A Practical Approach for Ischemic Preconditioning Intervention in Sports: A Pilot Study for Cuff Thigh Occlusion Pressure Estimation Based on Systolic Blood Pressure.

For the ischemic preconditioning (IPC) intervention, the accuracy of the protocol is paramount for mediating its possible ergogenic effects. However, the lack of standardization and widespread use of arbitrary cuff pressures (ranging from 130 to >300 mmHg) have been predominantly observed, potentially affecting the results and compromising the reproducibility of findings. Thus, the purpose of this study was to determine an appropriate cuff pressure during IPC. Seventeen healthy male participants were enrolled in the study. Anthropometric measurements were initially conducted, followed by systolic and diastolic blood pressure measurements. Subsequently, we determined the individual thigh occlusion pressure (TOP) for the right leg using a hand-held Doppler device. Based on these findings, we developed an estimation equation for TOP, considering the current brachial systolic blood pressure (SBP) values. We then conducted a retrospective analysis of its capacity to mediate occlusion. We observed the ability to estimate TOP using the equation (p = 0.01; ES: 0.86), presenting ~6% superiority in absolute values for occlusion compared to direct measurement (TOP equation: 169.9 ± 9.1; TOP direct measured: 161.2 ± 11.1). However, TOP estimation was insufficient to produce complete occlusion in two out of 17 subjects (11.8%). In conclusion, the estimation of TOP incorporating SBP values may offer a valid and practical means for cuff administration during IPC protocols with potential to minimize adverse effects and maximize its positive effects.

Posterior microphthalmos with retinal involvement related to MFRP gene: a report of 10 Brazilian patients.

BACKGROUND: To describe the phenotype and genotype of 10 Brazilian patients with variants in MFRP, posterior microphthalmos and retinal findings. METHODS: Complete ophthalmological evaluation was done at 4 different Brazilian centers. Genetic analysis was performed using commercial next generation sequencing panels for inherited retinal disorders. RESULTS: Ages of the patients ranged from 10 to 65 years and visual acuities from 0,05 to no perception of light. All were hyperopes (+4,25 to + 17,50) with a short axial length (14,4 mm to 18 mm). Common posterior segment features, though not present in all, were optic disc drusen (5/10), foveoschisis (5/10) and retinal pigmentary changes (8/10). Isolated patients presented with macular atrophy, serous retinal detachment, and chorioretinal folds. The most common variant in MFRP found in our patients was a deletion in exon 5 (c.498delC; p.Asn267Thrfs *25), present in all except 2 patients. Other variants found were c.523C>T (p.Gln175*), c.298delG (p.Ala100Argfs *37), c.666del (p.Thr223Argfs *83) and the novel variant c.257C>A (p.Ala86Asp). CONCLUSIONS: This is the first report of Brazilian patients with posterior microphthalmos and pathogenic variants in MFRP and the first describe of the variant p.Ala86Asp in literature. Our cases confirm the previously reported phenotype of high hyperopia, optic disc drusen, alterations in foveal architecture, retinal pigmentary changes with loss of photoreceptor function and visual field constriction. Report of such a rare condition is important to increase awareness to the phenotype of posterior microphthalmia with associated retinal conditions.

Targeted design of synthetic enhancers for selected tissues in the Drosophila embryo.

Enhancers control gene expression and have crucial roles in development and homeostasis1-3. However, the targeted de novo design of enhancers with tissue-specific activities has remained challenging. Here we combine deep learning and transfer learning to design tissue-specific enhancers for five tissues in the Drosophila melanogaster embryo: the central nervous system, epidermis, gut, muscle and brain. We first train convolutional neural networks using genome-wide single-cell assay for transposase-accessible chromatin with sequencing (ATAC-seq) datasets and then fine-tune the convolutional neural networks with smaller-scale data from in vivo enhancer activity assays, yielding models with 13% to 76% positive predictive value according to cross-validation. We designed and experimentally assessed 40 synthetic enhancers (8 per tissue) in vivo, of which 31 (78%) were active and 27 (68%) functioned in the target tissue (100% for central nervous system and muscle). The strategy of combining genome-wide and small-scale functional datasets by transfer learning is generally applicable and should enable the design of tissue-, cell type- and cell state-specific enhancers in any system.

Grynfeltt Hernia (GH): A Rare Case of Hernia.

