The nucleolar δ isoform of adapter protein SH2B1 enhances morphological complexity and function of cultured neurons.

The adapter protein SH2B1 is recruited to neurotrophin receptors, including TrkB (also known as NTRK2), the receptor for brain-derived neurotrophic factor (BDNF). Herein, we demonstrate that the four alternatively spliced isoforms of SH2B1 (SH2B1α-SH2B1δ) are important determinants of neuronal architecture and neurotrophin-induced gene expression. Primary hippocampal neurons from Sh2b1-/- [knockout (KO)] mice exhibit decreased neurite complexity and length, and BDNF-induced expression of the synapse-related immediate early genes Egr1 and Arc. Reintroduction of each SH2B1 isoform into KO neurons increases neurite complexity; the brain-specific δ isoform also increases total neurite length. Human obesity-associated variants, when expressed in SH2B1δ, alter neurite complexity, suggesting that a decrease or increase in neurite branching may have deleterious effects that contribute to the severe childhood obesity and neurobehavioral abnormalities associated with these variants. Surprisingly, in contrast to SH2B1α, SH2B1ß and SH2B1γ, which localize primarily in the cytoplasm and plasma membrane, SH2B1δ resides primarily in nucleoli. Some SH2B1δ is also present in the plasma membrane and nucleus. Nucleolar localization, driven by two highly basic regions unique to SH2B1δ, is required for SH2B1δ to maximally increase neurite complexity and BDNF-induced expression of Egr1, Arc and FosL1.

Identification of high-performing antibodies for the reliable detection of Tau proteoforms by Western blotting and immunohistochemistry.

Antibodies are essential research tools whose performance directly impacts research conclusions and reproducibility. Owing to its central role in Alzheimer's disease and other dementias, hundreds of distinct antibody clones have been developed against the microtubule-associated protein Tau and its multiple proteoforms. Despite this breadth of offer, limited understanding of their performance and poor antibody selectivity have hindered research progress. Here, we validate a large panel of Tau antibodies by Western blot (79 reagents) and immunohistochemistry (35 reagents). We address the reagents' ability to detect the target proteoform, selectivity, the impact of protein phosphorylation on antibody binding and performance in human brain samples. While most antibodies detected Tau at high levels, many failed to detect it at lower, endogenous levels. By WB, non-selective binding to other proteins affected over half of the antibodies tested, with several cross-reacting with the related MAP2 protein, whereas the "oligomeric Tau" T22 antibody reacted with monomeric Tau by WB, thus calling into question its specificity to Tau oligomers. Despite the presumption that "total" Tau antibodies are agnostic to post-translational modifications, we found that phosphorylation partially inhibits binding for many such antibodies, including the popular Tau-5 clone. We further combine high-sensitivity reagents, mass-spectrometry proteomics and cDNA sequencing to demonstrate that presumptive Tau "knockout" human cells continue to express residual protein arising through exon skipping, providing evidence of previously unappreciated gene plasticity. Finally, probing of human brain samples with a large panel of antibodies revealed the presence of C-term-truncated versions of all main Tau brain isoforms in both control and tauopathy donors. Ultimately, we identify a validated panel of Tau antibodies that can be employed in Western blotting and/or immunohistochemistry to reliably detect even low levels of Tau expression with high selectivity. This work represents an extensive resource that will enable the re-interpretation of published data, improve reproducibility in Tau research, and overall accelerate scientific progress.

Placental small extracellular vesicles from normal pregnancy and gestational diabetes increase insulin gene transcription and content in ß cells.

Insulin secretion increases progressively during pregnancy to maintain normal maternal blood glucose levels. The placenta plays a crucial role in this process by releasing hormones and extracellular vesicles into the maternal circulation, which drive significant changes in pregnancy physiology. Placental extracellular vesicles, which are detectable in the plasma of pregnant women, have been shown to signal peripheral tissues and contribute to pregnancy-related conditions. While studies using murine models have demonstrated that extracellular vesicles can modulate insulin secretion in pancreatic islets, it remains unclear whether these effects translate to human biology. Understanding how placental signals enhance insulin synthesis and secretion from ß cells could be pivotal in developing new therapies for diabetes. In our study, we isolated placental small extracellular vesicles from human placentae and utilised the human ß cell line, EndoC-ßH3, to investigate their effects on ß-cell function in vitro. Our results indicate that human ß cells internalise placental small extracellular vesicles, leading to enhanced insulin gene expression and increased insulin content within the ß cells. Moreover, these vesicles upregulated the expression of Annexin A1, a protein known to increase insulin content. This upregulation of Annexin A1 holds promise as a potential mechanism by which placental small extracellular vesicles enhance insulin biosynthesis.

