Medical Information During Trauma Resuscitations: Are Smartphones the Contemporary Medical ID Bracelet?

INTRODUCTION: Smartphone emergency medical identification (SEMID) applications are built-in health information-storing functions that are accessible without a passcode. The utility of these applications in the real-time resuscitation of trauma patients is unknown. METHODS: We prospectively evaluated all trauma activation patients ≥16 y and unable to provide a medical history for any reason for the presence of a smartphone at our urban level I center between October 2020 and September 2021. Available smartphones were queried for SEMID utilization, categories of information contained, and real-time clinical relevance. RESULTS: One hundred and forty three patients with a median age of 39 y [interquartile range 28-59] and Injury Severity Score of 16 [2-29] were included. 30 (21%) patients arrived with a smartphone, 27 (90%) of which were accessible. 8 (30%) of those individuals utilized a SEMID application, and SEMID information was relevant for patient care in 6 cases (75%). The extracted information included: identifiers (75%), emergency contacts (50%), height/weight (38%), allergies (38%), age (38%), medications (25%), medical history (13%), and blood type (13%). CONCLUSIONS: Approximately one in five altered trauma patients have smartphones present at arrival, some of which contain medical information pertinent for immediate care. There is a pressing need for education and our institution has developed a publicly-facing campaign with shareable materials to improve SEMID awareness and utilization. Other centers are likely to find similar benefit.

Chromosomal segregation analysis and HOST-based sperm selection in a complex reciprocal translocation carrier.

INTRODUCTION: Complex chromosomal rearrangements (CCRs) involve two or more chromosomes and at least three breakpoints. Due to their complexity, they are associated with a high number of unbalanced gametes, whose fertilization is often incompatible with viable fetal development. Preimplantation genetic diagnosis (PGD) is usually offered to those patients and typically shows modest results considering the high number of unbalanced embryos. We previously showed that a sperm selection process using the hypo-osmotic swelling test (HOST) allows for an 83% reduction in the proportion of unbalanced spermatozoa (US) in male rearrangements carriers. This is the first report of the use of this procedure in a CCR carrier. CASE DESCRIPTION: We report on the case of a 36-year-old male t(4;7;14)(q12;p21;q11.2) carrier who presented to our center for infertility. Sperm fluorescent in situ hybridization showed an 88% proportion of unbalanced spermatozoa. After hypo-osmotic incubation and selection of spermatozoa with a specific flagellar conformation, the proportion of unbalanced spermatozoa dropped to 15%. DISCUSSION: In the present case, we show that it is possible to select chromosomally balanced prior to in vitro fertilization in male CCR carriers. This technique has the potential of increasing the proportion of euploid embryos and therefore the chances of healthy pregnancy and birth.

Detailed cell-level analysis of sperm nuclear quality among the different hypo-osmotic swelling test (HOST) classes.

PURPOSE: We studied the quality differences between the different hypo-osmotic swelling test (HOST) classes, as measured by criteria of DNA fragmentation, DNA decondensation, and nuclear architecture. The aim was to find particular HOST classes associated with good-quality metrics, which may be potentially used in ICSI (intra-cytoplasmic sperm injection). METHODS: Ten patients from the Department of Reproductive Medicine at Tenon Hospital (Paris, France) were included. Their semen samples were collected and divided into two fractions: one was incubated in a hypo-osmotic solution as per HOST protocol and sorted by sperm morphology, and a second was incubated without undergoing the HOST protocol to serve as an unsorted baseline. Three parameters were assessed: DNA fragmentation (TUNEL assay), DNA decondensation (chromomycin A3 assay), and nuclear architecture (FISH, with telomeric and whole chromosome painting probes). The different HOST classes were evaluated for these three parameters, and statistical analysis was performed for each class versus the unsorted non-HOST-treated sperm. Results with p<0.05 were considered statistically significant. RESULTS: For each of the parameters evaluated, we found significant differences between HOST-selected spermatozoa and non-selected spermatozoa. Overall, spermatozoa of HOST classes B and B+ exhibited the highest quality based on four metrics (low DNA fragmentation, low DNA decondensation, short inter-telomeric distance, and small chromosome 1 territory area), while spermatozoa of HOST classes A and G exhibited the poorest quality by these metrics. CONCLUSION: In addition to their pathophysiological interest, our results open possibilities of sperm selection prior to ICSI, which may allow for optimization of reproductive outcomes in heretofore unstudied patient populations.

