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Purpose: Leg length discrepancy (LLD) is a common complication following total hip arthroplasty (THA). The direct anterior approach (DAA) for THA is gaining popularity due to its advantages, but there is limited research on the incidence and size of LLD. This systematic review aims to explore the differences in LLD between DAA and other approaches, as well as the techniques to control LLD in DAA. Methods: A comprehensive literature search was conducted to identify relevant studies comparing THA by DAA with other surgical approaches and investigating methods to control LLD in DAA, following PRISMA guidelines and a priori registration on PROSPERO (CRD42023412644). The quality of the included studies was assessed. Data on preoperative and postoperative LLD and other relevant outcomes were extracted and analyzed descriptively. Results: In total, 29 studies were included in this systematic review. The majority (86%) were classified as level IV evidence. Comparisons between DAA and posterior approach (PA) or anterolateral approach (ALA) showed DAA had lower rates of LLD >10 mm compared to PA and ALA. Different pre- and intra-operative techniques were evaluated, but no consensus on the best method for preventing LLD in DAA was reached. Conclusion: DAA shows comparable or superior results in the prevention of LLD compared to other surgical approaches. Supine patient placement, direct leg measurement, and the use of IF contribute to these outcomes. Intraoperative fluoroscopy with a grid and preoperative planning offers a good option, especially for training purposes, but its role in preventing LLD by experienced DAA surgeons needs further investigation.

Abstract Background Beneficial associations between plants and soil microorganisms are critical for crop fitness and resilience. However, it remains obscure how microorganisms are assembled across different root compartments and to what extent such recruited microbiomes determine crop performance. Here, we surveyed the root transcriptome and the root and rhizosphere microbiome via RNA sequencing and full-length (V1–V9) 16S rRNA gene sequencing from genetically distinct monogenic root mutants of maize (Zea mays L.) under different nutrient-limiting conditions. Results Overall transcriptome and microbiome display a clear assembly pattern across the compartments, i.e., from the soil through the rhizosphere to the root tissues. Co-variation analysis identified that genotype dominated the effect on the microbial community and gene expression over the nutrient stress conditions. Integrated transcriptomic and microbial analyses demonstrated that mutations affecting lateral root development had the largest effect on host gene expression and microbiome assembly, as compared to mutations affecting other root types. Cooccurrence and trans-kingdom network association analysis demonstrated that the keystone bacterial taxon Massilia (Oxalobacteraceae) is associated with root functional genes involved in flowering time and overall plant biomass. We further observed that the developmental stage drives the differentiation of the rhizosphere microbial assembly, especially the associations of the keystone bacteria Massilia with functional genes in reproduction. Taking advantage of microbial inoculation experiments using a maize early flowering mutant, we confirmed that Massilia-driven maize growth promotion indeed depends on flowering time. Conclusion We conclude that specific microbiota supporting lateral root formation could enhance crop performance by mediating functional gene expression underlying plant flowering time in maize. Video Abstract

O artigo propõe uma comparação entre as perspectivas teórico-metodológicas do historiador italiano Carlo Ginzburg e do etnólogo e seu conterrâneo Ernesto De Martino. Em diversas ocasiões, o historiador reconheceu a relevância do etnólogo em seu percurso intelectual, valendo-se da leitura de sua obra para traçar uma história genealógica do xamanismo. Outra aproximação entre os dois autores é que ambos produziram uma importante reflexão antirrelativista, embora fundada nos limites epistemológicos do etnocentrismo. Contudo, apesar dessas aproximações, os autores divergem radicalmente em aspectos sensíveis de suas reflexões, especificamente no que concerne a realidade e o sentido histórico dos poderes mágicos. A partir dessas diferenças, concluo argumentando que a obra de De Martino pode contribuir ao estudo das religiões no Brasil trazendo um aporte teórico-metodológico focado na importância das práticas rituais para a compreensão das religiões populares.

