bluuebunny/crossref_metadata_2025 huggingface dataset:
Higher polygenic risk for melanoma is associated with improved survival in a high ultraviolet radiation setting
Authors: Seviiri Mathias , Scolyer Richard A. , Bishop D. Timothy , Newton-Bishop Julia A. , Iles Mark M. , Lo Serigne N. , Stretch Johnathan R. , Saw Robyn P. M. , Nieweg Omgo E. , Shannon Kerwin F. , Spillane Andrew J. , Gordon Scott D. , Olsen Catherine M. , Whiteman David C. , Landi Maria Teresa , Thompson John F. , Long Georgina V. , MacGregor Stuart , Law Matthew H.
Published: September 2022

Background

The role of germline genetic factors in determining survival from cutaneous melanoma (CM) is not well understood.

Objective

To perform a genome-wide association study (GWAS) meta-analysis of melanoma-specific survival (MSS), and test whether a CM-susceptibility polygenic risk score (PRS) is associated with MSS.

Methods

We conducted two Cox proportional-hazard GWAS of MSS using data from the Melanoma Institute Australia, a high ultraviolet (UV) radiation setting (MIA; 5,762 patients with melanoma; 800 melanoma deaths) and UK Biobank (UKB: 5,220 patients with melanoma; 241 melanoma deaths), and combined them in a fixed-effects meta-analysis. Significant (P < 5 × 10–8) results were investigated in the Leeds Melanoma Cohort (LMC; 1,947 patients with melanoma; 370 melanoma deaths). We also developed a CM-susceptibility PRS using a large independent GWAS meta-analysis (23,913 cases, 342,870 controls). The PRS was tested for an association with MSS in the MIA and UKB cohorts.

Results

Two loci were significantly associated with MSS in the meta-analysis of MIA and UKB with lead SNPs rs41309643 (G allele frequency 1.6%, HR = 2.09, 95%CI = 1.61–2.71, P = 2.08 × 10–8) on chromosome 1, and rs75682113 (C allele frequency 1.8%, HR = 2.38, 95%CI = 1.77–3.21, P = 1.07 × 10–8) on chromosome 7. While neither SNP replicated in the LMC, rs75682113 was significantly associated in the combined discovery and replication sets. After adjusting for age at diagnosis, sex and the first ten principal components, a one standard deviation increase in the CM-susceptibility PRS was associated with improved MSS in the discovery meta-analysis (HR = 0.88, 95% CI = 0.83–0.94, P = 6.93 × 10–5; I2 = 88%). However, this was only driven by the high UV setting cohort (MIA HR = 0.84, 95% CI = 0.78–0.90).

Conclusion

We found two loci potentially associated with MSS. Increased genetic susceptibility to develop CM is associated with improved MSS in a high UV setting.
Atrial myocyte-derived exosomal microRNA contributes to atrial fibrosis in atrial fibrillation
Authors: Hao Hongting , Yan Sen , Zhao Xinbo , Han Xuejie , Fang Ning , Zhang Yun , Dai Chenguang , Li Wenpeng , Yu Hui , Gao Yunlong , Wang Dingyu , Gao Qiang , Duan Yu , Yuan Yue , Li Yue
Published: September 2022

Background

Atrial fibrosis plays a critical role in the development of atrial fibrillation (AF). Exosomes are a promising cell-free therapeutic approach for the treatment of AF. The purposes of this study were to explore the mechanisms by which exosomes derived from atrial myocytes regulate atrial remodeling and to determine whether their manipulation facilitates the therapeutic modulation of potential fibrotic abnormalities during AF.

Methods

We isolated exosomes from atrial myocytes and patient serum, and microRNA (miRNA) sequencing was used to analyze exosomal miRNAs in exosomes derived from atrial myocytes and patient serum. mRNA sequencing and bioinformatics analyses corroborated the key genes that were direct targets of miR-210-3p.

Results

The miRNA sequencing analysis identified that miR-210-3p expression was significantly increased in exosomes from tachypacing atrial myocytes and serum from patients with AF. In vitro, the miR-210-3p inhibitor reversed tachypacing-induced proliferation and collagen synthesis in atrial fibroblasts. Accordingly, miR-210-3p knock out (KO) reduced the incidence of AF and ameliorated atrial fibrosis induced by Ang II. The mRNA sequencing analysis and dual-luciferase reporter assay showed that glycerol-3-phosphate dehydrogenase 1-like (GPD1L) is a potential target gene of miR-210-3p. The functional analysis suggested that GPD1L regulated atrial fibrosis via the PI3K/AKT signaling pathway. In addition, silencing GPD1L in atrial fibroblasts induced cell proliferation, and these effects were reversed by a PI3K inhibitor (LY294002).

Conclusions

Atrial myocyte-derived exosomal miR-210-3p promoted cell proliferation and collagen synthesis by inhibiting GPD1L in atrial fibroblasts. Preventing pathological crosstalk between atrial myocytes and fibroblasts may be a novel target to ameliorate atrial fibrosis in patients with AF.

Graphical Abstract
11β-HSD1 participates in epileptogenesis and the associated cognitive impairment by inhibiting apoptosis in mice
Authors: Li Xueying , Qiu Wanhua , Deng Lu , Lin Jingjing , Huang Wenting , Xu Yuchen , Zhang Mulan , Jones Nigel C. , Lin Runxuan , Xu Huiqin , Lin Li , Li Peijun , Wang Xinshi
Published: September 2022

Background

Glucocorticoid signalling is closely related to both epilepsy and associated cognitive impairment, possibly through mechanisms involving neuronal apoptosis. As a critical enzyme for glucocorticoid action, the role of 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) in epileptogenesis and associated cognitive impairment has not previously been studied.