Simple FISH-based evaluation of spermatic nuclear architecture shows an abnormal chromosomal organization in balanced chromosomal rearrangement carriers.

INTRODUCTION: Interphasic DNA has a constant three-dimensional conformation, which is particularly striking for spermatic DNA, with distinct chromosomal territories and a constant chromosomal conformation. We hypothesized that this organization is fragile, and that an excess or a lack of chromosomal segments could hinder the genomic structure as a whole. METHODS: Five human male chromosomal translocation carriers and five controls were included. Spermatic DNA spatial organization was studied, in both balanced and unbalanced spermatozoa, with two-dimensional fluorescent in situ hybridization (FISH) via analysis of chromosomes not implicated in the cases' translocations, compared to that of normal controls. Two parameters were studied: the distance between the two telomeric ends of chromosome 1, and the area of the chromosomal territories of chromosomes 1 and 17. RESULTS: Sperm FISH analysis of rearrangement carriers revealed changes in the nuclear architecture compared to that of controls. Inter-telomeric distance and chromosomal territories areas were both significantly increased. DISCUSSION: We show that an excess or lack of chromosomal segments can hinder the normal spatial nuclear architecture in sperm. These results show that nuclear architecture is a fragile assembly, and that local chromosomal abnormalities may impact the nucleus as a whole. This suggests a potential avenue for selection of spermatozoa prior to in vitro fertilization, not only in rearrangement carriers but also in the infertile population at large. Furthermore, we suggest that 2D-FISH could possibly be a useful tool in assessing spermatic nuclear organization in a way to evaluate male fertility.

Double chromosomal translocation in an infertile man: one-step FISH meiotic segregation analysis and reproductive prognosis.

BACKGROUND: The prevalence of chromosomal translocations is 1/500 in the general population. While in the vast majority of cases, carriers have a normal phenotype; they can present with difficulty conceiving due to the presence of a proportion of unbalanced gametes as a consequence of abnormal chromosomal segregation during meiosis. Since complex translocations involve three or more chromosomes, meiotic segregation leads to a greater number of possible combinations which effectively complicate both their study and therapeutic care. CASE PRESENTATION: We report on the case of a male carrier of a complex homogeneous double Robertsonian translocation: 44, XY, der(13;14)(q10;q10),der(21;22)(q10;q10). We studied his meiotic segregation by FISH on spermatozoa from the initial sample, as well as following discontinuous gradient centrifugation and after incubation in an hypo-osmotic solution. CONCLUSION: We report a method to study in a simple single-step manner the meiotic segregation of double Robertsonian translocations in spermatozoa. Further, our results suggest that reproductive prognosis of affected individuals may be markedly improved by HOST-based sperm selection (HBSS).

IQSEC2-Associated Intellectual Disability and Autism.

Mutations in IQSEC2 cause intellectual disability (ID), which is often accompanied by seizures and autism. A number of studies have shown that IQSEC2 is an abundant protein in excitatory synapses and plays an important role in neuronal development as well as synaptic plasticity. Here, we review neuronal IQSEC2 signaling with emphasis on those aspects likely to be involved in autism. IQSEC2 is normally bound to N-methyl-D-aspartate (NMDA)-type glutamate receptors via post synaptic density protein 95 (PSD-95). Activation of NMDA receptors results in calcium ion influx and binding to calmodulin present on the IQSEC2 IQ domain. Calcium/calmodulin induces a conformational change in IQSEC2 leading to activation of the SEC7 catalytic domain. GTP is exchanged for GDP on ADP ribosylation factor 6 (ARF6). Activated ARF6 promotes downregulation of surface α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors through a c-jun N terminal kinase (JNK)-mediated pathway. NMDA receptors, AMPA receptors, and PSD-95 are all known to be adversely affected in autism. An IQSEC2 transgenic mouse carrying a constitutively active mutation (A350V) shows autistic features and reduced levels of surface AMPA receptor subunit GluA2. Sec7 activity and AMPA receptor recycling are presented as two targets, which may respond to drug treatment in IQSEC2-associated ID and autism.

Potential selection of genetically balanced spermatozoa based on the hypo-osmotic swelling test in chromosomal rearrangement carriers.

