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We give some versions of Hahn-Banach, sandwich, duality, Moreau--Rockafellar-type theorems, optimality conditions and a formula for the subdifferential of composite functions for order continuous vector lattice-valued operators, invariant or equivariant with respect to a fixed group G of homomorphisms. As applications to optimization problems with both convex and linear constraints, we present some Farkas and Kuhn-Tucker-type results.

Aim This article seeks to clarify and define the concept of tremors. Design The Walker & Avant (2005) concept analysis method was followed. Methods A search of PubMed, Academic Search Complete, CINAHL, ERIC, Google and Google Scholar was performed. Results Through this process, uses of the concept were assessed including definitions and categories of tremors. Defining attributes were found to include “movement disorder,” “shaking motions,” “involuntary,” “oscillatory,” “rhythmic,” “not painful or life threatening,” “always present but variable” and “can sometimes be repressed.” We identified two model cases and a borderline case, antecedents, consequences and empirical referents (including measurement tools) of tremors. Conclusion The concept analysis process has clarified and illuminated an operational definition of tremors: that tremors are a movement disorder characterized by shaking motions that are involuntary, oscillatory, rhythmic, non‐painful, always present although vary in severity, and can be repressed by changing posture or going into a rest position.

Cerebellar mutism syndrome (CMS) is a common complication following surgical resection of childhood tumors arising in the posterior fossa. Alteration of linguistic production, up to muteness and emotional lability, generally reported at least 24 h after the intervention, is the hallmark of post-operative CMS. Other associated traits include hypotonia and other cerebellar motor signs, cerebellar cognitive-affective syndrome, motor deficits from the involvement of the long pathways, and cranial neuropathies. Recovery usually takes 6 months, but most children are burdened with long-term residual deficits. The pathogenic mechanism is likely due to the damage occurring to the proximal efferent cerebellar pathway, including the dentate nucleus, the superior cerebellar peduncle, and its decussation in the mesencephalic tegmentum. Proven risk factors include brain stem invasion, diagnosis of medulloblastoma, midline localization, tumor size, invasion of the fourth ventricle, invasion of the superior cerebellar peduncle, left-handedness, and incision of the vermis. Currently, rehabilitation is the cornerstone of the treatment of patients with cerebellar mutism syndrome, and it must consider the three main impaired domains, namely speech, cognition/behavior, and movement.

Mosaic variants in the PIK3CA gene, encoding the catalytic subunit of phosphoinositide 3-kinase (PI3K), produce constitutive PI3K activation, which causes PIK3CA-related overgrowth spectrum disorders. To date, fewer than 20 patients have been described with germline alterations in PIK3CA. In this study, we describe three unrelated individuals with overgrowth and germline PIK3CA variants. These variants were discovered through whole-exome sequencing and confirmed as germline by testing multiple tissue types, when available. Functional analysis using Patient 1’s fibroblast cell line and two previously reported patients’ cell lines showed increased phosphorylation of AKT during cellular starvation revealing constitutive activation of the phosphoinositide-3-kinase/protein kinase B/mechanistic target of rapamycin (PI3K/AKT/mTOR) pathway. Alternatively, stimulation of the cells by fetal bovine serum produced a reduced response, indicating an activated status of the PI3K complex reducing the pathway response to further external stimulation. Additional studies utilizing Biolog Phenotype Microarray technology indicated reduced energy production when cells were exposed to growth factors stimulating the PI3K/AKT/mTOR pathway, confirming the trend observed in the AKT phosphorylation test after stimulation. Furthermore, treatment with inhibitors of the PI3K/AKT/mTOR pathway rescued the normal energy response in the patients’ cells. Collectively, these data demonstrate that disease-causing germline PIK3CA variants have a functional consequence, similar to mosaic variants in the PI3K/AKT/mTOR pathway.