Methods

We first investigated the expression of 11β-HSD1 in the pentylenetetrazole (PTZ) kindling mouse model of epilepsy. We then observed the effect of overexpressing 11β-HSD1 on the excitability of primary cultured neurons in vitro using whole-cell patch clamp recordings. Further, we assessed the effects of adeno-associated virus (AAV)-induced hippocampal 11β-HSD1 knockdown in the PTZ model, conducting behavioural observations of seizures, assessment of spatial learning and memory using the Morris water maze, and biochemical and histopathological analyses.

Results

We found that 11β-HSD1 was primarily expressed in neurons but not astrocytes, and its expression was significantly (p < 0.05) increased in the hippocampus of PTZ epilepsy mice compared to sham controls. Whole-cell patch clamp recordings showed that overexpression of 11β-HSD1 significantly decreased the threshold voltage while increasing the frequency of action potential firing in cultured hippocampal neurons. Hippocampal knockdown of 11β-HSD1 significantly reduced the severity score of PTZ seizures and increased the latent period required to reach the fully kindled state compared to control knockdown. Knockdown of 11β-HSD1 also significantly mitigated the impairment of spatial learning and memory, attenuated hippocampal neuronal damage and increased the ratio of Bcl-2/Bax, while decreasing the expression of cleaved caspase-3.

Conclusions

11β-HSD1 participates in the pathogenesis of both epilepsy and the associated cognitive impairment by elevating neuronal excitability and contributing to apoptosis and subsequent hippocampal neuronal damage. Inhibition of 11β-HSD1, therefore, represents a promising strategy to treat epilepsy and cognitive comorbidity.
Interest of phenomic prediction as an alternative to genomic prediction in grapevine
Authors: Brault Charlotte , Lazerges Juliette , Doligez Agnès , Thomas Miguel , Ecarnot Martin , Roumet Pierre , Bertrand Yves , Berger Gilles , Pons Thierry , François Pierre , Le Cunff Loïc , This Patrice , Segura Vincent
Published: September 2022

Background

Phenomic prediction has been defined as an alternative to genomic prediction by using spectra instead of molecular markers. A reflectance spectrum provides information on the biochemical composition within a tissue, itself being under genetic determinism. Thus, a relationship matrix built from spectra could potentially capture genetic signal. This new methodology has been mainly applied in several annual crop species but little is known so far about its interest in perennial species. Besides, phenomic prediction has only been tested for a restricted set of traits, mainly related to yield or phenology. This study aims at applying phenomic prediction for the first time in grapevine, using spectra collected on two tissues and over two consecutive years, on two populations and for 15 traits, related to berry composition, phenology, morphological and vigour. A major novelty of this study was to collect spectra and phenotypes several years apart from each other. First, we characterized the genetic signal in spectra and under which condition it could be maximized, then phenomic predictive ability was compared to genomic predictive ability.

Results

For the first time, we showed that the similarity between spectra and genomic relationship matrices was stable across tissues or years, but variable across populations, with co-inertia around 0.3 and 0.6 for diversity panel and half-diallel populations, respectively. Applying a mixed model on spectra data increased phenomic predictive ability, while using spectra collected on wood or leaves from one year or another had less impact. Differences between populations were also observed for predictive ability of phenomic prediction, with an average of 0.27 for the diversity panel and 0.35 for the half-diallel. For both populations, a significant positive correlation was found across traits between predictive ability of genomic and phenomic predictions.

Conclusion

NIRS is a new low-cost alternative to genotyping for predicting complex traits in perennial species such as grapevine. Having spectra and phenotypes from different years allowed us to exclude genotype-by-environment interactions and confirms that phenomic prediction can rely only on genetics.
Sacral osteotomy combined with triangular osteosynthesis in the treatment of malunion and nonunion of vertically displaced pelvic fractures
Authors: Luo Yangxing , He Li , Li Yue , Xie Jie , Gong Song , Zhang Qian , Yin Enzhi , Gu Meiqi , Yi Chengla
Published: September 2022

Background

Malunion and nonunion of vertically displaced pelvic fractures result in lower limb length discrepancies, claudication, and pain. There have been few previous reports of this type of corrective surgery for these old pelvic fractures. We present a surgical technique of sacral osteotomy combined with triangular osteosynthesis in the treatment of malunion and nonunion of vertically displaced pelvic fractures and report on its short-term clinical results.

Methods

We retrospectively reviewed nine patients (five males and four females) with malunion or nonunion of vertically displaced pelvic fractures treated with sacral osteotomy and triangular osteosynthesis from April 2015 to January 2020. The age ranged from 14 to 45 years (average, 30.7 years). The time from injury to deformity correction surgery ranged from 3 months to 5 years (average, 12.8 months). The vertical displacement of a unilateral hemipelvis was 3.0–4.5 cm (average, 3.80 cm). According to AO/OTA classification at the initial fracture, there are eight cases in type C1.3 and one case in type C3.3. Sacral osteotomy and triangular osteosynthesis were used in all nine patients. The degree of unilateral hemipelvic reduction was assessed postoperatively based on measurements from the anteroposterior (AP) X-ray. Majeed score and pain visual analog scale (VAS) were used to assess the therapeutic effect of the patients during follow-up.