Chromosomal translocations and other balanced rearrangements, although usually associated with a normal phenotype, can lead to the transmission of an abnormal unbalanced genome to the offspring. Balanced and unbalanced spermatozoa, being indistinguishable, cannot be selected or deselected for prior to IVF and pre-implantation genetic diagnosis. Spermatozoa from 16 chromosomal rearrangement carriers were studied. After incubation in a hypo-osmotic solution (hypo-osmotic swelling test, or HOST), spermatozoa were fixed on microscope slides. The chromosomally balanced or unbalanced status corresponding to each observed class of flagellar conformation was evaluated through fluorescent in-situ hybridization (FISH). We show here a specific type of spermatozoa, with a distinct flagellar conformation that was associated with a balanced genetic content. HOST is a simple, low-cost and time-honoured procedure initially developed to distinguish immotile viable from non-viable spermatozoa. We demonstrate that it can also be used to identify genetically balanced spermatozoa in chromosomal rearrangement carriers, with a 96% decrease in the proportion of unbalanced spermatozoa after selection. This may potentially improve reproductive prognosis in affected couples if used prior to pre-implantation genetic diagnosis (PGD), and clinical utility and efficacy should be evaluated in further studies.

Different Nuclear Architecture in Human Sperm According to Their Morphology.

Human sperm parameters serve as a first step in diagnosing male infertility, but not in determining the potential for successful pregnancy during assisted reproductive technologies (ARTs) procedures. Here, we investigated the relationship between sperm head morphology at high magnification, based on strict morphologic criteria, and the nuclear architecture analyzed by fluorescence in situ hybridization (FISH). We included five men. Two of them had an elevated high-magnification morphology score of 6 points (Score 6) indicating high fertility potential, whereas three had a low score of 0 points (Score 0), indicating low fertility potential. We used FISH to study the inter-telomeric distance and the chromosomal territory area of chromosome 1 (Chr. 1). We then compared these two parameters between subjects with high and low scores. FISH data analysis showed that the inter-telomeric distance (ITD) and chromosomal territory area (CTA) of Chr. 1 were significantly higher in subjects with low scores (score 0) than high scores (score 6). Our results suggest that (i) there is a link between nuclear architecture and sperm head abnormalities, particularly vacuoles; and (ii) it is possible to select spermatozoa with normal nuclear architecture, which might indirectly explain the positive ART outcomes observed with this technique.

Coexistence of a Heterozygous Caveolin-3 Deletion and a Novel Dystrophin Gene Mutation in a Duchenne Muscular Dystrophy Patient.

Inherited muscular abnormalities are debilitating disorders that greatly diminish the quality of life in affected individuals. Mutations in proteins such as dystrophin and caveolin, which together with other proteins form structural connections between the cytoskeleton and the extracellular matrix, are frequently the culprit of muscular dystrophies. In this case report, we describe a patient with a novel pathogenic dystrophin mutation co-existing with a caveolin-3 deletion. While genetically composed of this unique combination, the patient phenotypically presented with a primary clinical manifestation of Duchenne muscular dystrophy (DMD) in contrast to other cases of dual mutations in dystrophin and dystrophin-associated proteins.

Carotid Intimal Sarcoma Presenting as Large Vessel Occlusion and Diagnosed by Embolus Histopathology: Case Report.

Objective: The objective of this study was to present the clinical, histopathologic, and radiographic findings of a unique case of intimal sarcoma (IS) embolus presenting as a large vessel occlusion causing an ischemic stroke without a detectable primary tumor site. Methods: Extensive examinations, multimodal imaging, laboratory testing, and histopathologic analysis were used in evaluation. Results: We report the case of a patient who presented with acute embolic ischemic stroke and was found to have IS based on a histopathologic evaluation of his embolectomy specimen. Subsequent comprehensive imaging studies failed to detect a primary tumor site. Multidisciplinary interventions including a course of radiotherapy were performed. The patient died of recurrent multifocal strokes 92 days after diagnosis. Discussion: Meticulous histopathologic analysis should be conducted on cerebral embolectomy specimens. Histopathology may be useful in diagnosing IS.

Whole exome sequencing in a cohort of familial premature ovarian insufficiency cases reveals a broad array of pathogenic or likely pathogenic variants in 50% of families.