Grynfeltt hernia (GH) is extremely rare among all abdominal wall hernias, so both diagnosis and treatment can be challenging. Surgery, open or laparoscopic, is the only definitive treatment. We present a case of a 71-year-old woman with GH (initially misdiagnosed as a lipoma), its approach, and treatment. We performed a hernioplasty with two meshes (preperitoneal and subaponeurotic position) by an open approach: Sandwich technique. This technique is safe, feasible, and associated with no short-term complications or relapses.

Enhancers display constrained sequence flexibility and context-specific modulation of motif function.

The information about when and where each gene is to be expressed is mainly encoded in the DNA sequence of enhancers, sequence elements that comprise binding sites (motifs) for different transcription factors (TFs). Most of the research on enhancer sequences has been focused on TF motif presence, whereas the enhancer syntax, that is, the flexibility of important motif positions and how the sequence context modulates the activity of TF motifs, remains poorly understood. Here, we explore the rules of enhancer syntax by a two-pronged approach in Drosophila melanogaster S2 cells: we (1) replace important TF motifs by all possible 65,536 eight-nucleotide-long sequences and (2) paste eight important TF motif types into 763 positions within 496 enhancers. These complementary strategies reveal that enhancers display constrained sequence flexibility and the context-specific modulation of motif function. Important motifs can be functionally replaced by hundreds of sequences constituting several distinct motif types, but these are only a fraction of all possible sequences and motif types. Moreover, TF motifs contribute with different intrinsic strengths that are strongly modulated by the enhancer sequence context (the flanking sequence, the presence and diversity of other motif types, and the distance between motifs), such that not all motif types can work in all positions. The context-specific modulation of motif function is also a hallmark of human enhancers, as we demonstrate experimentally. Overall, these two general principles of enhancer sequences are important to understand and predict enhancer function during development, evolution, and in disease.

Systematic identification and characterization of repressive domains in Drosophila transcription factors.

All multicellular life relies on differential gene expression, determined by regulatory DNA elements and DNA-binding transcription factors that mediate activation and repression via cofactor recruitment. While activators have been extensively characterized, repressors are less well studied: the identities and properties of their repressive domains (RDs) are typically unknown and the specific co-repressors (CoRs) they recruit have not been determined. Here, we develop a high-throughput, next-generation sequencing-based screening method, repressive-domain (RD)-seq, to systematically identify RDs in complex DNA-fragment libraries. Screening more than 200,000 fragments covering the coding sequences of all transcription-related proteins in Drosophila melanogaster, we identify 195 RDs in known repressors and in proteins not previously associated with repression. Many RDs contain recurrent short peptide motifs, which are conserved between fly and human and are required for RD function, as demonstrated by motif mutagenesis. Moreover, we show that RDs that contain one of five distinct repressive motifs interact with and depend on different CoRs, such as Groucho, CtBP, Sin3A, or Smrter. These findings advance our understanding of repressors, their sequences, and the functional impact of sequence-altering mutations and should provide a valuable resource for further studies.

Pediatric emergency care admissions for somatic symptom disorders during the COVID-19 pandemic.

During the COVID-19 pandemic, children and adolescents with psychiatric disorders experienced an exacerbation of their symptoms with more access to the emergency department (ED). However, little is known about the experience of somatic symptom disorders (SSDs) during the COVID-19 pandemic in children. Therefore, we aimed to compare the rates of pediatric ED admissions for SSDs before and during the COVID-19 pandemic and to understand whether the relative risk of ED admissions for SSDs changed between the two periods. We retrospectively enrolled all children between 4 and 14 years admitted for SSDs in the pediatric ED of Santobono-Pausilipon Hospital, Naples, Italy, from March 11th, 2020, to March 11th, 2021 (pandemic period), and in the same time period of the previous year (pre-pandemic period). We identified 205/95,743 (0,21%) children with SSDs presenting in ED in the pre-pandemic year and 160/40,165 (0,39%) in the pandemic year (p < 0.05). Considering the accesses for age, we observed a relative decrease of the accesses for SSDs over 12 years old (IRR 0,59; CI 0,39-0,88), while we found no differences under 12 years old (IRR 0,87; CI 0,68-1,10).   Conclusion: In this study, we found that despite the massive decrease in pediatric admissions due to the COVID-19 pandemic, somatic symptom disorders' admissions to the pediatric ED increased, suggesting an impact of the pandemic also on pediatric psychiatric disorders. What is Known: • During the COVID -19 pandemic, children and adolescents with a psychiatric disorder experienced exacerbation of their symptoms with more accesses in Emergency Department. What is New: • We found that despite the massive decrease of the pediatric admissions due to the COVID-19 pandemic, somatic symptom disorders admissions in healthy children to the pediatric Emergency Department increased ,suggesting an impact of the pandemic also on the pediatric psychiatric disorders.