Results

In all nine patients, postoperative AP X-ray showed correction displacement of 1.7–3.9 cm (average, 3.20 cm). All the patients were followed up for 6–36 months (average, 12.7 months). At the last follow-up, the Majeed score of pelvic fracture increased from an average of 53.9 points (30–84 points) preoperatively to 87.0 points (72–94 points), and the VAS score for pain decreased from an average of 6.0 points (4–8 points) preoperatively to 1.2 points (0–3 points). None had complications like infection, implant broken, screw loosening, iatrogenic nerve, and blood vessel injury.

Conclusion

Sacral osteotomy combined with triangular osteosynthesis for the treatment of pelvic malunion and nonunion caused by sacral fractures can correct significantly vertical displacement of a unilateral pelvis, prolong limb length, and reconstruct the stability of a pelvic ring, achieving good clinical results.
Clinical improvements after treatment with a low-valine and low-fat diet in a pediatric patient with enoyl-CoA hydratase, short chain 1 (ECHS1) deficiency
Authors: Pata Silvia , Flores-Rojas Katherine , Gil Angel , López-Laso Eduardo , Marti-Sánchez Laura , Baide-Mairena Heydi , Pérez-Dueñas Belén , Gil-Campos Mercedes
Published: September 2022

Background

Enoyl-CoA hydratase short-chain 1 (ECHS1) is a key mitochondrial enzyme that is involved in valine catabolism and fatty acid beta-oxidation. Mutations in theECHS1gene lead to enzymatic deficiency, resulting in the accumulation of certain intermediates from the valine catabolism pathway. This disrupts the pyruvate dehydrogenase complex and the mitochondrial respiratory chain, with consequent cellular damage. Patients present with a variable age of onset and a wide spectrum of clinical features. The Leigh syndrome phenotype is the most frequently reported form of the disease. Herein, we report a case of a male with ECHS1 deficiency who was diagnosed at 8 years of age. He presented severe dystonia, hyperlordosis, moderate to severe kyphoscoliosis, great difficulty in walking, and severe dysarthria. A valine-restricted and total fat-restricted diet was considered as a therapeutic option after the genetic diagnosis. An available formula that restricted branched-chain amino acids and especially restricted valine was used. We also restricted animal protein intake and provided a low-fat diet that was particularly low in dairy fat.

Results

This protein- and fat-restricted diet was initiated with adequate tolerance and adherence. After three years, the patient noticed an improvement in dystonia, especially in walking. He currently requires minimal support to walk or stand. Therefore, he has enhanced his autonomy to go to school or establish a career for himself. His quality of life and motivation for treatment have greatly increased.

Conclusions

There is still a substantial lack of knowledge about this rare disorder, especially knowledge about future effective treatments. However, early diagnosis and treatment with a valine- and fat-restricted diet, particularly dairy fat-restricted diet, appeared to limit disease progression in this patient with ECHS1 deficiency.
Head circumference and anthropometric changes and their relation to plexiform and skin neurofibromas in sporadic and familial neurofibromatosis 1 Brazilian adults: a cross-sectional study
Authors: Basto Diogo Lisbôa , de Souza Vieira Gustavo , Andrade-Losso Raquel M. , Almeida Paula Nascimento , Riccardi Vincent M. , Rozza-de-Menezes Rafaela Elvira , Cunha Karin Soares
Published: September 2022

Background

Neurofibromatosis 1 (NF1) is a common autosomal dominant syndrome with complete penetrance and highly variable expressivity. The cutaneous neurofibroma (Cnf) and plexiform neurofibroma (Pnf), café-au-lait spots, and freckle-like lesions are common in NF1, but many other manifestations can occur. We aimed to evaluate head circumference, height, weight, body mass index (BMI), head circumference-to-height ratio (HCHR) and waist–hip ratio (WHR) in adult NF1 Brazilian individuals versus a paired control group and investigate their correlation with the presence of clinically visible Pnfs, and number of “skin neurofibromas” (Snf), which include both cutaneous and subcutaneous neurofibromas.

Methods

A case–control study was conducted with 168 individuals, 84 with NF1 and 84 without NF1, paired by sex and age. Head circumference and anthropometric measurements, Snf quantification, evaluation of clinically visible Pnf and familial inheritance were accessed.

Results

Prevalence of macrocephaly was significantly higher in NF1 women. Height and weight were significantly lower in both males and females with NF1. HCHR was higher in the NF1 group than in the control group for both sexes. BMI was significantly lower in men with NF1. Waist and hip circumferences were significantly reduced in NF compared with the controls, but the mean WHR was significantly lower only in NF1 women. No correlation was found between the Snf and head circumference and anthropometric measurements, sex or family history. The presence and larger size of clinically visible plexiform neurofibromas were associated with normal stature (p = 0.037 and p = 0.003, respectively).

Conclusions

NF1 individuals have increased prevalence of macrocephaly, short stature, low BMI, and reduced abdominal fat. There is no relation between head circumference and anthropometric data with family history, or neurofibromas.
Comparison of growth dynamics in different types of MPS: an attempt to explain the causes
Authors: Różdżyńska-Świątkowska Agnieszka , Zielińska Anna , Tylki-Szymańska Anna
Published: September 2022

Background

Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders caused by deficient activity of enzymes responsible for the catabolism of glycosaminoglycans (GAGs), resulting in progressive damage to various tissues and organs. Affected individuals present with skeletal deformities, bone growth impairment, joint stiffness and frequently mental retardation.