Identifying the Cerebral Physiologic Response to Aerobic Exercise Following Concussion: A Scoping Review.

OBJECTIVE: The purpose of this study was to identify the cerebral physiologic response to aerobic exercise in individuals with a symptomatic concussion, highlighting available knowledge and knowledge gaps in the literature. DESIGN: A systematic scoping review was conducted and reported in keeping with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension for scoping reviews. A search of EMBASE, MEDLINE, SCOPUS, BIOSIS, and Cochrane libraries was conducted on June 15, 2023 (from database inception). An online systematic/scoping review management system was used to remove duplicates, and the remaining articles were screened for inclusion by 2 researchers. Inclusion criteria required articles to be original research published in peer-reviewed journals. Additionally, studies were required to have an aerobic exercise component, include a measure of cerebral physiology during a bout of aerobic exercise, exclude moderate and/or severe traumatic brain injury (TBI) populations, and be in the English language. Both human and animal studies were included, with participants of any age who were diagnosed with a mild TBI/concussion only (ie, Glasgow Coma Scale score ≥ 13). Studies could be of any design as long as a measure of cerebral physiologic response to a bout of aerobic exercise was included. RESULTS: The search resulted in 1773 articles to be screened and data from 3 eligible studies were extracted. CONCLUSIONS: There are currently too few studies investigating the cerebral physiologic response to aerobic exercise following concussion or mild TBI to draw definitive conclusions. Further research on this topic is necessary since understanding the cerebral physiologic response to aerobic exercise in the concussion and mild TBI populations could assist in optimizing exercise-based treatment prescription and identifying other targeted therapies.

The Use of Remote Presence Robotic Tele-Presentation in Rural and Remote Canada: A Systematic Review.

Objective: One potential solution to limited health care in rural and remote regions is remote presence robotic tele-presentation to allow health care providers to care for patients in their home community via a robotic interface. We synthesized evidence regarding the use of remote presence robotic tele-presentation in rural and/or remote Canadian health settings. Methods: Medline, PubMed, and Embase were searched up to August 2023. Remote presence robotic tele-presentation refers to any robotic device used for the purpose of presenting and/or collecting patient information. Primary research was included if the patient was located in remote and/or rural Canada, featured remote presence robotic tele-presentation, and assessed patient, family, or clinician satisfaction, patient transport to nearby regional or urban center, health care costs, clinical outcomes, infrastructure outcomes, adverse events, or telementoring. Results: Six studies were included. Patients, nurses, and physicians all reported high levels of satisfaction when using the remote presence robotic tele-presentation. Fifty to sixty-three percent of patients were managed in their home community and did not require transfer to another center. Remote presence robotic sonography resulted in adequate imaging in 81% of first trimester ultrasound limited exams but was less useful for second trimester complete obstetric ultrasounds (20% adequate imaging). Two of eight laparoscopic colorectal surgeries had to be converted to open surgeries. Telerobotic ultrasound clinics resulted in a diagnosis in 70% of cases. Conclusions: Evidence suggests remote presence robotic tele-presentation is a safe and cost-effective approach to providing care in distant communities and can prevent some transfers and evacuations to tertiary hospitals.

Incidence of Subsequent Mental Health Disorders and Social Adversity Following Pediatric Concussion: A Longitudinal, Population-Based Study.