BackgroundWhile nasopharyngeal (NP) swabs are considered the gold standard for severe acute respiratory coronavirus 2 (SARS-CoV-2) real-time reverse transcriptase-polymerase chain reaction (RT-PCR) detection, several studies have shown that saliva is an alternative specimen for COVID-19 diagnosis and screening.MethodsTo analyze the utility of saliva for the diagnosis of COVID-19 during the circulation of the Omicron variant, participants were enrolled in an ongoing cohort designed to assess the natural history of SARS-CoV-2 infection in adults and children. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and Cohen's kappa coefficient were calculated to assess diagnostic performance.ResultsOverall, 818 samples were collected from 365 outpatients from January 3 to February 2, 2022. The median age was 32.8 years (range: 3-94 years). RT-PCR for SARS-CoV-2 was confirmed in 97/121 symptomatic patients (80.2%) and 62/244 (25.4%) asymptomatic patients. Substantial agreement between saliva and combined nasopharyngeal/oropharyngeal samples was observed with a Cohen's kappa value of 0.74 [95% confidence interval (CI): 0.67-0.81]. Sensitivity was 77% (95% CI: 70.9-82.2), specificity 95% (95% CI: 91.9-97), PPV 89.8% (95% CI: 83.1-94.4), NPV 87.9% (95% CI: 83.6-91.5), and accuracy 88.5% (95% CI: 85.0-91.4). Sensitivity was higher among samples collected from symptomatic children aged three years and older and adolescents [84% (95% CI: 70.5-92)] with a Cohen's kappa value of 0.63 (95% CI: 0.35-0.91).ConclusionsSaliva is a reliable fluid for detecting SARS-CoV-2, especially in symptomatic children and adolescents during the circulation of the Omicron variant.

ABSTRACT: Acute abdomen cases are among the most prevalent and challenging illnesses in equine medicine. The diagnosis includes anamnesis and detailed clinical evaluation of the patient, allowing the gathering of several important information and, additionally, the use of complementary exams helps to define the diagnosis and prognosis of each case. This research applied the multiple correspondence analysis (MCA) in data referring to clinical examination information and outcome of horses with colic referred to a hospital in Rio Grande do Sul, Brazil. Fifty eight horses were included in the analysis and, it was possible to identify significant differences between the groups, survivors and non-survivors. Related to clinical signs, non-survivor cases are distinguished by severe pain, lack of motility, mucosal alteration, capillary refill time greater than 2sec, heart rate more than 48bpm and presence of nasogastric reflux. As complementary exams, hematocrits and blood lactate demonstrate significative difference among the groups. The cardiovascular parameters, including heart rate, mucosal color and capillary refill time, were the variables with the greatest contribution to discriminate animals that non-survive from those that were discharged. Thus, clinical evaluation should not be underestimated and complementary exams should be used in conjunction to seek a better prognosis. The MCA allowed to visualize the data and predict the outcome of the patients.

Glyphosate is a chemical compound derived from glycine, marketed as a broad-spectrum herbicide, and represents one of the most widely used pesticides in the world. For a long time, it was assumed that glyphosate was harmless, either due to its selective enzymatic acting method on plants, and because commercial formulations were believed to contain only inert chemicals. Glyphosate is widely spread in the environment, the general population is daily exposed to it via different routes, including the consumption of both plant, and non-plant based foods. Glyphosate has been detected in high amounts in workers’ urine, but has been detected likewise in bodily fluids, such as blood and maternal milk, and also in 60%–80% of general population, including children. Considering its massive presence, daily exposure to glyphosate could be considered a health risk for humans. Indeed, in 2015, the IARC (International Agency for Research on Cancer) classified glyphosate and its derivatives in Group 2A, as probable human carcinogens. In 2022, nevertheless, EFSA (European Food Safety Authority) stated that the available data did not provide sufficient evidence to prove the mutagenic/carcinogenic effects of glyphosate. Therefore, the European Commission (EC) decided to renew the approval of glyphosate for another 10 years. The purpose of this review is to examine the scientific literature, focusing on potential risks to human health arising from exposure to glyphosate, its metabolites and its commercial products (e.g., Roundup®), with particular regard to its mutagenic and carcinogenic potential and its effects as endocrine disrupter (ED) especially in the human reproductive system.