Results

The objective of the study was to summarise over 30 years of observations of the growth dynamics in patients with different types of MPS, performed at the Children’s Memorial Health Institute (CMHI, Warsaw, Poland). A retrospective analysis of anthropometric data collected from 1989 to 2020 was performed for 195 patients with MPS I, MPS II, MPS III, MPS IVA and MPS VI. Mean values for birth body length were statistically significantly greater than in the general population. The mean z-scores for other MPS groups showed that until the 24th month of life, the growth pattern for all patients was similar, and the average z-scores for body height were greater than in reference charts. Afterwards, growth patterns began to differentiate for MPS groups.

Conclusions

The long-term follow up showed that the growth pattern in patients with all types of mucopolysaccharidoses significantly deviates from the general population. Patients with MPS IVA had the most severe growth impairments compared to other patients in the study group. Neuropathic MPS I and II demonstrated severe growth impairments compared to other patients in this study. Patients with MPS III showed the mildest growth impairments compared to other MPS patients and reached the 3rd percentile last.
Rare diseases in Tanzania: a National Call for Action to address policy and urgent needs of individuals with rare diseases
Authors: Kaywanga Frida , Alimohamed Mohamed Zahir , David Aneth Bella , Maeda Daniel , Mbarak Sharifa , Mavura Togolani , Nkya Siana , Ishengoma Deus S.
Published: September 2022

A rare disease is generally defined as a condition which affects about 1 among 2000 people and currently, there are approximately 5000–8000 rare diseases (RDs) affecting over 400 million people world-wide. Although RDs may arise from different causes such as infections and environmental factors, about 80% are caused by genetic abnormalities. In Tanzania, there are no reports of the types of RDs, their incidence, distribution and numbers of individuals affected. In addition, there have been no strategies to map RDs in the country and develop a definition that fits the local context. Public awareness and understanding of RDs are very limited, and these lead to poor management and stigmatisation of patients. To address the ongoing problems, Tanzania joined other countries world-wide and global partners to commemorate the rare diseases day (RDD) for the first time in 2016 and subsequently every year. Unlike previous years where the RDD was organised by Ali Kimara Rare Diseases Foundation (AKRDF) with few partners, in 2020, a bigger event was co-hosted by Ali AKRDF and Tanzania Human Genetics Organization together with government representatives and other multiple partners. The organisers, government representatives and participants proposed a national “Call for Action” with the overall goal of improving the lives of patients/individuals with RDs. The call focuses and aims to address 17 strategic issues that are broadly categorised into four areas. These include generating demographic data of individuals with RDs; advocating for policies and guidelines for diagnosis, care, treatment and health financing; developing policies supporting public education, awareness and advocacy; and strengthening research, innovation and public–private partnerships. If adopted and implemented, the potential impacts of these recommendations will include improved access to adequate and high-quality health and education services, and policies and guidelines to address the current and future challenges facing individuals with RDs and their families.
Protein profiling of testicular tissue from boars with different levels of hyperactive sperm motility
Authors: van Son Maren , Våge Dag Inge , Skaugen Morten , Tremoen Nina Hårdnes , Gaustad Ann Helen , Zeremichael Teklu Tewoldebrhan , Myromslien Frøydis Deinboll , Grindflek Eli
Published: September 2022

Hyperactive sperm motility is important for successful fertilization. In the present study, a proteome profiling approach was performed to identify the differences between Landrace boars with different levels of hyperactive sperm motility in liquid extended semen. Two contrasts were studied: (i) high versus low levels of sperm hyperactivity at semen collection day and (ii) high versus low change in levels of sperm hyperactivity after 96 h semen storage. Testicular samples were analyzed on a Q Exactive mass spectrometer and more than 6000 proteins were identified in the 13 samples. The most significant differentially expressed proteins were mediator complex subunit 28 (MED28), cell division cycle 37 like 1 (CDC37L1), ubiquitin specific peptidase 10 (USP10), zinc finger FYVE-type containing 26 (ZFYVE26), protein kinase C delta (PRKCD), actinin alpha 4 (ACTN4), N(alpha)-acetyltransferase 30 (NAA30), C1q domain-containing (LOC110258309) and uncharacterized LOC100512926. Of the differentially expressed proteins, 11 have previously been identified as differentially expressed at the corresponding mRNA transcript level using the same samples and contrasts. These include sphingosine kinase 1 isoform 2 (SPHK1), serine and arginine rich splicing factor 1 (SRSF1), and tubulin gamma-1 (TUBG1) which are involved in the acrosome reaction and sperm motility. A mass spectrometry approach was applied to investigate the protein profiles of boars with different levels of hyperactive sperm motility. This study identified several proteins previously shown to be involved in sperm motility and quality, but also proteins with no known function for sperm motility. Candidates that are differentially expressed on both mRNA and protein levels are especially relevant as biological markers of semen quality.
Impact of IDH1 and IDH2 mutational subgroups in AML patients after allogeneic stem cell transplantation
Authors: Kunadt Desiree , Stasik Sebastian , Metzeler Klaus H. , Röllig Christoph , Schliemann Christoph , Greif Philipp A. , Spiekermann Karsten , Rothenberg-Thurley Maja , Krug Utz , Braess Jan , Krämer Alwin , Hochhaus Andreas , Scholl Sebastian , Hilgendorf Inken , Brümmendorf Tim H. , Jost Edgar , Steffen Björn , Bug Gesine , Einsele Hermann , Görlich Dennis , Sauerland Cristina , Schäfer-Eckart Kerstin , Krause Stefan W. , Hänel Mathias , Hanoun Maher , Kaufmann Martin , Wörmann Bernhard , Kramer Michael , Sockel Katja , Egger-Heidrich Katharina , Herold Tobias , Ehninger Gerhard , Burchert Andreas , Platzbecker Uwe , Berdel Wolfgang E. , Müller-Tidow Carsten , Hiddemann Wolfgang , Serve Hubert , Stelljes Matthias , Baldus Claudia D. , Neubauer Andreas , Schetelig Johannes , Thiede Christian , Bornhäuser Martin , Middeke Jan M. , Stölzel Friedrich ,   the A. M. L. Cooperative Group (AMLCG), Study Alliance Leukemia (SAL)
Published: September 2022