Background: As technology advances and genomic testing becomes commonplace, incidental findings, or the discovery of unrelated results, have increased. The American College of Genetics and Genomics (ACMG) established recommendations for the return of pathologic variants in 78 genes in the clinical setting based on medically actionable conditions from genes linked with preventable or treatable diseases. However, the lack of policy in the research setting poses a serious ethical dilemma for researchers, potentially threatening the participant’s trust and willingness to contribute to a process with more significant risk than benefit. Purpose: Our goal was to determine the preferred ethical approach to handling incidental research findings and suggest a new standard for investigators and participants. Methods: By employing Wueste’s IAJD Framework of ethical evaluation, the current research policy, as well as a proposed policy, were analyzed, and then a policy analysis was employed to ascertain feasibility. Results and Discussion: The current policy of leaving the decision of returning incidental findings up to the researcher’s discretion is an ethical failure from the consequential, deontological, and intellectual freedom perspectives. However, the proposed policy of implementing the ACMG guidance for researchers to satisfy ethical demands reinforces its moral fortitude. In a period of increasing public awareness, the community, which is the prospective research pool, has increased demands for autonomy and less paternalistic behavior from medicine and science. This paper synthesizes recommendations by numerous organizations to establish a mutually beneficial policy that will ensure the U.S. Department of Health and Human Services (HHS) goal, stated in the 2014 Joint Rule, of making participants “partners” in research a reality.

In the last two decades, thanks to the data that have been obtained from the Human Genome Project and the development of next-generation sequencing (NGS) technologies, research in oncology has produced extremely important results in understanding the genomic landscape of pediatric cancers, which are the main cause of death during childhood. NGS has provided significant advances in medicine by detecting germline and somatic driver variants that determine the development and progression of many types of cancers, allowing a distinction between hereditary and non-hereditary cancers, characterizing resistance mechanisms that are also related to alterations of the epigenetic apparatus, and quantifying the mutational burden of tumor cells. A combined approach of next-generation technologies allows us to investigate the numerous molecular features of the cancer cell and the effects of the environment on it, discovering and following the path of personalized therapy to defeat an “ancient” disease that has had victories and defeats. In this paper, we provide an overview of the results that have been obtained in the last decade from genomic studies that were carried out on pediatric cancer and their contribution to the more accurate and faster diagnosis in the stratification of patients and the development of new precision therapies.

MEF2C-related disorders (aka MEF2C-haploinsufficiency) are caused by variations in or involving the MEF2C gene and are characterized by intellectual disability, developmental delay, lack of speech, limited walking, and seizures. Despite these findings, the disorder is not easily recognized clinically. We performed a systematic review following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to assemble the most comprehensive list of patients and their phenotypes. Through searching PubMed, Web of Science, and MEDLINE, 43 articles met the inclusion criteria and were fully reviewed. One hundred and seventeen patients were identified from these publications with most having a phenotype of intellectual disability, developmental delay, seizures, hypotonia, absent speech, inability to walk, stereotypic movements, and MRI abnormalities. Nonclassical findings included one patient with a question mark ear, two patients with a jugular pit, one patient with a unique neuroendocrine finding, and nine patients that did not have MEF2C deletions or disruptions but may be affected due to a positional effect on MEF2C. This systematic review characterizes the phenotype of MEF2C-related disorders, documents the severity of this condition, and will help providers to better diagnose and care for patients and their families. Additionally, this compiled information provides a comprehensive resource for investigators interested in pursuing specific genotype-phenotype correlations.

Background: Autism spectrum disorder (ASD) is a complex neurodevelopmental condition that poses several challenges in terms of clinical diagnosis and investigation of molecular etiology. The lack of knowledge on the pathogenic mechanisms underlying ASD has hampered the clinical trials that so far have tried to target ASD behavioral symptoms. In order to improve our understanding of the molecular abnormalities associated with ASD, a deeper and more extensive genetic profiling of targeted individuals with ASD was needed. Methods: The recent availability of new and more powerful sequencing technologies (third-generation sequencing) has allowed to develop novel strategies for characterization of comprehensive genetic profiles of individuals with ASD. In particular, this review will describe integrated approaches based on the combination of various omics technologies that will lead to a better stratification of targeted cohorts for the design of clinical trials in ASD. Results: In order to analyze the big data collected by assays such as whole genome, epigenome, transcriptome, and proteome, it is critical to develop an efficient computational infrastructure. Machine learning models are instrumental to identify non-linear relationships between the omics technologies and therefore establish a functional informative network among the different data sources. Conclusion: The potential advantage provided by these new integrated omics-based strategies is to better characterize the genetic background of ASD cohorts, identify novel molecular targets for drug development, and ultimately offer a more personalized approach in the design of clinical trials for ASD.