The economic burden of malaria: a systematic review.

BACKGROUND: Quantifying disease costs is critical for policymakers to set priorities, allocate resources, select control and prevention strategies, and evaluate the cost-effectiveness of interventions. Although malaria carries a very large disease burden, the availability of comprehensive and comparable estimates of malaria costs across endemic countries is scarce. METHODS: A literature review to summarize methodologies utilized to estimate malaria treatment costs was conducted to identify gaps in knowledge. RESULTS: Only 45 publications met the inclusion criteria. They utilize different methods, include distinct cost components, have varied geographical coverage (a country vs a city), include different periods in the analysis, and focus on specific parasite types or population groups (e.g., pregnant women). CONCLUSIONS: Cost estimates currently available are not comparable, hindering broad statements on the costs of malaria, and constraining advocacy efforts towards investment in malaria control and elimination, particularly with the finance and development sectors of the government.

Allelic expression imbalance of PIK3CA mutations is frequent in breast cancer and prognostically significant.

PIK3CA mutations are the most common in breast cancer, particularly in the estrogen receptor-positive cohort, but the benefit of PI3K inhibitors has had limited success compared with approaches targeting other less common mutations. We found a frequent allelic expression imbalance between the missense mutant and wild-type PIK3CA alleles in breast tumors from the METABRIC (70.2%) and the TCGA (60.1%) projects. When considering the mechanisms controlling allelic expression, 27.7% and 11.8% of tumors showed imbalance due to regulatory variants in cis, in the two studies respectively. Furthermore, preferential expression of the mutant allele due to cis-regulatory variation is associated with poor prognosis in the METABRIC tumors (P = 0.031). Interestingly, ER-, PR-, and HER2+ tumors showed significant preferential expression of the mutated allele in both datasets. Our work provides compelling evidence to support the clinical utility of PIK3CA allelic expression in breast cancer in identifying patients of poorer prognosis, and those with low expression of the mutated allele, who will unlikely benefit from PI3K inhibitors. Furthermore, our work proposes a model of differential regulation of a critical cancer-promoting gene in breast cancer.

Malignancy Diseases in Kidney Transplantation, Clinical Outcomes, Patient, and Allograft Survival: A Case-Control Study.

BACKGROUND: Malignancy is a well-known complication in patients after kidney transplantation (KT), but its effect on posttransplant outcomes, allograft, and patient survival remains unexplored. The aim of this study is to report the impact of the comorbidity on clinical outcome, function, and failure of an allograft kidney. METHODS: This case-control study included 101 KT patients. Twenty-six patients who developed cancer (CA) were assigned to the case group and 75 to the control group. Statistical analysis was performed using logistic regression models, and graft survival was analyzed using the Kaplan-Meier curve. RESULTS: Non-melanoma skin CA was the most common malignancy, accounting for almost 60% of cases, followed by stomach CA, prostate CA, and lymphoproliferative diseases (7.70% each). Difference in graft and patient survival was not significant between the two groups (P > .05). A tumor in nonfunctioning in the first nonfunctioning KT was identified in 1 KT patient with a second allograft and by anatomopathological was detect Fuhrman grade II renal cell carcinoma. This KT patient was in good clinical condition with serum creatinine level of 1.5 mg/dL. CONCLUSIONS: No association was observed between CA development and risk factors, including family history and smoking habit, and no differences in allograft and patient survival were found. Nevertheless, in our data, CA in KT patients occurred early after transplantation. Renal cell carcinoma in allograft failure was identified in a patient; that suggested that nephrectomy of kidney failure must be performed to avoid patient allosensitization and neoplasia. Thus, we suggest continuous screening of malignancy diseases for KT patients.

Are there sex differences in energy expenditure and enjoyment in older adults playing active video games?

The aim of this study was to compare sex differences in energy expenditure and enjoyment in older adults during Active Video Game activities and sedentary behavior (watching television). In a within-subjects design, n = 32 older adults were included (15 men and 17 women). Energy expenditure was measured during each activity using indirect calorimetry. Energy expenditure was expressed in J.kg-1.min-1 and Metabolic Equivalents. Enjoyment was measured after each activity with the Physical Activity Enjoyment Scale. Energy expenditure was greater in Active Video Game activities compared to sedentary behavior in both men and women, but no differences were observed between sexes. The women reported greater enjoyment in Active Video Game activities compared to the men, and women reported greater enjoyment in Active Video Game activities compared to watching television, whereas the men did not report differences in enjoyment between Active Video Game vs. television watching. In conclusion, despite no difference in Energy expenditure, older women enjoy more than men playing Active Video Game, maybe they can be targeted for this intervention. (Clinical Trials Registration - NCT04352543).