Background

The role of allogeneic hematopoietic cell transplantation (alloHCT) in acute myeloid leukemia (AML) with mutatedIDH1/2has not been defined. Therefore, we analyzed a large cohort of 3234 AML patients in first complete remission (CR1) undergoing alloHCT or conventional chemo-consolidation and investigated outcome in respect toIDH1/2mutational subgroups (IDH1R132C, R132H and IDH2 R140Q, R172K).

Methods

Genomic DNA was extracted from bone marrow or peripheral blood samples at diagnosis and analyzed forIDHmutations with denaturing high-performance liquid chromatography, Sanger sequencing and targeted myeloid panel next-generation sequencing, respectively. Statistical as-treated analyses were performed using R and standard statistical methods (Kruskal–Wallis test for continuous variables, Chi-square test for categorical variables, Cox regression for univariate and multivariable models), incorporating alloHCT as a time-dependent covariate.

Results

Among 3234 patients achieving CR1, 7.8% harboredIDH1mutations (36% R132C and 47% R132H) and 10.9% carriedIDH2mutations (77% R140Q and 19% R172K). 852 patients underwent alloHCT in CR1. Within the alloHCT group, 6.2% had anIDH1mutation (43.4% R132C and 41.4% R132H) and 10% were characterized by anIDH2mutation (71.8% R140Q and 24.7% R172K). Variants IDH1 R132C and IDH2 R172K showed a significant benefit from alloHCT for OS (p = .017 andp = .049) and RFS (HR = 0.42,p = .048 andp = .009) compared with chemotherapy only. AlloHCT in IDH2 R140Q mutated AML resulted in longer RFS (HR = 0.4,p = .002).

Conclusion

In this large as-treated analysis, we showed that alloHCT is able to overcome the negative prognostic impact of certainIDHmutational subclasses in first-line consolidation treatment and could pending prognostic validation, provide prognostic value for AML risk stratification and therapeutic decision making.
Epstein-Barr virus-associated acute pancreatitis: a clinical report and review of literature
Authors: Accomando Salvatore , Restivo Giulia Angela , Scalzo Simona , Guardino Melania , Corsello Giovanni , Giuffrè Mario
Published: September 2022

Background

Acute pancreatitis is a disorder of reversible inflammation of the pancreas. Only a few cases are related to infections and the most common pathogens are the viruses responsible for mumps, parotitis, and influenza. Epstein-Barr virus (EBV)-associated acute pancreatitis is a rare condition and it may occur in children and adults.

Case presentation

A 3-year-old female was admitted to the “G. Di Cristina” Children's Hospital in Palermo for vomiting and abdominal pain. Laboratory investigations revealed elevated amylase and lipase, with normal liver function tests. Abdominal ultrasound demonstrated an enlarged pancreas, with hypoechogenic areas; no biliary lithiasis was observed. Infectious disease serology was positive for the presence of EBV VCA IgM and IgG. A diagnosis of EBV-associated acute pancreatitis was made. The patient was treated conservatively and recovered.

Conclusions

Acute pancreatitis is rarely associated with EBV infection; a review of the English literature revealed only 10 pediatric and 6 adult cases. Patients with pancreatitis should always be evaluated for EBV serology, even in the absence of the typical clinical and hematological features of infectious mononucleosis. For these patients, good prognosis is generally expected.
The year 2021 in COVID-19 pandemic in children
Authors: Bozzola Elena , Caffarelli Carlo , Santamaria Francesca , Corsello Giovanni
Published: September 2022

In this article, the developments in the field of COVID-19 pandemic published in the Italian Journal of Pediatrics in 2021 are reflected. We describe progresses in SARS-CoV-2 transmission route, clinical presentation, diagnosis, treatment, and access to health care facilities in children. They led to substantial changes in the clinical approach.
Building Emotional Awareness and Mental Health (BEAM): study protocol for a phase III randomized controlled trial of the BEAM app-based program for mothers of children 18–36 months
Authors: Xie E. Bailin , Simpson Kaeley M. , Reynolds Kristin A. , Giuliano Ryan J. , Protudjer Jennifer L. P. , Soderstrom Melanie , Sauer-Zavala Shannon , Giesbrecht Gerald F. , Lebel Catherine , Mackinnon Anna L. , Rioux Charlie , Penner-Goeke Lara , Freeman Makayla , Salisbury Marlee R. , Tomfohr-Madsen Lianne , Roos Leslie E.
Published: September 2022

Background

The prevalence of maternal depression and anxiety has increased during the COVID-19 pandemic, and pregnant individuals are experiencing concerningly elevated levels of mental health symptoms worldwide. Many individuals may now be at heightened risk of postpartum mental health disorders. There are significant concerns that a cohort of children may be at-risk for impaired self-regulation and mental illness due to elevated exposure to perinatal mental illness. With both an increased prevalence of depression and limited availability of services due to the pandemic, there is an urgent need for accessible eHealth interventions for mothers of young children. The aims of this trial are to evaluate the efficacy of the Building Emotion Awareness and Mental Health (BEAM) app-based program for reducing maternal depression symptoms (primary outcome) and improve anxiety symptoms, parenting stress, family relationships, and mother and child functioning (secondary outcomes) compared to treatment as usual (TAU).