Sleep is essential to maintaining a healthy life. Sleep disturbances among individuals with neurodevelopmental disorders are not well studied, affecting their early detection and treatment. Sleep disturbances in individuals with Phelan-McDermid Syndrome (PMS) are among the primary concerns reported by parents. However, little research has been aimed at addressing their concern.The purpose of this investigation was to identify and quantify specific sleep disturbances in people with PMS by analyzing data collected by the PMS Foundation International Registry.The registry shows that 284 out of 384 (73.4%) individuals with confirmed chromosome 22q13 deletions or SHANK3 pathogenic variants have a sleep disturbance. The prevalence of sleep disturbances increases with age with 56% reporting a sleep disturbance in the 0-3 year age group and 90% reporting these disturbances in those over age 18 years old. The primary sleep disturbances were circadian rhythm sleep disorders that included difficulty falling asleep, frequent nighttime awakenings, difficulty returning to sleep after a nighttime awakening event, and hypersomnia and parasomnias including enuresis, night terrors, sleepwalking, and sleep apnea. Sleep disturbances were similarly frequent among individuals with SHANK3 pathogenic variants (84.8%) and those with deletions (71.9%), supporting the role of haploinsufficiency of SHANK3 in sleep.Sleep disturbances are a common feature of PMS and should be considered in clinical evaluation and management because of the effect they have on the quality of life of the patients and their families.

Study question Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can enter and actively infect human follicular and granulosa cells? Summary answer Follicular Granulosa (GCs) and Cumulus cells (CCs) are susceptible to SARS-CoV-2 infection that is able to reproduce. What is known already To enter host cells, SARS-CoV-2 uses Spike S1 subunit to bind the receptor angiotensin-converting enzyme2 (ACE2), S2 subunit is cleaved by the host transmembrane serine protease 2 (TMPRSS2) or by cathepsin L (CSTL) to produce unlocked, fusion-catalyzing viral forms. CD147 (BSG) has been proposed as an additional host receptor for SARS-CoV-2. Female fertility is strictly dependent on oocyte quality and competence. ACE2 is highly expressed in the human ovaries and in the stromal endometrial cells, as well as in GCs and oocytes. The expression of ACE2 strongly suggests that it is potentially at a high risk of SARS-CoV-2 infection. Study design, size, duration In order to analyze the presence of host receptors ACE2 and co-receptors TMPRSS2-CSTL and BSG and consequently the susceptibility of GCs and CCs to SARS-CoV2 infection. GCs and CCs were collected from about 25 patients undergoing IVF/ICSI cycles at the UOSA of Assisted Reproductive techniques, from March 2020 to October 2021 at the Center of Couple Sterility, Siena University Hospital. Participants/materials, setting, methods GCs and CCs were collected from women undergoing IVF cycle. GCs were recovered from the follicular fluid according to the procedure previously published. After oocyte denuding, CCs were isolated and both GCs and CCs co-cultured with SARS-CoV-2 then the supernatant was used to infect VERO6 Cells. Host factors and SARS-CoV2 expression/localization were confirmed by RT-PCR, Western blot and Immunofluorescence. SARS-CoV2 infection and its effect on GCs and CCs were evaluated by Transmission and Immuno-electron microscopy. Main results and the role of chance qRT-PCR analysis and WB showed that ACE2, TMPRSS2, BSG and CTSL transcripts were expressed in both GCs and CCs cells, even if at different levels. ACE2 transcript was significantly increased in the CCs (0.43 vs 0.15; p Limitations, reasons for caution This is a human in vitro study, and we cannot predict all the implications in female fertility and related to the oocyte Wider implications of the findings We provide evidence in favor of SARS-CoV-2 infection in GCs and CCs, the ovarian somatic cells that support oocyte development and competence acquisition. The close relationship between oocytes and follicular cells raises the hypothesis that these cells may represent a vehicle for the oocyte SARS-CoV-2 infection Trial registration number Not applicable

The main purpose of this paper is to apply the theory of vector lattices and the related abstract modular convergence to the context of Mellin-type kernels and (non)linear vector lattice-valued operators, following the construction of an integral given in earlier papers., 15 pages