OBJECTIVE: To determine the long-term risk of new adverse psychosocial outcomes among adolescents diagnosed with a concussion compared with those not diagnosed. STUDY DESIGN: A retrospective, population-based cohort study was conducted. Adolescents (10-18 years) with a physician-diagnosed concussion between 2000 and 2005 were matched on neighborhood and age with 5 controls without concussion from the general population. New-onset mental health disorders, medication use, social, and justice outcomes were extracted using datasets linked to the population data repository. Adolescents were followed for 11-16 years. Adjusted hazard ratios (95% CIs) were estimated. RESULTS: In total, 2082 adolescents with a concussion were matched to 10 510 without. Adolescents with a concussion had an increased risk of any mental health disorder (HR 1.34; 95% CI 1.25-1.45), mood disorder (HR 1.30; 95% 1.18-1.43), psychosis (HR 1.43; 95% CI 1.18-1.74), substance abuse disorder (HR 1.67; 95% 1.31-2.14), and receiving a psychotropic prescription (HR 1.31; 95% CI 1.20-1.42). Female adolescents had an increased risk of ADHD following concussion (HR 1.89; 95% CI 1.17-3.05). Adolescents with a concussion had an increased risk of being accused (HR 1.22; 95% CI 1.11-1.34), victim (HR 1.29; 95% CI 1.11-1.48), or witness (HR 1.16; 95% CI 1.01-1.32) of a crime, or contact with Child and Family Services (HR 1.33; 95% CI 1.10-1.62). There was no association between concussion and attempting or completing suicide, receiving housing support, or collecting income support. CONCLUSIONS: Concussion was associated with an increased risk for multiple adverse psychosocial outcomes. Future work should focus on early identification of those at risk of these outcomes to help optimize longitudinal medical care and support.

Current Use and Future Considerations for Concussion Telemedicine Healthcare in Canada.

OBJECTIVE: To examine the use of telemedicine among Canadian concussion providers and clinics before and after the COVID-19 pandemic onset and identify barriers and facilitators for future use. METHODS: Ninety-nine concussion clinics and healthcare providers across Canada that offered one or more clinical concussion-related service were identified using standardized online searches and approached to complete a cross-sectional online survey. RESULTS: Thirty clinics or providers completed the survey and two completed subsections of the survey (response rate of 32.3%). Only 28.1% of respondents indicated that they used telemedicine to provide care prior to the COVID-19 pandemic. Providers most commonly using telemedicine prior to the pandemic were occupational therapists and physicians, while the most commonly used services were in-person videoconferencing and eConsultation. Most respondents (87%) indicated their clinic's use of telemedicine changed following the onset of the COVID-19 pandemic including new use of in-person video-conferencing, telephone calls, and eConsultation. Ninety-three percent indicated that they would consider using telemedicine to provide care to their concussion patients once the pandemic was over. Barriers needed to be overcome to facilitate use or greater use of telemedicine-based services were the inability to conduct a complete physical examination, lack of appropriate reimbursement, lack of start-up, and maintenance funding and medico-legal risk. CONCLUSION: Telemedicine was used by a minority of Canadian concussion clinics and providers prior to the COVID-19 pandemic but was rapidly adopted by many facilities. This study provides important insight into the factors that must be considered to optimize use of telemedicine in concussion care in the future.

Supervisor Cultural Humility and Supervisee Nondisclosure: The Supervisory Working Alliance Matters.

Given that half or more of supervisees (therapist trainees) never have their clinical work monitored or observed, supervisees who withhold salient information in clinical supervision compromise supervisors' ability to monitor client welfare and promote supervisees' professional development. Attempting to further understand the factors explaining supervisee nondisclosure, we tested the supervisory working alliance as a mediator of the hypothesized inverse relations of cultural humility and collaborative supervision with supervisee nondisclosure (supervision-related and clinically-related nondisclosure) among a diverse sample of 214 supervisees in applied psychology and allied mental health programs. Results supported the hypotheses that (1) descriptively, supervision-related nondisclosure was more prominent than clinically-related nondisclosure, (2) cultural humility substantially inversely predicted supervisee nondisclosure, and (3) the supervisory working alliance fully mediated the inverse relations of cultural humility and collaborative supervision with supervisee nondisclosure. Understanding the mechanisms underlying supervisee nondisclosure have broad implications for clinicians and researchers alike.

Clinical Outcomes of Pediatric Acute Sport- and Non-Sport-Related Concussions.