Background The optimal treatment for acute minor ischemic stroke is still undefined. and options include dual antiplatelet treatment (DAPT), intravenous thrombolysis (IVT), or their combination. We aimed to investigate benefits and risks of combining IVT and DAPT versus DAPT alone in patients with MIS. Methods and Results This is a prespecified propensity score‐matched analysis from a prospective multicentric real‐world study (READAPT [Real‐Life Study on Short‐Term Dual Antiplatelet Treatment in Patients With Ischemic Stroke or Transient Ischemic Attack]). We included patients with MIS (National Institutes of Health Stroke Scale score at admission ≤5), without prestroke disability (modified Rankin scale [mRS] score ≤2). The primary outcomes were 90‐day mRS score of 0 to 2 and ordinal mRS distribution. The secondary outcomes included 90‐day risk of stroke and other vascular events and 24‐hour early neurological improvement or deterioration (≥2‐point National Institutes of Health Stroke Scale score decrease or increase from the baseline, respectively). From 1373 patients with MIS, 240 patients treated with IVT plus DAPT were matched with 427 patients treated with DAPT alone. At 90 days, IVT plus DAPT versus DAPT alone showed similar frequency of mRS 0 to 2 (risk difference, 2.3% [95% CI −2.0% to 6.7%]; P=0.295; risk ratio, 1.03 [95% CI 0.98–1.08]; P=0.312) but more favorable ordinal mRS scores distribution (odds ratio, 0.57 [95% CI 0.41–0.79]; P

Enterólitos são concreções mineralizadas encontradas no intestino grosso dos equinos, que podem causar cólicas obstrutivas ao impedir o fluxo entérico normal, geralmente em pontos de redução do diâmetro intestinal. Apresenta alta incidência e causa grandes prejuízos no meio equestre. O diagnóstico presuntivo é realizado com base no histórico e sinais clínicos enquanto o diagnóstico definitivo só é possível na celiotomia exploratória ou radiografia abdominal. O presente trabalho teve como objetivo verificar a aplicabilidade clínica de parâmetros já estabelecidos para realização de diagnóstico radiográfico em casos de enterolitíase equina, e comparar esses achados entre um grupo com enterolitíase e um grupo controle. A partir dos prontuários de 92 equinos atendidos com síndrome cólica em um período que compreendeu junho de 2022 a outubro de 2023, os registros foram avaliados de maneira retrospectiva e incluíram 32 animais, que foram atendidos com sinais clínicos de cólica obstrutiva advinda do intestino grosso ou com histórico de dor abdominal recorrente, que realizaram exame de radiografia abdominal e que foi possível obter o diagnóstico definitivo por meio de celiotomia. Doze animais compuseram o grupo controle e vinte o grupo enterolitíase. Foi verificada a influência do tamanho, número e localização do enterólito na detecção radiográfica, além de identificação de fatores que dificultaram a realização da técnica diagnóstica e (correlacionados aos achados cirúrgicos. Durante o estudo, 85,5% dos animais do grupo enterolitíase (17/20) obtiveram o diagnóstico pré-cirurgico de enterólito por meio da radiografia abdominal enquanto três animais apresentaram falso-negativo e obtiveram o diagnóstico na celiotomia exploratória. O número de concreções apresentou relevância estatística significativa. Os principais fatores que interferiram no diagnóstico radiográfico foram a distensão abdominal, peso e o escore de condição corporal, indicando essa forma diagnóstica, independente do segmento obstruído e do número de enterólitos, sendo mais fácil a identificação quando existir mais de uma concreção. O presente estudo evidenciou que a radiografia digital abdominal é um importante método auxiliar de diagnóstico pré-cirúrgico nos casos de enterolitíase equina, sendo verificado a possibilidade dessa forma diagnóstica independente do segmento obstruído e do número de enterólitos, apresentando mais facilidade de observação nos animais com mais de uma concreção. No entanto, ressalta-se a necessidade de cautela na interpretação de imagens de equinos obesos e com presença de distensão abdominal por gás, situações em que ocorreram diagnósticos falso negativos. O presente estudo elucidou a importância da radiografia abdominal no atendimento de casos de enterólito para uma intervenção terapêutica precoce e um melhor prognóstico.