Phelan-McDermid syndrome (PMS) is a neurodevelopmental disorder caused by chromosomal rearrangements affecting the 22q13.3 region or by SHANK3 pathogenic variants. The scientific literature suggests that up to 40% of individuals with PMS have kidney disorders, yet little research has been conducted on the renal system to assess candidate genes attributed to these disorders. Therefore, we first conducted a systematic review of the literature to identify kidney disorders in PMS and then pooled the data to create a cohort of individuals to identify candidate genes for renal disorders in PMS. We found 7 types of renal disorders reported: renal cysts, renal hypoplasia or agenesis, hydronephrosis, vesicoureteral reflux, kidney dysplasia, horseshoe kidneys, and pyelectasis. Association analysis from the pooled data from 152 individuals with PMS across 22 articles identified three genomic regions spanning chromosomal bands 22q13.31, 22q13.32, and 22q13.33, significantly associated with kidney disorders. We propose UPK3A, FBLN1, WNT7B, and CELSR1, located from 4.5 Mb to 5.5 Mb from the telomere, as candidate genes. Our findings support the hypothesis that genes included in this region may play a role in the pathogenesis of kidney disorders in PMS.

In the last decade, the market for new psychoactive substances has been enriched by numerous psychedelic phenethylamines, which mimic the psychoactive effect of lysergic acid diethylamide (LSD). In particular, the -NBOMe series, which are more potent than their 2C compounds analogs, are considered worthy substitutes for LSD by users. The purpose of this study was to assess the effects of 25H-NBOMe and its halogenated derivatives (25I-NBOMe and 25B-NBOMe) in comparison to their 2C compounds analogs and LSD on the sensorimotor (visual, acoustic, and overall tactile), reaction time, spontaneous (total distance traveled) and stimulated (drag, accelerod test) motor activity, grip strength test, and prepulse inhibition (PPI) responses in mice. Systemic administration of -NBOMe, 2C compounds analogs, and LSD (0.001–10 mg/kg) differently impaired the sensorimotor, reaction time, motor, and PPI responses in mice. In particular, halogenated (25I and 25B)-NBOMe derivatives appear to be more effective than the entire class of 2C compounds analogs in altering visual and acoustic responses, affecting reaction time, and motor and sensory gating in PPI test. In fact, the specific rank order of compounds potency for nearly all of the experiments showed that (25I and 25B)-NBOMe were more potent than 2C compounds analogs and LSD. -NBOMe and 2C compounds analogs impaired not only the reception of incoming sensory stimuli (visual and acoustic), but their correct brain processing (PPI) in an equal and sometimes stronger way than LSD. This sensory impairment directly affected the spontaneous motor response and reaction time of mice, with no change in performance in stimulated motor activity tests. These aspects should be carefully considered to better understand the potential danger that psychedelic phenethylamines, in particular -NBOMe, may pose to public health, with particular reference to decreased performance in driving and hazardous works that require special sensorimotor skills.

MEF2C-related disorders are characterized by developmental and cognitive delay, limited language and walking, hypotonia, and seizures. A recent systematic review identified 117 patients with MEF2C-related disorders across 43 studies. Despite these reports, the disorder is not easily recognized and assessments are hampered by small sample sizes. Our objective was to gather developmental and clinical information on a large number of patients.We developed a survey based on validated instruments and subject area experts to gather information from parents of children with this condition. No personal identifiers were collected. Surveys and data were collected via REDCap and analyzed using Excel and SAS v9.4.Seventy-three parents completed the survey, with 39.7% reporting a MEF2C variant and 54.8% reporting a deletion involving MEF2C. Limited speech (82.1%), seizures (86.3%), bruxism (87.7%), repetitive movements (94.5%), and high pain tolerance (79.5%) were some of the prominent features. Patients with MEF2C variants were similarly affected as those with deletions. Female subjects showed higher verbal abilities.This is the largest natural history study to date and establishes a comprehensive review of developmental and clinical features for MEF2C-related disorders. This data can help providers diagnose patients and form the basis for longitudinal or genotype-phenotype studies.

The classification and interpretation of genetic variants associated with genetic disease have been shown to vary between clinical genetic laboratories. This can lead to errors introduced in the interpretation and public presentation of genetic findings in the literature and available databases. This qualitative study utilizes real-world evidence to introduce a taxonomic schema of potential pitfalls associated with public and commercial resources commonly used for sequence variant analysis. A modified and expanded version of Reason’s Model of Human Error with respect to variant analysis is proposed and discussed. This study complements professional standards and published recommendations of interpretive considerations associated with variant analysis and expands the scope of professional competency.