OBJECTIVES: The objectives were to examine clinical characteristics, length of recovery, and the prevalence of delayed physician-documented recovery, compare clinical outcomes among those with sport-related concussion (SRC) and non-sport-related concussion (nSRC), and identify risk factors for delayed recovery. METHODS: Included patients (8-18 years) were assessed ≤14 days post-injury at a multidisciplinary concussion program and diagnosed with an acute SRC or nSRC. Physician-documented clinical recovery was defined as returning to pre-injury symptom status, attending full-time school without symptoms, completing Return-to-Sport strategy as needed, and normal physical examination. Delayed physician-documented recovery was defined as >28 days post-injury. RESULTS: Four hundred and fifteen patients were included (77.8% SRC). There was no difference in loss of consciousness (SRC: 9.9% vs nSRC: 13.0%, p = 0.39) or post-traumatic amnesia (SRC: 24.1% vs SRC: 31.5%, p = 0.15) at the time of injury or any differences in median Post-Concussion Symptom Scale scores (SRC: 20 vs nSRC: 23, p = 0.15) at initial assessment. Among those with complete clinical follow-up, the median physician-documented clinical recovery was 20 days (SRC: 19 vs nSRC: 23; p = 0.37). There was no difference in the proportion of patients who developed delayed physician-documented recovery (SRC: 27.7% vs nSRC: 36.1%; p = 0.19). Higher initial symptom score increased the risk of delayed physician-documented recovery (IRR: 1.39; 95% CI: 1.29, 1.49). Greater material deprivation and social deprivation were associated with an increased risk of delayed physician-documented recovery. CONCLUSIONS: Most pediatric concussion patients who undergo early medical assessment and complete follow-up appear to make a complete clinical recovery within 4 weeks, regardless of mechanism.

Addressing the Shadow Pandemic: COVID-19 Related Impacts, Barriers, Needs, and Priorities to Health Care and Support for Women Survivors of Intimate Partner Violence and Brain Injury.

Intimate partner violence (IPV) affects 1 in 3 women and has intensified during the COVID-19 pandemic. Although most injuries are to the head, face, and neck, leaving survivors vulnerable to sustaining traumatic brain injury (TBI), the intersection of IPV and TBI remains largely unrecognized. This article reports on COVID-19-related effects, barriers, needs, and priorities to health care and support services for women survivors of IPV-TBI. Using a participatory research model, we engaged 30 stakeholders in virtual meetings drawn from an IPV-TBI Knowledge to Practice Network in two virtual meetings. Stakeholders included women survivors, service providers, researchers, and decision makers across the IPV, TBI, and healthcare sectors. Data were gathered through small group breakout sessions facilitated by the research team using semistructured discussion guides. Sessions were recorded, transcribed verbatim, and analyzed using thematic analysis techniques. Stakeholders were given the opportunity to contribute to the analysis and knowledge transfer through member checking activities. Ethics approval was obtained through the University of Toronto. Stakeholders shared that COVID-19 has increased rates and severity of IPV and barriers to services and help-seeking. These effects have been exacerbated by infrastructure difficulties in rural and remote areas, including limited access to services. They noted the need to carefully consider implications of virtual care such as safety, privacy, and usability. Requests from survivors for peer support have increased significantly, indicating a need for more formalized and better-supported peer roles. Stakeholders further noted that an overwhelming lack of awareness of the intersection of IPV-TBI continues. Increasing education and awareness among health care and IPV service providers, survivors, and the public remains a priority. The COVID-19 pandemic has intensified IPV-TBI, increased challenges for women survivors, and accentuated the continued lack of IPV-TBI awareness. Key recommendations for health care and rehabilitation to address this priority are discussed.

The Intersection of Intimate Partner Violence and Traumatic Brain Injury: Findings From an Emergency Summit Addressing System-Level Changes to Better Support Women Survivors.

BACKGROUND: Traumatic brain injury (TBI) occurring during intimate partner violence (IPV) is a largely unrecognized but significant public health crisis. One in 3 women will experience IPV in their lifetime, up to 75% of whom will sustain a TBI as a result. This article reports on the systems-level findings from a national summit to address barriers, needs, and priorities related to healthcare and support services for women survivors of IPV-TBI. OBJECTIVES: (1) To identify key needs, facilitators, and barriers to care for women survivors of IPV presenting with TBI; and (2) to cocreate ideas for resources and principles for identification, clinical care, and support for healthcare practitioners who treat women exposed to IPV and TBI. METHODS: Using a community-based participatory research approach, we engaged 30 stakeholders-drawn from a national IPV-TBI Knowledge-to-Practice (K2P) Network including diverse women survivors, service providers, researchers, and decision makers-in 2 half-day virtual meetings. Data were gathered through small group breakout sessions using semistructured discussion guides. Sessions were recorded, transcribed verbatim, and analyzed using thematic analysis techniques. Stakeholders contributed to the analysis and knowledge translation through member-checking activities. Ethics approval was obtained through the University of Toronto. FINDINGS: Three main systems-level themes arose during these discussions: (1) the need for trauma-informed, anti-racist, and equitable health and social care systems; (2) the need for cross-pollination of knowledge between disciplines; and (3) the need for systems-level support for integrated and coordinated care. This article explores these needs and provides recommendations and suggestions for paths forward. CONCLUSIONS: The findings of this project enhance understanding of system-level needs among women survivors and provide a template for a national agenda for IPV-TBI research and practice.