Methods

A two-arm randomized controlled trial (RCT) with repeated measures will be used to evaluate the efficacy of the BEAM intervention compared to TAU among a sample of 140 mothers with children aged 18 to 36 months, who self-report moderate-to-severe symptoms of depression and/or anxiety. Individuals will be recruited online, and those randomized to the treatment group will participate in 10 weeks of psychoeducation modules, an online social support forum, and weekly group teletherapy sessions. Assessments will occur at 18–36 months postpartum (pre-test, T1), immediately after the last week of the BEAM intervention (post-test, T2), and at 3 months after the intervention (follow-up, T3).

Discussion

eHealth interventions have the potential to address elevated maternal mental health symptoms, parenting stress, and child functioning concerns during and after the COVID-19 pandemic and to provide accessible programming to mothers who are in need of support. This RCT will build on an open pilot trial of the BEAM program and provide further evaluation of this evidence-based intervention. Findings will increase our understanding of depression in mothers with young children and reveal the potential for long-term improvements in maternal and child health and family well-being.

Trial registration

ClinicalTrials.govNCT05306626. Registered on April 1, 2022
Protocol for the development of a core domain set for individuals with ankle osteoarthritis
Authors: Alanazi Sultan Ayyadah , Vicenzino Bill , van Bergen Christiaan J. A. , Hunter David J. , Wikstrom Erik A. , Menz Hylton B. , Golightly Yvonne M. , Smith Michelle D.
Published: September 2022

Background

Ankle osteoarthritis (OA) is a debilitating health condition that is increasing in prevalence. Currently, there are no evidence-based guidelines for managing ankle OA. One of the current challenges to establishing guidelines is the lack of a widely agreed-upon set of outcome measures that are consistently used in ankle OA research. Without a set of agreed-upon outcome measures, it is difficult to synthesise clinical trial outcomes through meta-analysis—an essential element of evidence-informed practice. In order to develop an appropriate set of outcome measures for ankle OA, it is important first to develop a core domain set. In this protocol, we describe the methodological approach that we will use to develop such a core domain set for ankle OA.

Methods

We established an international steering committee to guide the development of a core domain set for ankle OA. The core domain set development will follow a multi-staged approach consisting of three phases, involving participation by patients and clinicians/healthcare professionals. In phase 1, a list of candidate domains will be gleaned from (a) a scoping review of outcome measures used in ankle OA research, (b) qualitative interviews with individuals with ankle OA, and (c) qualitative interviews with healthcare professionals with expertise in ankle OA. In phase 2, the steering committee will review and generate a list of candidate domains from those gleaned in phase 1. In phase 3, this list of candidate domains will be considered in a Delphi process to reach a consensus on a core domain set. We anticipated this will involve 3 rounds of surveys.

Conclusion

This protocol describes the methods that will be used to develop a core domain set of health-related aspects for ankle OA. Importantly, it will include both healthcare professional and patient involvement. This is a prerequisite step to developing a core outcome set for ankle OA that should be reported in all clinical trials for ankle OA. The findings will be widely disseminated across peer-refereed publication(s) and national and international conferences, as well as via relevant professional societies, patient support group organisations, and social media platforms.

Project registration

This project is registered with the Core Outcome Measures in Effectiveness Trials (COMET) database on 17 March 2021. https://www.comet-initiative.org/Studies/Details/1837.
Hamstrings force-length relationships and their implications for angle-specific joint torques: a narrative review
Authors: Kellis Eleftherios , Blazevich Anthony J.
Published: September 2022

Temporal biomechanical and physiological responses to physical activity vary between individual hamstrings components as well as between exercises, suggesting that hamstring muscles operate differently, and over different lengths, between tasks. Nevertheless, the force-length properties of these muscles have not been thoroughly investigated. The present review examines the factors influencing the hamstrings’ force-length properties and relates them to in vivo function. A search in four databases was performed for studies that examined relations between muscle length and force, torque, activation, or moment arm of hamstring muscles. Evidence was collated in relation to force-length relationships at a sarcomere/fiber level and then moment arm-length, activation-length, and torque-joint angle relations. Five forward simulation models were also used to predict force-length and torque-length relations of hamstring muscles. The results show that, due to architectural differences alone, semitendinosus (ST) produces less peak force and has a flatter active (contractile) fiber force-length relation than both biceps femoris long head (BFlh) and semimembranosus (SM), however BFlh and SM contribute greater forces through much of the hip and knee joint ranges of motion. The hamstrings’ maximum moment arms are greater at the hip than knee, so the muscles tend to act more as force producers at the hip but generate greater joint rotation and angular velocity at the knee for a given muscle shortening length and speed. However, SM moment arm is longer than SM and BFlh, partially alleviating its reduced force capacity but also reducing its otherwise substantial excursion potential. The current evidence, bound by the limitations of electromyography techniques, suggests that joint angle-dependent activation variations have minimal impact on force-length or torque-angle relations. During daily activities such as walking or sitting down, the hamstrings appear to operate on the ascending limbs of their force-length relations while knee flexion exercises performed with hip angles 45–90° promote more optimal force generation. Exercises requiring hip flexion at 45–120° and knee extension 45–0° (e.g. sprint running) may therefore evoke greater muscle forces and, speculatively, provide a more optimum adaptive stimulus. Finally, increases in resistance to stretch during hip flexion beyond 45° result mainly from SM and BFlh muscles.
Chicken cathelicidin-2 promotes NLRP3 inflammasome activation in macrophages
Authors: Peng Lianci , Tian Hongliang , Lu Yi , Jia Kaixiang , Ran Jinrong , Tao Qi , Li Gang , Wan Chao , Ye Chao , Veldhuizen Edwin J. A. , Chen Hongwei , Fang Rendong
Published: September 2022

