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Parent–child language interaction in early childhood carries long-term implications for children's language and reading development. Conversational interaction, in particular, has been linked to white matter organization of neural pathways critical for language and reading. However, shared book reading serves an important role for language interaction as it exposes children to sophisticated vocabulary and syntax. Despite this, it remains unclear whether shared reading also relates to white matter characteristics subserving language and reading development. If so, to what extent do these environmentally associated changes in white matter organization relate to subsequent reading outcomes? This longitudinal study examined shared reading and white matter organization in kindergarten in relation to subsequent language and reading outcomes among 77 typically developing children. Findings reveal positive associations between the number of hours children are read to weekly (shared reading time) and the fractional anisotropy of the left arcuate fasciculus, as well as left lateralization of the superior longitudinal fasciculus (SLF). Furthermore, left lateralization of the SLF in these kindergarteners is associated with subsequent reading abilities in second grade. Mediation analyses reveal that left lateralization of the SLF fully mediates the relationship between shared reading time and second-grade reading abilities. Results are significant when controlling for age and socioeconomic status. This is the first evidence demonstrating how white matter structure, in relation to shared reading in kindergarten, is associated with school-age reading outcomes. Results illuminate shared reading as a key proxy for the home language and literacy environment and further our understanding of how language interaction may support neurocognitive development.

Interferon-gamma release assays (IGRAs) that measure pathogen-specific T-cell response rates can provide a more reliable estimate of protection than specific antibody levels but have limited potential for widespread use due to their workflow, personnel, and instrumentation demands. The major vaccines for SARS-CoV-2 have demonstrated substantial efficacy against all of its current variants, but approaches are needed to determine how these vaccines will perform against future variants, as they arise, to inform vaccine and public health policies. Here we describe a rapid, sensitive, nanolayer polylysine-integrated microfluidic chip IGRA read by a fluorescent microscope that has a 5 h sample-to-answer time and uses ∼25 μL of a fingerstick whole blood sample. Results from this assay correlated with those of a comparable clinical IGRA when used to evaluate the T-cell response to SARS-CoV-2 peptides in a population of vaccinated and/or infected individuals. Notably, this streamlined and inexpensive assay is suitable for high-throughput analyses in resource-limited settings for other infectious diseases.

Severe pain and pulmonary complications commonly follow rib fractures, both of which may be improved by surgical stabilization of rib fractures (SSRFs). However, significant postoperative pain still persists which may negatively impact in-hospital outcomes. Combining intercostal nerve cryoablation (INCA) with SSRF may improve those outcomes by further decreasing postoperative pain, opioid consumption, and pulmonary complications. The hypothesis is that INCA plus SSRF reduces opioids consumption compared with SSRF alone.The retrospective analysis included trauma patients 18 years or older who underwent SSRF, with or without INCA, in a Level I trauma center between 2015 and 2021. Patients received INCA at the surgeons' discretion based on familiarity with the procedure and absence of contraindications. Patients without INCA were the historical control group. Reported data include demographics, mechanism and severity of injury, number of ribs stabilized, cryoablated nerves, intubation rates and duration of mechanical ventilation. The primary outcome was total morphine milligrams equivalent consumption. Secondary outcomes were intensive care unit length of stay, hospital length of stay, incidence of pneumonia, and tracheostomy rates, and discharge disposition. Long-term outcomes were examined up to 6 months for adverse events.Sixty-eight patients were included, with 44 receiving INCA. There were no differences in rates of pneumonia ( p = 0.106) or duration of mechanical ventilation ( p = 0.687), and hospital length of stay was similar between groups ( p = 0.059). However, the INCA group demonstrated lower total morphine milligrams equivalent ( p = 0.002), shorter intensive care unit length of stay ( p = 0.021), higher likelihood of home discharge ( p = 0.044), and lower rate of intubation ( p = 0.002) and tracheostomy ( p = 0.032).Combining INCA with SSRF may further improve in-hospital outcomes for patients with traumatic rib fractures.Therapeutic/Care Management; Level III.