RNA surveillance by uridylation-dependent RNA decay in Schizosaccharomyces pombe.

Uridylation-dependent RNA decay is a widespread eukaryotic pathway modulating RNA homeostasis. Terminal uridylyltransferases (Tutases) add untemplated uridyl residues to RNA 3'-ends, marking them for degradation by the U-specific exonuclease Dis3L2. In Schizosaccharomyces pombe, Cid1 uridylates a variety of RNAs. In this study, we investigate the prevalence and impact of uridylation-dependent RNA decay in S. pombe by transcriptionally profiling cid1 and dis3L2 deletion strains. We found that the exonuclease Dis3L2 represents a bottleneck in uridylation-dependent mRNA decay, whereas Cid1 plays a redundant role that can be complemented by other Tutases. Deletion of dis3L2 elicits a cellular stress response, upregulating transcription of genes involved in protein folding and degradation. Misfolded proteins accumulate in both deletion strains, yet only trigger a strong stress response in dis3L2 deficient cells. While a deletion of cid1 increases sensitivity to protein misfolding stress, a dis3L2 deletion showed no increased sensitivity or was even protective. We furthermore show that uridylyl- and adenylyltransferases cooperate to generate a 5'-NxAUUAAAA-3' RNA motif on dak2 mRNA. Our studies elucidate the role of uridylation-dependent RNA decay as part of a global mRNA surveillance, and we found that perturbation of this pathway leads to the accumulation of misfolded proteins and elicits cellular stress responses.

Coupling of shoulder joint torques in individuals with chronic stroke mirrors controls, with additional non-load-dependent negative effects in a combined-torque task.

BACKGROUND: After stroke, motor control is often negatively affected, leaving survivors with less muscle strength and coordination, increased tone, and abnormal synergies (coupled joint movements) in their affected upper extremity. Humeral internal and external rotation have been included in definitions of abnormal synergy but have yet to be studied in-depth. OBJECTIVE: Determine the ability to generate internal and external rotation torque under different shoulder abduction and adduction loads in persons with chronic stroke (paretic and non-paretic arm) and uninjured controls. METHODS: 24 participants, 12 with impairments after stroke and 12 controls, completed this study. A robotic device controlled abduction and adduction loading to 0, 25, and 50% of maximum strength in each direction. Once established against the vertical load, each participant generated maximum internal and external rotation torque in a dual-task paradigm. Four linear mixed-effects models tested the effect of group (control, non-paretic, and paretic), load (0, 25, 50% adduction or abduction), and their interaction on task performance; one model was created for each combination of dual-task directions (external or internal rotation during abduction or adduction). The protocol was then modeled using OpenSim to understand and explain the role of biomechanical (muscle action) constraints on task performance. RESULTS: Group was significant in all task combinations. Paretic arms were less able to generate internal and external rotation during abduction and adduction, respectively. There was a significant effect of load in three of four load/task combinations for all groups. Load-level and group interactions were not significant, indicating that abduction and adduction loading affected each group in a similar manner. OpenSim musculoskeletal modeling mirrored the experimental results of control and non-paretic arms and also, when adjusted for weakness, paretic arm performance. Simulations incorporating increased co-activation mirrored the drop in performance observed across all dual-tasks in paretic arms. CONCLUSION: Common biomechanical constraints (muscle actions) explain limitations in external and internal rotation strength during adduction and abduction dual-tasks, respectively. Additional non-load-dependent effects such as increased antagonist co-activation (hypertonia) may cause the observed decreased performance in individuals with stroke. The inclusion of external rotation in flexion synergy and of internal rotation in extension synergy may be over-simplifications.

Optimized plant compound with potent anti-biofilm activity across gram-negative species.