Vorasidenib and ivosidenib inhibit mutant forms of isocitrate dehydrogenase (mIDH) and have shown preliminary clinical activity against mIDH glioma. We evaluated both agents in a perioperative phase 1 trial to explore the mechanism of action in recurrent low-grade glioma (IGG) and select a molecule for phase 3 testing. Primary end-point was concentration of D-2-hydroxyglutarate (2-HG), the metabolic product of mIDH enzymes, measured in tumor tissue from 49 patients with mIDH1-R132H nonenhancing gliomas following randomized treatment with vorasidenib (50 mg or 10 mg once daily, q.d.), ivosidenib (500 mg q.d. or 250 mg twice daily) or no treatment before surgery. Tumor 2-HG concentrations were reduced by 92.6% (95% credible interval (CrI), 76.1-97.6) and 91.1% (95% CrI, 72.0-97.0) in patients treated with vorasidenib 50 mg q.d. and ivosidenib 500 mg q.d., respectively. Both agents were well tolerated and follow-up is ongoing. In exploratory analyses, 2-HG reduction was associated with increased DNA 5-hydroxymethylcytosine, reversal of 'proneural' and 'stemness' gene expression signatures, decreased tumor cell proliferation and immune cell activation. Vorasidenib, which showed brain penetrance and more consistent 2-HG suppression than ivosidenib, was advanced to phase 3 testing in patients with mIDH LGGs. Funded by Agios Pharmaceuticals, Inc. and Servier Pharmaceuticals LLC; ClinicalTrials.gov number NCT03343197.

Retinoic acid (RA) regulates stemness and differentiation in human embryonic stem cells (ESCs). Ewing sarcoma (ES) is a pediatric tumor that may arise from the abnormal development of ESCs. Here we show that RA impairs the viability of SK-ES-1 ES cells and affects the cell cycle. Cells treated with RA showed increased levels of p21 and its encoding gene, CDKN1A. RA reduced mRNA and protein levels of SRY-box transcription factor 2 (SOX2) as well as mRNA levels of beta III Tubulin (TUBB3), whereas the levels of CD99 increased. Exposure to RA reduced the capability of SK-ES-1 to form tumorspheres with high expression of SOX2 and Nestin. Gene expression of CD99 and CDKN1A was reduced in ES tumors compared to non-tumoral tissue, whereas transcript levels of SOX2 were significantly higher in tumors. For NES and TUBB3, differences between tumors and control tissue did not reach statistical significance. Low expression of CD99 and NES, and high expression of SOX2, were significantly associated with a poorer patient prognosis indicated by shorter overall survival (OS). Our results indicate that RA may display rather complex modulatory effects on multiple target genes associated with the maintenance of stem cell’s features versus their differentiation, cell cycle regulation, and patient prognosis in ES.

Abstract CO2 capture and storage in geological reservoirs have the potential to significantly mitigate the effects of anthropogenic gas emissions on global climate. Here, we report the results of the first laboratory experiments of CO2 injection in continental flood basalts of South America. The results show that the analyzed basalts have a mineral assemblage, texture and composition that efficiently allows a fast carbonate precipitation that starts 72 h after injection. Based on the availability of calcium, chemical monitoring indicates an estimated CO2 storage of ~ 75%. The carbonate precipitation led to the precipitation of aragonite (75.9%), dolomite (19.6%), and calcite (4.6%).

Abstract Antisense RNAs (asRNAs) represent an underappreciated yet crucial layer of gene expression regulation. Generally thought to modulate their sense genes in cis through sequence complementarity or their act of transcription, asRNAs can also regulate different molecular targets in trans, in the nucleus or in the cytoplasm. Here, we performed an in-depth molecular characterization of NFYC Antisense 1 (NFYC-AS1), the asRNA transcribed head-to-head to NFYC subunit of the proliferation-associated NF-Y transcription factor. Our results show that NFYC-AS1 is a prevalently nuclear asRNA peaking early in the cell cycle. Comparative genomics suggests a narrow phylogenetic distribution, with a probable origin in the common ancestor of mammalian lineages. NFYC-AS1 is overexpressed pancancer, preferentially in association with RB1 mutations. Knockdown of NFYC-AS1 by antisense oligonucleotides impairs cell growth in lung squamous cell carcinoma and small cell lung cancer cells, a phenotype recapitulated by CRISPR/Cas9-deletion of its transcription start site. Surprisingly, expression of the sense gene is affected only when endogenous transcription of NFYC-AS1 is manipulated. This suggests that regulation of cell proliferation is at least in part independent of the in cis transcription-mediated effect on NFYC and is possibly exerted by RNA-dependent in trans effects converging on the regulation of G2/M cell cycle phase genes. Accordingly, NFYC-AS1-depleted cells are stuck in mitosis, indicating defects in mitotic progression. Overall, NFYC-AS1 emerged as a cell cycle-regulating asRNA with dual action, holding therapeutic potential in different cancer types, including the very aggressive RB1-mutated tumors.

