stress ( P = .04), and negative pre-occupations ( P = .04; Professional Quality of Life Scale). Qualitative analysis revealed themes of improved confidence at work and enhanced feelings of trust and teamwork.

CONCLUSION:

Firgun is a tool that can potentially reduce BO and stress in interdisciplinary providers, facilitate teamwork, and promote positive work environments in clinical oncology and beyond.
Inflammatory Myopathies
Authors: Manousakis Georgios
Published: December 2022

PURPOSE OF REVIEW

This article outlines the salient clinical, serologic, electrophysiologic, imaging, and histopathologic findings and treatment options for the idiopathic inflammatory myopathies, including those related to immune checkpoint inhibitors and SARS-CoV-2.

RECENT FINDINGS

The classification of idiopathic inflammatory myopathies has improved with the integration of myositis-specific antibodies and histopathologic findings. Characteristic features of immune checkpoint inhibitor–related myositis have been identified, allowing early recognition and treatment of the syndrome. The COVID-19 pandemic has had a profound impact on the care of patients with idiopathic inflammatory myopathies, and several mechanisms of virus-related muscle injury have been proposed.

A comprehensive evaluation including clinical examination, EMG, imaging, antibody testing, muscle biopsy, and cancer screening, when appropriate, can lead to an earlier accurate diagnosis and an individualized treatment approach for patients with idiopathic inflammatory myopathies.
Inclusion Body Myositis
Authors: Goyal Namita A.
Published: December 2022

PURPOSE OF REVIEW

This article highlights the clinical and diagnostic features of inclusion body myositis (IBM) and provides recent insights into the pathomechanisms and therapeutic strategies of the disease.

RECENT FINDINGS

IBM is an often-misdiagnosed myopathy subtype. Due to the insidious onset and slow progression of muscle weakness, it can often be dismissed as a sign of aging as it commonly presents in older adults. While challenging to recognize upon initial clinical evaluation, the recent recognition of specialized stains highlighting features seen on muscle pathology, the use of diagnostic tools such as the anti-cytosolic 5’-nucleotidase 1A antibody biomarker, and the ability of muscle imaging to detect patterns of preferential muscle involvement seen in IBM has allowed for earlier diagnosis of the disease than was previously possible. While the pathogenesis of IBM has historically been poorly understood, several ongoing studies point toward mechanisms of autophagy and highly differentiated cytotoxic T cells that are postulated to be pathogenic in IBM.

Overall advancements in our understanding of IBM have resulted in improvements in the management of the disease and are the foundation of several strategies for current and upcoming novel therapeutic drug trials in IBM.
The Practice of Experimental Neurotherapeutics in Neuromuscular Disease
Authors: Reoma Lauren B. , Nath Avindra , Griggs Robert C.
Published: December 2022

PURPOSE OF REVIEW

The discipline of experimental neurotherapeutics targets the process and operation of translating scientific discoveries into new treatments for neurologic diseases and has been instrumental in the progression of many areas of neurology.

RECENT FINDINGS

From the US Food and Drug Administration (FDA) market approval of the first systemic in vivo gene therapy in neurology to multiple current gene-targeting therapeutics, monoclonal antibodies, and new drugs under development or approved in the last several years, the field of experimental neurotherapeutics has a presence in every neuromuscular clinic in the United States.

This article provides an overview of experimental neurotherapeutics with guidance on the clinical trials landscape, using examples in the field of neuromuscular disease. It covers the regulatory framework, clinical trial methodology, and offers advice on common pitfalls encountered when embarking on a clinical trials program in the clinic.
The Location of Anticolonialism; or, Al-Afghānī, Qāsim Amīn, and Sayyid Quṭb at the Peripheries
Authors: Idris Murad
Published: December 2022

Recent decades have seen a turn toward colonialism and anticolonial thought in the discipline of political theory. This turn has done the crucial work of bringing questions of dispossession, racialization, and the critical imaginaries of marginalized bodies of thought into the mainstream of the discipline. The expansion, however, has been marked by a tendency to typecast the archive of anticolonial thought with a handful of figures. This article examines the edge of the archive, or three thinkers who are only at its margins. They are Jamāl al-Dīn al-Afghānī, Qāsim Amīn, and Sayyid Quṭb, each of whom occupies a central place in the archive of modern Islamic thought. The article reads the peripheries of their works, tracing the arcs formed by their incidental references to places around the world, and, ultimately, probing their location in anticolonialism and contemporary critical thought. The article calls this double method of selection and interpretation periphereia.
The Flickering Torch
Authors: Degani Michael
Published: December 2022

This essay offers an ethnographic analysis of Tanzania's electrical power crisis in 2011 and the national disposition to endure suffering that it seemed to make evident. It shows that in asking citizens to suffer the near-total breakdown of the power supply in good faith, the ruling party, Chama Cha Mapinduzi (CCM, or Party of the Revolution), drew on a cultural-political orientation developed during the socialist era and sustained through a long period of partial neoliberal reform. While some Tanzanians saw this suffering in good faith as an expression of docility and credulity, the essay suggests that it also speaks to the moral power of socialism's underlying vision of collective interdependence, and might be read as a utopian insistence on that vision in an era of growing oligarchy and inequality.