Many human diseases, including cystic fibrosis lung infections, are caused or exacerbated by bacterial biofilms. Specialized modes of motility, including swarming and twitching, allow gram-negative bacteria to spread across surfaces and form biofilms. Compounds that inhibit these motilities could slow the spread of biofilms, thereby allowing antibiotics to work better. We previously demonstrated that a set of plant-derived triterpenes, including oleanolic acid and ursolic acid, inhibit formation of Escherichia coli and Pseudomonas aeruginosa biofilms, and alter expression of genes involved in chemotaxis and motility. In the present study, we have prepared a series of analogs of oleanolic acid. The analogs were evaluated against clinical isolates of E. coli and P. aeruginosa in biofilm formation assays and swarming assays. From these analogs, compound 9 was selected as a lead compound for further development. Compound 9 inhibits E. coli biofilm formation at 4 µg/mL; it also inhibits swarming at ≤1 µg/mL across multiple clinical isolates of P. aeruginosa, E. coli, Burkholderia cepacia, and Salmonella enterica, and at <0.5 µg/mL against multiple agricultural strains. Compound 9 also potentiates the activity of the antibiotics tobramycin and colistin against swarming P. aeruginosa; this is notable, as tobramycin and colistin are inhaled antibiotics commonly used to treat P. aeruginosa lung infections in people with cystic fibrosis. qPCR experiments suggested that 9 alters expression of genes involved in regulating Type IV pili; western blots confirmed that expression of Type IV pili components PilA and PilY1 decreases in P. aeruginosa in the presence of 9.

Benign Paroxysmal Positional Vertigo After Pediatric Sports-Related Concussion.

OBJECTIVE: Report the clinical findings and outcomes among pediatric patients diagnosed with benign paroxysmal positional vertigo (BPPV) after sports-related concussion (SRC). DESIGN: Retrospective case series. SETTING: Multidisciplinary pediatric concussion program. PATIENTS: Patients younger than 19 years with a sport or recreation activity-related concussion referred for comprehensive vestibular physiotherapy assessment. MAIN OUTCOME MEASURE: Symptom resolution after targeted particle repositioning (PR). RESULTS: During the study period, 115 pediatric SRC patients underwent vestibular physiotherapy assessment including 12 (10.4%) who were diagnosed with BPPV. Unilateral posterior semicircular canal (SCC) BPPV was diagnosed in 8/12 (75%) patients, and unilateral anterior SCC BPPV diagnosed in 4/12 (25%) patients. Benign paroxysmal positional vertigo was successfully treated in all patients with a mean of 1.58 targeted PR maneuvers (range = 1-4). CONCLUSIONS: Comprehensive management of pediatric SRC requires a multidisciplinary approach to address the heterogeneous pathophysiology of persistent postconcussion symptoms. Pediatric SRC patients with coexisting BPPV should be considered for targeted PR.

Emerging Concepts in the Treatment of Diabetic Retinopathy.

PURPOSE OF REVIEW: Diabetic retinopathy (DR) is the leading cause of vision loss in working-age adults in the developed world. This review discusses the current approach to managing the disease, such as glycemic and blood pressure control, as well as laser photocoagulation, as well as emerging concepts and controversies on novel therapies. RECENT FINDINGS: In recent years, the rise of intraocular anti-angiogenesis treatments is changing the paradigm of classic laser photocoagulation in the management of DR, but its long-term benefits remain an area of controversy. We also discuss new targets including anti-inflammation, neuroprotection, and novel laser technologies. Finally, we discuss new advances in retinal imaging that has vastly improved the diagnosis and management of DR. Diagnosis and management of diabetic retinopathy is a rapidly progressing field. Emerging concepts in ophthalmic imaging, medical treatments, and surgical approaches provide insights into how DR management will evolve in the near future.

Genomic epidemiology of MRSA infection and colonization isolates among military trainees with skin and soft tissue infection.

PURPOSE: Individuals with methicillin-resistant Staphylococcus aureus (MRSA) skin and soft tissue infection (SSTI) can be simultaneously colonized with MRSA on multiple body sites. Using whole genome sequencing (WGS), the intrahost relatedness of MRSA colonization and infection isolates was investigated. METHODS: In the context of a prospective case-control study of SSTI, we analyzed colonization and infection isolates from US Army Infantry trainees with purulent infection due to MRSA. At the time of clinical presentation for SSTI, culture swabs were obtained from the infection site, as well as from the patient's nasal, oral, inguinal, and perianal regions. S. aureus culture and susceptibility was performed by standard methods. DNA from MRSA isolates was extracted and libraries were produced. Sequences were generated on an Illumina MiSeq, sequence reads were assembled, and single nucleotide variant (SNV) data were analyzed. RESULTS: Of 74 trainees with MRSA SSTI, 19 (25.7%) were colonized with MRSA. Ten (52.6%) were colonized on more than one body site. Colonization frequency by anatomic site was as follows: inguinal region (33%), nasal region (30%), perianal region (22%), and oral region (14%). A total of 36 MRSA colonization isolates were characterized. The intrahost median number of SNVs between infection and colonization isolates was 17. Among trainees with recurrent MRSA SSTI, limited intrahost diversity suggests that persistent colonization is a major contributor to recurrence risk. CONCLUSIONS: Among military trainees with MRSA SSTI, genomic characterization of infection and colonization isolates revealed a high degree of strain relatedness. Single acquisition events may account for MRSA colonization and infection in this population.