Chicken cathelicidin-2 (CATH-2) as a host defense peptide has been identified to have potent antimicrobial and immunomodulatory activities. Here, we reported the mechanism by which CATH-2 modulates NLRP3 inflammasome activation. Our results show that CATH-2 and ATP as a positive control induced secretion of IL-1β and IL-1α in LPS-primed macrophages but did not affect secretion of IL-6, IL-12 and TNF-α. Furthermore, CATH-2 induced caspase-1 activation and oligomerization of apoptosis-associated speck-like protein containing a carboxy- terminal caspase recruitment domain (ASC), which is essential for NLRP3 inflammasome activation. However, CATH-2 failed to induce IL-1β secretion in Nlrp3−/−, Asc−/− and Casp1−/− macrophages. Notably, IL-1β and NLRP3 mRNA expression were not affected by CATH-2. In addition, CATH-2-induced NLRP3 inflammasome activation was mediated by K+ efflux but independent of the P2X7 receptor that is required for ATP-mediated K+ efflux. Gene interference of NEK7 kinase which has been identified to directly interact with NLRP3, significantly reduced IL-1β secretion and caspase-1 activation induced by CATH-2. Furthermore, confocal microscopy shows that CATH-2 significantly induced lysosomal leakage with the diffusion of dextran fluorescent signal. Cathepsin B inhibitors completely abrogated IL-1β secretion and caspase-1 activation as well as attenuating the formation of ASC specks induced by CATH-2. These results all indicate that CATH-2-induced activation of NLRP3 inflammasome is mediated by K+ efflux, and involves the NEK7 protein and cathepsin B. In conclusion, our study shows that CATH-2 acts as a second signal to activate NLRP3 inflammasome. Our study provides new insight into CATH-2 modulating immune response.
Metabolomic changes in polyunsaturated fatty acids and eicosanoids as diagnostic biomarkers in Mycobacterium avium ssp. paratuberculosis (MAP)-inoculated Holstein–Friesian heifers
Authors: Taylor Emma N. , Beckmann Manfred , Hewinson Glyn , Rooke David , Mur Luis A. J. , Koets Ad P.
Published: September 2022

Mycobacterium avium subspecies paratuberculosis (MAP) is the causative organism of Johne’s disease, a chronic granulomatous enteritis of ruminants. We have previously used naturally MAP-infected heifer calves to document metabolomic changes occurring in MAP infections. Herein, we used experimentally MAP-inoculated heifer calves to identify biomarkers for MAP infections. At 2-weeks of age, 20 Holstein–Friesian (HF) calves were experimentally inoculated with MAP. These calves, along with 20 control calves, were sampled biweekly up to 13-months of age and then monthly up to 19-months of age. Sera were assessed using flow infusion electrospray high-resolution mass spectrometry (FIE-HRMS) on a Q Exactive hybrid quadrupole-Orbitrap mass spectrometer for high throughput, sensitive, non-targeted metabolite fingerprinting. Partial least squares-discriminate analysis (PLS-DA) and hierarchical cluster analysis (HCA) discriminated between MAP-inoculated and control heifer calves. Out of 34 identified metabolites, six fatty acyls were able to differentiate between experimental groups throughout the study, including 8, 11, 14-eicosatrienoic acid and cis-8, 11, 14, 17-eicosatetraenoic acid which were also detected in our previous study and so further suggested their value as biomarkers for MAP infection. Pathway analysis highlighted the role of the alpha-linoleic acid and linoleic acid metabolism. Within these pathways, two broad types of response, with a rapid increase in some saturated fatty acids and some n-3 polyunsaturated fatty acids (PUFAs) and later n-6 PUFAs, became predominant. This could indicate an initial anti-inflammatory colonisation phase, followed by an inflammatory phase. This study demonstrates the validity of the metabolomic approach in studying MAP infections. Nevertheless, further work is required to define further key events, particularly at a cell-specific level.
The score after 10 years of registration of systematic review protocols
Authors: van der Braak Kim , Ghannad Mona , Orelio Claudia , Heus Pauline , Damen Johanna A. A. , Spijker René , Robinson Karen , Lund Hans , Hooft Lotty
Published: September 2022

Background

With the exponential growth of published systematic reviews (SR), there is a high potential for overlapping and redundant duplication of work. Prospective protocol registration gives the opportunity to assess the added value of a new study or review, thereby potentially reducing research waste and simultaneously increasing transparency and research quality. The PROSPERO database for SR protocol registration was launched 10 years ago. This study aims to assess the proportion SRs of intervention studies with a protocol registration (or publication) and explore associations of SR characteristics with protocol registration status.

Methods

PubMed was searched for SRs of human intervention studies published in January 2020 and January 2021. After random-stratified sampling and eligibility screening, data extraction on publication and journal characteristics, and protocol registration status, was performed. Both descriptive and multivariable comparative statistical analyses were performed.