Introduction: Nausea and vomiting are frequent multifactorial symptoms in oncological patients. These manifestations, mainly affecting the advanced disease stages, may lead to existential, psychological, and physical suffering, with a negative impact on the quality of life (QoL) of the individual and his family. The medical approach makes use of a wide range of drugs, with different antiemetic potency and various mechanisms of action, taking into account the etiology and the patient’s response to the different therapeutic strategies. In recent years, in addition to pharmacological treatments, some endoscopic procedures have been integrated into clinical practice as promising palliative approaches. Case Presentation: Herein, we describe and discuss a case of a 64-year-old female affected by advanced stage pancreatic adenocarcinoma, in which different techniques – both medical and endoscopic – have been used to approach a refractory symptomatology with a negative impact on the patient’s QoL. In the context of a multidisciplinary approach in primary palliative care, a tailored intervention encompassing invasive methods for palliative purposes, may be considered adequate and appropriate when the prognostic expectation and the physical functionality indices allow it. Conclusion: Minimally invasive palliative interventions should be offered to patients with advanced cancer when symptoms become refractory to standard medical therapies, as part of the holistic approach in modern treatments. Therefore, the integration of an early palliative approach into the patient’s therapeutic path becomes essential for the management of all the individual’s needs.

Treatment options for secondary progressive MS (SPMS) are limited, especially considering that the new drugs recently approved are licensed for actively relapsing patients. We aimed to compare the disability progression in a real-world cohort of SPMS patients treated with natalizumab (NTZ) or interferon beta-1b (IFNb-1b). This multicenter retrospective enrolled patients with a diagnosis of SPMS according to 2014 Lublin criteria, who received NTZ or IFNb-1b for at least 48 months between the 1st June 2012 and the 15th May 2018 ​at 33 Italian MS centers contributing to the Italian MS Registry NTZ or IFNb-1b. Confirmed Expanded Disability Status Scale worsening (CEW) and progression independent of relapse (PIRA) were evaluated. In order to correct for non-randomization, a propensity score matching of the groups was performed. Out of 5206 MS patients identified at the time of data extraction, 421 SPMS patients treated with NTZ (224 [53.2%] females, mean age 45.3 ​± ​25.4 years) and 353 with IFNb-1b (133 [37.8%] females, mean age 48.5 ​± ​19.8 years) were enrolled. After applying the matching procedure, 102 patients were retained in the NTZ group and 98 in the IFNb-2b group. The proportion of patients who reached the 48-month 1-point CEW was significantly higher in IFNb-1b compared to NTZ group (58.2% versus 30.4%, p ​= ​0.01). The proportion of patients who developed PIRA at 48 months were significantly higher in IFNb-1b compared to NTZ (72.4% versus 40.2%, p ​= ​0.01). EDSS before treatment initiation and SPMS duration were risk factors for disability progression in terms of PIRA (HR 2.54, 25%CI 1.67–5.7; p ​= ​0.006 and HR 2.04, 25%CI 1.22–3.35; p ​= ​0.01, respectively). Patients treated with IFNb-1b were 1.64 times more to likely to develop PIRA (HR 1.64, 25%CI 1.04–4.87; p ​= ​0.001). Treatment with NTZ in SPMS patients showed more favorable disability outcomes compared to IFNb-1b with beneficial effects over 48 months.