DeepSTARR predicts enhancer activity from DNA sequence and enables the de novo design of synthetic enhancers.

Enhancer sequences control gene expression and comprise binding sites (motifs) for different transcription factors (TFs). Despite extensive genetic and computational studies, the relationship between DNA sequence and regulatory activity is poorly understood, and de novo enhancer design has been challenging. Here, we built a deep-learning model, DeepSTARR, to quantitatively predict the activities of thousands of developmental and housekeeping enhancers directly from DNA sequence in Drosophila melanogaster S2 cells. The model learned relevant TF motifs and higher-order syntax rules, including functionally nonequivalent instances of the same TF motif that are determined by motif-flanking sequence and intermotif distances. We validated these rules experimentally and demonstrated that they can be generalized to humans by testing more than 40,000 wildtype and mutant Drosophila and human enhancers. Finally, we designed and functionally validated synthetic enhancers with desired activities de novo.

The Perceptions of Women About Their High Experience of Using Crack Cocaine.

Introduction: The aim of this study was to explore the perceptions of women about their experience in using crack cocaine, discussing their motivations for using it and the repercussions in their lives. Objective: To investigate these experiences, a qualitative exploratory study was conducted, using the inductive thematic analyses of the content. Methods: Eight female crack cocaine users took part in this study. They were assessed by a semi-structured interview, addressing the crack cocaine use experience. Four main themes emerged in the interviews: (1) crack cocaine "high" experience; (2) symptoms related to crack cocaine use; (3) circumstances of crack cocaine use; and (4) crack cocaine use consequences. Results: The main perceptions reported by the users were related to a feeling of being disconnected to the world preceded by a pleasant experience, especially during the first moments of use. They revealed that the drug fulfills a key role of coping strategy to handle with negative thoughts, emotions or life experiences. An important influence of social issues was reported in relation to the onset of crack cocaine use. Negative consequences and significant impact on their lives appeared in their reports, regarding the loss of family ties, involvement with prostitution, traumatic experiences and violence. Conclusion: Taking together all women's perceptions suggests that beyond the positive immediate rewarding effect, the maintenance of use might be related to the dissociative experience and self-medication role, acting as negative reward by relieving of negative life experiences that, in turn, are both cause and consequence of the drug use.

Neuropsychiatric syndrome with myoclonus after SARS-CoV-2 infection in a paediatric patient.

We report the case of a 12-years-old patient who subacutely developed a positive and negative myoclonus of limbs and face, drowsiness and memory deficits after getting infected by SARS-CoV-2. On admission, nasopharyngeal swab for SARS-CoV-2, brain and spinal MRI with and without contrast, EEG, chest X-ray and abdominal ultrasound were negative. CSF physical-chemical examination, culture, PCR testing for SARS-CoV-2 and other pathogens, and oligoclonal IgG bands were negative as well. A full panel blood test, including clotting, autoimmunity and paraneoplastic blood studies, did not show any alteration. The neuropsychological examination showed an impairment in memory, visual-motor coordination, inductive reasoning skills, attention, and concentration. The patient was first treated with clonazepam and then with intravenous methylprednisolone for five days, with poor response. For this reason, he then received a cycle of IVIG, thus reaching a gradual and complete recovery. To date, this is the first case of a COVID-19 associated myoclonus affecting a paediatric patient.

Evaluating the Adequacy of Emoji Use in Positive and Negative Messages from Close and Distant Senders.

Computer-mediated communication allows people to communicate across several contexts (e.g., friends, professional settings) by using video-based or text-based channels. In the latter case, communication lacks nonverbal cues (e.g., tone of voice) that are critical to message interpretation. Including emoji can help express emotion and reinforce or clarify the meaning of a message. However, the benefits of using emoji are likely to depend on the context (e.g., the relationship between interlocutors) and the messages' features (e.g., the valence of the message). To date, studies have not systematically and empirically examined how the use of emoji is perceived across different communication scenarios. In the current study, we asked 175 participants (49.5 percent women; Mage = 36.32, SD = 12.22) to imagine receiving either a negative or a positive message from 22 senders (e.g., friend; bank manager) and to indicate, for each case, how much they would like to receive an emoji and how useful and appropriate they considered the use of emoji. These ratings were combined into a single index of emoji use adequacy. Based on factor analysis, the 22 scenarios were aggregated in distant and close scenarios. Overall, results showed that participants considered emoji use more inadequate in distant (vs. close) scenarios and for negative (vs. positive) messages. These findings suggest that the perceived benefits of emoji use for text-based communication may not be generalized to all text-based communication contexts, such that relationship proximity and message valence should not be overlooked. Implications for the fields of consumer psychology and communication are discussed.