OBJECTIVE: To study the diagnostic yield, including variants in genes yet to be incriminated, of whole exome sequencing (WES) in familial cases of premature ovarian insufficiency (POI). DESIGN: Cross-sectional study. SETTING: Endocrinology and reproductive medicine teaching hospital departments. PATIENTS: Familial POI cases were recruited as part of a nationwide multicentric cohort. A total of 36 index cases in 36 different families were studied. Fifty-two relatives were available, including 25 with POI and 27 affected who were nonaffected. Karyotype analysis, FMR1 screening, single nucleotide polymorphism array analysis, and WES were performed in all subjects. INTERVENTIONS: None. MAIN OUTCOME MEASURES: The primary outcome was a molecular etiology, as diagnosed by karyotype, FMR1 screening, single nucleotide polymorphism array, and WES. RESULTS: A likely molecular etiology (pathogenic or likely pathogenic variant) was identified in 18 of 36 index cases (50% diagnostic yield). In 12 families, we found a pathogenic or likely pathogenic variant in a gene previously incriminated in POI, and in 6 families, we found a pathogenic or likely pathogenic variant in new candidate genes. Most of the variants identified were located in genes involved in cell division and meiosis (n = 11) or DNA repair (n = 4). CONCLUSIONS: The genetic etiologic diagnosis in POI allows for genetic familial counseling, anticipated pregnancy planning, and ovarian tissue preservation or oocyte preservation. Identifying new genes may lead to future development of therapeutics in reproduction based on disrupted molecular pathways. CLINICAL TRIAL REGISTRATION NUMBER: NCT 01177891.

An IQSEC2 Mutation Associated With Intellectual Disability and Autism Results in Decreased Surface AMPA Receptors.

We have recently described an A350V mutation in IQSEC2 associated with intellectual disability, autism and epilepsy. We sought to understand the molecular pathophysiology of this mutation with the goal of developing targets for drug intervention. We demonstrate here that the A350V mutation results in interference with the binding of apocalmodulin to the IQ domain of IQSEC2. We further demonstrate that this mutation results in constitutive activation of the guanine nucleotide exchange factor (GEF) activity of IQSEC2 resulting in increased production of the active form of Arf6. In a CRISPR generated mouse model of the A350V IQSEC2 mutation, we demonstrate that the surface expression of GluA2 AMPA receptors in mouse hippocampal tissue was significantly reduced in A350V IQSEC2 mutant mice compared to wild type IQSEC2 mice and that there is a significant reduction in basal synaptic transmission in the hippocampus of A350V IQSEC2 mice compared to wild type IQSEC2 mice. Finally, the A350V IQSEC2 mice demonstrated increased activity, abnormal social behavior and learning as compared to wild type IQSEC2 mice. These findings suggest a model of how the A350V mutation in IQSEC2 may mediate disease with implications for targets for drug therapy. These studies provide a paradigm for a personalized approach to precision therapy for a disease that heretofore has no therapy.

Associations Between Falls and Driving Outcomes in Older Adults: Systematic Review and Meta-Analysis.

OBJECTIVES: To examine associations between falls and subsequent motor vehicle crashes (MVCs), crash-related injuries, driving performance, and driving behavior. DESIGN: Systematic review and metaanalysis. PARTICIPANTS: Observational studies including drivers aged 55 and older or with a mean age of 65 and older. MEASUREMENTS: Two authors independently extracted study and participant characteristics, exposures, and outcomes and assessed risk of bias. Pooled risk estimates for MVCs and MVC-related injuries were calculated using random-effects models. Other results were synthesized narratively. RESULTS: From 3,286 potentially eligible records, 15 studies (N = 27-17,349 subjects) met inclusion criteria. Risk of bias was low to moderate, except for cross-sectional studies (n = 3), which all had a high potential for bias. A fall history was associated with a significantly greater risk of subsequent MVC (summary risk estimate = 1.40, 95% confidence interval (CI) = 1.20-1.63; I2  = 28%, N = 5 studies). One study found a significantly greater risk of MVC-related hospitalizations and deaths after a fall (hazard ratio = 3.12, 95% CI = 1.71-5.69). Evidence was inconclusive regarding an association between falls and driving cessation and showed no association between falls and driving performance or behavior. CONCLUSION: Falls in older adults appear to be a risk marker for subsequent MVCs and MVC-related injury. Given the nature of the evidence, which is limited to observational studies, the identified associations may also result at least partly from confounding or bias. Further research is needed to clarify the mechanisms linking falls to crash risk and to develop effective interventions to ensure driving safety in older adults with a history of falls.