Ventilation plays a key role in the livestock buildings since it is important to guarantee a comfortable environment and adequate indoor air quality for the animals. Naturally ventilated barns are usually characterized by high variability in the ventilation conditions. Moreover, the ventilation efficiency can be very different in different areas of a barn because of the different presence of the animals. On the other hand, appropriate ventilation is an essential requirement to ensure animal welfare and efficient and sustainable production since a proper ventilation is the most efficient way to remove undesirable air pollutants and to obtain a comfortable microclimate for the welfare of the animals. In this regard, the computational fluid dynamic (CFD) simulations represent a powerful and useful tool because they can be used to assess ventilation and microclimate conditions. In this context, the present study has the object to assess whether different CFD modelling approaches (i.e. model with animals modelled as obstacles with closed volume and model enriched with cows modelled as obstacles capable of exchanging heat with the surrounding air volume) show differences in relation to the climatic conditions inside a naturally ventilated dairy barn. The comparison of the results, set in terms of indoor air temperature and air velocity contours of the two different models, arises that if a precise definition of the microclimatic features is necessary, in order to correlate them with production parameters or assess animal welfare indexes, thermal simplification is not acceptable since can lead to completely misleading conclusions and incorrect evaluations. Then, only adopting CFD models considering the animal thermal behaviour is possible to obtain effective information both for the proper barn system management and for the creation of useful tools driving the farmers' choices.

Resumo Objetivo Analisar a associação entre a adesão à terapia medicamentosa com nível de entendimento e complexidade da prescrição, bem como avaliar a concordância entre dois questionários de adesão aplicados a pessoas idosas polimedicadas. Método Trata-se de estudo transversal, com pessoas idosas atendidas no ambulatório de geriatria de um hospital universitário do Rio de Janeiro, Brasil. Nesses pacientes foi avaliado a adesão à terapia medicamentosa (Brief Medication Questionarie - BMQ e Instrumento de Avaliação da Atitude frente à tomada de remédios - IAAFTR), o conhecimento sobre os medicamentos prescritos e a complexidade da farmacoterapia. Para análise estatística foram utilizados testes qui-quadrado e exato de Fisher sendo considerado o nível de significância de p-valor ≤0,05. A concordância entre os dois métodos de adesão foi avaliada pelo índice Kappa. Resultados Dos 49 idosos entrevistados, 75,5% eram mulheres, hipertensão arterial (82%) e diabetes (37%) as doenças mais prevalentes. Observou-se pelos testes BMQ e IAAFTR que 35% e 45% dos pacientes, respectivamente, eram aderentes a terapia medicamentosa. Não houve concordância de resultado entre os métodos de adesão. Grande parte dos pacientes apresentou bom nível de informação sobre seus medicamentos, porém, a maioria deles foi considerada não aderente. Não foi observado associação estatisticamente significativa entre a complexidade da prescrição frente a adesão e ao nível de informação sobre medicamentos. Conclusão A adesão a terapia medicamentosa é um processo multifatorial e as ferramentas de avaliação de adesão e de outros fatores que a influência deve ser criteriosamente escolhida de acordo com a população de estudo, pois em nosso trabalho elas apresentaram respostas diferenciadas.

BackgroundPregnancy is a complex time characterized by major transformations in a woman, which impact her physical, mental, and social well-being. How a woman adapts to these changes can affect her quality of life and psychological well-being. The literature indicates that pregnant women commonly experience psychological symptoms, with anxiety, stress, and depression being among the most frequent. Hence, promoting a healthy lifestyle focused on women’s psychological well-being is crucial. Recently developed digital solutions have assumed a crucial role in supporting psychological well-being in physiologically pregnant women. Therefore, the need becomes evident for the development and implementation of digital solutions, such as a virtual coach implemented in a smartphone, as a support for the psychological well-being of pregnant women who do not present psychological and psychiatric disorders. ObjectiveThis study aims to assess the feasibility, acceptability, and utility of a mindfulness-based mobile app. The primary objective is to explore the feasibility of using a virtual coach, Maia, developed within the TreC Mamma app to promote women’s psychological well-being during pregnancy through a psychoeducational module based on mindfulness. Finally, through the delivery of this module, the level of psychological well-being will be explored as a secondary objective. MethodsThis is a proof-of-concept study in which a small sample (N=50) is sufficient to achieve the intended purposes. Recruitment will occur within the group of pregnant women belonging to the pregnancy care services of the Trento Azienda Provinciale per i Servizi Sanitari di Trento. The convenience sampling method will be used. Maia will interact with the participating women for 8 weeks, starting from weeks 24 and 26 of pregnancy. Specifically, there will be 2 sessions per week, which the woman can choose, to allow more flexibility toward her needs. ResultsThe psychoeducational pathway is expected to lead to significant results in terms of usability and engagement in women’s interactions with Maia. Furthermore, it is anticipated that there will be improvements in psychological well-being and overall quality of life. The analysis of the data collected in this study will be mainly descriptive, orientated toward assessing the achievement of the study objectives. ConclusionsLiterature has shown that women preferred web-based support during the perinatal period, suggesting that implementing digital interventions can overcome barriers to social stigma and asking for help. Maia can be a valuable resource for regular psychoeducational support for women during pregnancy. International Registered Report Identifier (IRRID)RR1-10.2196/53890