Results

A total of 357 SRs (2020: n = 163; 2021: n = 194) were included from a random sample of 1267 publications. Of the published SRs, 38% had a protocol. SRs that reported using PRISMA as a reporting guideline had higher odds of having a protocol than publications that did not report PRISMA (OR 2.71; 95% CI: 1.21 to 6.09). SRs with a higher journal impact factor had higher odds of having a protocol (OR 1.12; 95% CI 1.04 to 1.25). Publications from Asia had a lower odds of having a protocol (OR 0.43; 95% CI 0.23 to 0.80, reference category = Europe). Of the 33 SRs published in journals that endorse PROSPERO, 45% did not have a protocol. Most SR protocols were registered in PROSPERO (n = 129; 96%).

Conclusions

We found that 38% of recently published SRs of interventions reported a registered or published protocol. Protocol registration was significantly associated with a higher impact factor of the journal publishing the SR and a more frequent self-reported use of the PRISMA guidelines. In some parts of the world, SR protocols are more often registered or published than others. To guide strategies to increase the uptake of SR protocol registration, further research is needed to gain understanding of the benefits and informativeness of SRs protocols among different stakeholders.

Systematic review registration

osf.io/9kj7r/
Digital behaviour change interventions to promote physical activity in overweight and obese adolescents: a systematic review protocol
Authors: Kassim Puteri Shanaz Jahn , Muhammad Noor Azimah , Rahman Nur Faraheen Abdul , Sidik Sherina Mohd , Essau Cecilia A. , Shah Shamsul Azhar
Published: September 2022

Background

With the increasing prevalence of obesity in youth, behavioural interventions to alter its modifiable risk factors such as physical activity can support the management of this epidemic. Digital behaviour changes interventions (DBCI) such as mobile applications, websites and wearables have the potential to reach many adolescents to promote physical activity as its use may be more accessible, effective and engaging compared to traditional face-to-face approaches. However, there is insufficient evidence on their use at promoting physical activity amongst overweight and obese adolescents. This review aims to assess the effectiveness of DBCIs aiming to increase physical activity in overweight and obese adolescents (aged 10–19 years) and the behaviour change techniques used in these interventions.

Methods

Electronic databases (MEDLINE, EMBASE, PsycINFO, CINAHL, Cochrane and Scopus) will be searched for English language studies from January 2000 to December 2022 using appropriate search terms relating to digital interventions, physical activity, adolescents and obesity. Experimental studies (either randomised or non-randomised controlled trials) assessing effects of DBCIs on physical activity behaviour, objectively or subjectively measured, in overweight and obese (body mass index [BMI] ≥ 85th percentile for age) adolescents will be eligible for inclusion. Intervention characteristics will be coded using the Template for Intervention Description and Replication (TIDieR) checklist and the BCT taxonomy v1. Risk of bias and the overall quality of the included studies will be assessed using Cochrane’s Collaboration’s tool and GRADE approach respectively. If the data allows, meta-analyses using random effect models will be conducted to assess the effects of DBCIs on physical activity.

Discussion

The proposed systematic review will summarise the effectiveness of digital behaviour change interventions aiming to increase physical activity in overweight and obese adolescents, as well as adding new information on the behaviour change techniques used in these interventions. The findings of this review will facilitate stakeholders with a current, rigorous and reliable research base to support the development and implementation of effective health promotion interventions for this population.

Systematic review registration

PROSPERO CRD42021270008.
An online self-directed program combining Community Reinforcement Approach and Family Training and parenting training for concerned significant others sharing a child with a person with problematic alcohol consumption: a randomized controlled trial
Authors: Siljeholm Ola , Lindner Philip , Johansson Magnus , Hammarberg Anders
Published: September 2022

Background

There is an urgent need for interventions helping children affected by parental problematic alcohol consumption (PAC). Such interventions could target partners to individuals with PAC, partners who often themselves show impaired quality of life and mental health. The aim of this study was to investigate the efficacy of an online self-directed intervention combining components from Community Reinforcement Approach and Family Training (CRAFT) with a parenting training program for concerned significant others (CSOs) sharing a child with a co-parent with PAC.

Methods

A randomized controlled parallel-group superiority trial compared the efficacy of the online intervention for CSOs sharing a child (3–11 y/o) with a co-parent with PAC (N = 37), to an active control group (N = 39) receiving written psychoeducational material. Assessment of outcomes was conducted at baseline, 3 weeks, 8 weeks and 12 weeks. Primary outcome was children’s mental health, while secondary outcomes included parental self-efficacy, CSO mental health and co-parent alcohol consumption and level of dependence. Linear mixed effect models with a factorial time variable were used to model time by group interaction effects.

Results

Recruitment rate was slow and a vast majority of interested CSOs were excluded at baseline assessment, mainly due experience of co-parent violence. The target sample size was not met. The intention to treat analysis did not show any significant time by group effects on either the primary or secondary outcomes during the follow-up period: the CSOs reported a significant reduction in co-parent alcohol consumption and severity of alcohol dependence and showed significant improvements in parental self-efficacy for how to handle effects of co-parent alcohol consumption, but no differences were found between the two conditions.

Conclusions

The current study found no evidence supporting efficacy of a novel, online self-directed intervention on children’s mental health, CSO mental health and co-parent alcohol related outcomes. Engaging in a support program or receiving information appears to initiate behavior change in the CSOs which affects the alcohol consumption and severity of dependence for co-parents with PAC. It is suggested that future studies may preferably focus on CSOs in more severely affected contexts.

Trial registration The trial was pre-registered at isrctn.com reference number ISRCTN38702517, November 28, 2017.