A transposon-derived small RNA regulates gene expression in Salmonella Typhimurium.

Bacterial sRNAs play an important role in regulating many cellular processes including metabolism, outer membrane homeostasis and virulence. Although sRNAs were initially found in intergenic regions, there is emerging evidence that protein coding regions of the genome are a rich reservoir of sRNAs. Here we report that the 5΄UTR of IS200 transposase mRNA (tnpA) is processed to produce regulatory RNAs that affect expression of over 70 genes in Salmonella Typhimurium. We provide evidence that the tnpA derived sRNA base-pairs with invF mRNA to repress expression. As InvF is a transcriptional activator of SPI-1 encoded and other effector proteins, tnpA indirectly represses these genes. We show that deletion of IS200 elements in S. Typhimurium increases invasion in vitro and reduces growth rate, while over-expression of tnpA suppresses invasion. Our work indicates that tnpA acts as an sRNA 'sponge' that sets a threshold for activation of Salmonella pathogenicity island (SPI)-1 effector proteins and identifies a new class of 'passenger gene' for bacterial transposons, providing the first example of a bacterial transposon producing a regulatory RNA that controls host gene expression.

Cervical Spine Dysfunction Following Pediatric Sports-Related Head Trauma.

OBJECTIVE: To examine the prevalence of cervical spine injuries among children and adolescents referred with suspected and diagnosed sports-related concussion (SRC); and evaluate the effect of cervical spine dysfunction (CSD) on physician-documented clinical recovery following SRC. SETTING: A multidisciplinary pediatric concussion program. PARTICIPANTS: A total of 266 patients (6-19 years) referred with suspected SRC. DESIGN: A retrospective cohort study. MAIN MEASURES: CSD defined as neurological symptoms localized to the cervical spine or the presence of neck pain, headache, or dizziness and abnormal cervical spine examination findings; physician-documented clinical recovery. RESULTS: One patient was diagnosed with a T1 compression fracture. Of the 246 patients diagnosed with SRC, 80 (32.5%) met the clinical criteria for CSD including 4 patients with central cord neuropraxia and 1 with a spinal cord injury without radiographic abnormality (SCIWORA). Excluding patients with central cord neuropraxia OR SCIWORA, patients with SRC with CSD took longer to achieve physician-documented clinical recovery (28.5 days vs 17 days, P < .0001) and were 3.95 times more likely to experience delayed physician-documented clinical recovery (>4 weeks postinjury) compared with those without CSD. CONCLUSIONS: Patients with suspected and diagnosed SRC can present with a wide spectrum of coincident cervical spine injuries. Cervical spine dysfunction may be a risk factor for delayed clinical recovery.

Recent acceleration in coastal cliff retreat rates on the south coast of Great Britain.

Rising sea levels and increased storminess are expected to accelerate the erosion of soft-cliff coastlines, threatening coastal infrastructure and livelihoods. To develop predictive models of future coastal change we need fundamentally to know how rapidly coasts have been eroding in the past, and to understand the driving mechanisms of coastal change. Direct observations of cliff retreat rarely extend beyond 150 y, during which humans have significantly modified the coastal system. Cliff retreat rates are unknown in prior centuries and millennia. In this study, we derived retreat rates of chalk cliffs on the south coast of Great Britain over millennial time scales by coupling high-precision cosmogenic radionuclide geochronology and rigorous numerical modeling. Measured 10Be concentrations on rocky coastal platforms were compared with simulations of coastal evolution using a Monte Carlo approach to determine the most likely history of cliff retreat. The 10Be concentrations are consistent with retreat rates of chalk cliffs that were relatively slow (2-6 cm⋅y-1) until a few hundred years ago. Historical observations reveal that retreat rates have subsequently accelerated by an order of magnitude (22-32 cm⋅y-1). We suggest that acceleration is the result of thinning of cliff-front beaches, exacerbated by regional storminess and anthropogenic modification of the coast.