Summary: 2′3′-cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) is the endogenous agonist of STING; as such, cGAMP has powerful immunostimulatory activity, due to its capacity to stimulate type I interferon-mediated immunity. Recent evidence indicates that cancer cells, under certain conditions, can release cGAMP extracellularly, a phenomenon currently considered important for therapeutic responses and tumor rejection. Nonetheless, the mechanisms that regulate cGAMP activity in the extracellular environment are still largely unexplored.In this work, we collected evidence demonstrating that CD38 glycohydrolase can inhibit extracellular cGAMP activity through its direct binding.We firstly used different cell lines and clinical samples to demonstrate a link between CD38 and extracellular cGAMP activity; we then performed extensive in silico molecular modeling and cell-free biochemical assays to show a direct interaction between the catalytic pocket of CD38 and cGAMP. Altogether, our findings expand the current knowledge about the regulation of cGAMP activity.

Summary: Zebrafish have a lifelong cardiac regenerative ability after damage, whereas mammals lose this capacity during early postnatal development. This study investigated whether the declining expression of growth factors during postnatal mammalian development contributes to the decrease of cardiomyocyte regenerative potential. Besides confirming the proliferative ability of neuregulin 1 (NRG1), interleukin (IL)1b, receptor activator of nuclear factor kappa-Β ligand (RANKL), insulin growth factor (IGF)2, and IL6, we identified other potential pro-regenerative factors, with BMP7 exhibiting the most pronounced efficacy. Bmp7 knockdown in neonatal mouse cardiomyocytes and loss-of-function in adult zebrafish during cardiac regeneration reduced cardiomyocyte proliferation, indicating that Bmp7 is crucial in the regenerative stages of mouse and zebrafish hearts. Conversely, bmp7 overexpression in regenerating zebrafish or administration at post-mitotic juvenile and adult mouse stages, in vitro and in vivo following myocardial infarction, enhanced cardiomyocyte cycling. Mechanistically, BMP7 stimulated proliferation through BMPR1A/ACVR1 and ACVR2A/BMPR2 receptors and downstream SMAD5, ERK, and AKT signaling. Overall, BMP7 administration is a promising strategy for heart regeneration.

Although delivery of a wild-type copy of the mutated gene to cells represents the most effective approach for a monogenic disease, proof-of-concept studies highlight significant efficacy caveats for treatment of brain disorders. Herein, we develop a cross-correction-based strategy to enhance the efficiency of a gene therapy for CDKL5 deficiency disorder, a severe neurodevelopmental disorder caused by CDKL5 gene mutations. We created a gene therapy vector that produces an Igk-TATk-CDKL5 fusion protein that can be secreted via constitutive secretory pathways and, due to the cell-penetration property of the TATk peptide, internalized by cells. We found that, although AAVPHP.B_Igk-TATk-CDKL5 and AAVPHP.B_CDKL5 vectors had similar brain infection efficiency, the AAVPHP.B_Igk-TATk-CDKL5 vector led to higher CDKL5 protein replacement due to secretion and penetration of the TATk-CDKL5 protein into the neighboring cells. Importantly, Cdkl5 KO mice treated with the AAVPHP.B_Igk-TATk-CDKL5 vector showed a behavioral and neuroanatomical improvement in comparison with vehicle or AAVPHP.B_CDKL5 vector-treated Cdkl5 KO mice. In conclusion, we provide the first evidence that a gene therapy based on a cross-correction approach is more effective at compensating Cdkl5-null brain defects than gene therapy based on the expression of the native CDKL5, opening avenues for the development of this innovative approach for other monogenic diseases.