Allosteric Antagonist Modulation of TRPV2 by Piperlongumine Impairs Glioblastoma Progression.

The use of computational tools to identify biological targets of natural products with anticancer properties and unknown modes of action is gaining momentum. We employed self-organizing maps to deconvolute the phenotypic effects of piperlongumine (PL) and establish a link to modulation of the human transient receptor potential vanilloid 2 (hTRPV2) channel. The structure of the PL-bound full-length rat TRPV2 channel was determined by cryo-EM. PL binds to a transient allosteric pocket responsible for a new mode of anticancer activity against glioblastoma (GBM) in which hTRPV2 is overexpressed. Calcium imaging experiments revealed the importance of Arg539 and Thr522 residues on the antagonistic effect of PL and calcium influx modulation of the TRPV2 channel. Downregulation of hTRPV2 reduces sensitivity to PL and decreases ROS production. Analysis of GBM patient samples associates hTRPV2 overexpression with tumor grade, disease progression, and poor prognosis. Extensive tumor abrogation and long term survival was achieved in two murine models of orthotopic GBM by formulating PL in an implantable scaffold/hydrogel for sustained local therapy. Furthermore, in primary tumor samples derived from GBM patients, we observed a selective reduction of malignant cells in response to PL ex vivo. Our results establish a broadly applicable strategy, leveraging data-motivated research hypotheses for the discovery of novel means tackling cancer.

Examining the Relationship between Sugar Content, Packaging Features, and Food Claims of Breakfast Cereals.

Excessive free-sugar intake has become highly prevalent in numerous countries, and Portugal is not the exception. One product category that contributes to the daily intake of free sugars is breakfast cereals. In the current work, we identified 289 exemplars from two major retailers in Portugal and collected information on their nutritional profile (e.g., sugar, salt, fiber per 100 g), price, packaging features, type of food claims present (e.g., statements about the composition, sensory features, the origin of the product), and ingredients list. Overall, the sugar content of breakfast cereals was high (Mean = 19.9 g), and less than 10% of the products complied with the current national guidelines (i.e., 5 g of sugar per 100 g of product). Sugar (or other sugar sources) was listed in the top three ingredients for over 85% of the products. On average, each product included about four claims (Mean = 3.9), and sugar content was lower when the claims were related to the product composition. Critically, the sugar content was particularly high for children-oriented products (Mean = 26.4 g). Correlation analysis showed that breakfast cereals with higher sugar content also were cheaper and had lower quantities of fiber, proteins, and salt. Our findings suggest the need to implement strategies to reduce sugar in this product category (e.g., incentivize manufacturers to reformulate products). Also, our results may inform strategies aimed at promoting consumers' awareness about the sugar content in breakfast cereals and other processed foods, facilitating healthier decision-making.

Parental perceptions and practices regarding sugar intake by school-aged children: A qualitative study with Portuguese parents.

Excessive sugar intake is one of the factors contributing to the alarming rates of childhood obesity and overweight in Portugal. Children's preferences and food consumption patterns are largely determined by the foods that are more familiar to them. Parents and caregivers are responsible for shaping children's eating habits since they are the ones who choose the food available in the household. The present study explores parental perceptions about sugar and sugar intake and its consequences on children's health. Moreover, we also examined the practices that parents use to regulate their children's diet, namely, to promote the consumption of desired foods (e.g., vegetables) and limit the intake of undesired food (e.g., sweets), and the perceived barriers and facilitators of sugar intake regulation. To this end, 42 interviews were conducted with parents of school-aged children (ages 6-10 years). A thematic analysis revealed that parents perceive sugar as highly negative (e.g., "evil", "poison", "addiction") and its consumption as harmful (e.g., hyperactivity; overweight). Nonetheless, the view that sugary food consumption is not necessarily problematic was also common. Indeed, most parents considered that sugar intake should be regulated but not forbidden. To control the intake of sugary foods (e.g., sodas, cookies), they reported using strategies such as restriction, explanation, or negotiation. Several barriers to sugar intake regulation were identified (e.g., birthday parties, parents' lack of knowledge), but also a few facilitators (e.g., bringing food from home to school). Our findings may inform the development of interventions or policies to promote healthier eating habits in school-age children.