Parent-child language interaction in early childhood carries long-term implications for children’s language and reading development. Naturalistic conversational interaction, in particular, has been linked to white matter organization of neural pathways critical for language and reading. Yet parent-child shared book reading serves a unique role for language interaction as it exposes children to diverse concepts and sophisticated vocabulary and syntax beyond the scope of everyday conversational interaction. Despite this, it remains unclear whether shared reading also contributes to white matter mechanisms subserving language and reading development. If so, to what extent do these environmentally-associated changes in white matter organization relate to subsequent reading outcomes? To address these questions, the present longitudinal study examined shared book reading and white matter organization in kindergarten in relation to subsequent language and reading outcomes among 77 typically-developing children. Findings reveal positive associations between the number of hours children are read to weekly in kindergarten and fractional anisotropy of the left arcuate fasciculus, as well as left lateralization of the superior longitudinal fasciculus (SLF). Further, left lateralization of the SLF in these kindergarteners is associated with subsequent reading abilities in second grade. Mediation analyses further reveal that the amount children are read to weekly is indirectly associated with second-grade reading abilities via left lateralization of the SLF. All results are significant when controlling for children’s age and their family’s socioeconomic status. This study provides the first evidence illuminating how white matter structure in relation to shared reading experiences in kindergarten is associated with subsequent school-age reading outcomes. These results carry implications for understanding specific contexts of parent-child language interaction that may support neurocognitive development, independent of socioeconomic factors.

The BRAF kinase plays a critical role in the MAPK signaling pathway and is mutated in ~8% of all human cancers including melanoma (~60%), thyroid (~60%), and lung adenocarcinoma (~10%). The most common mutation in BRAF is V600E (Class I), which is found in >70% in these cancers. Despite the clinical success of approved small molecule inhibitors of BRAF V600E (vemurafenib, dabrafenib and encorafenib), this remains an area of unmet medical need because nearly all patients progress, due to either primary or acquired resistance. A bifunctional degradation activating compound (or BiDACTM degrader) may address the liabilities of approved drugs by overcoming, or preventing the emergence of, resistance to BRAF inhibitors. Here we describe CFT1946, an orally bioavailable cereblon-based BiDAC degrader of BRAF V600 mutant proteins, and provide an overview of the medicinal chemistry path leading to its discovery. CFT1946 degrades BRAF V600 mutant proteins, while maintaining exquisite selectivity against the proteome, sparing wild type BRAF (BRAF-WT), ARAF, and CRAF. In A375 cells, CFT1946 potently degraded BRAF V600E and inhibited ERK phosphorylation and cell growth while having no effect in the mutant KRAS, BRAF-WT driven cell line HCT116. In the A375 xenograft model, oral delivery of CFT1946 at 10 mg/kg PO BID resulted in deeper and more durable tumor regression compared to a clinically relevant dose of encorafenib. Further evaluation of CFT1946 in an engineered, clinically relevant BRAFi-resistant A375 cell line (endogenous BRAF V600E + engineered expression of NRAS Q61K) demonstrated that CFT1946 both degraded BRAF V600E and caused a loss of viability in these cells, while treatment with encorafenib had no effect. In xenografts derived from this BRAFi-resistant cell line, oral dosing of CFT1946 as a single agent led to tumor growth inhibition, while treatment with a clinically relevant dose of encorafenib had no effect on tumor growth. Furthermore, dosing CFT1946 in combination with the MEK inhibitor, trametinib, resulted in significant tumor regression, whereas combining encorafenib with the same dose of trametinib had no effect. The medicinal chemistry campaign resulting in CFT1946 focused on the improvement of in vivo pharmacokinetics and rational linker design to achieve high oral bioavailability in a beyond Rule of 5 heterobifunctional degrader. The preclinical data presented herein support the planned Phase 1/2 clinical trial of CFT1946 for the treatment of BRAF-V600 mutant solid tumors. Citation Format: Yanke Liang, Mathew E. Sowa, Katrina L. Jackson, Jeffrey R. Simard, Bridget Kreger, Ping Li, Laura Poling, Joelle Baddour, Andrew Good, Hongwei Huang, Scott Eron, Christopher G. Nasveschuk, Robert Yu, Mark Fitzgerald, Victoria Garza, Morgan W. O’Shea, Gesine Veits, Jeremy Y. Yap, Moses Moustakim, Ashley Hart, Roman V. Agafonov, Grace Sarkissian, Joe S. Patel, Richard Deibler, Kyle S. Cole, David Cocozziello, Fazlur Rahman, Andrew J. Phillips, Elizabeth Norton, Adam S. Crystal, Roy M. Pollock, Stewart L. Fisher. The discovery and characterization of CFT1946: A potent, selective, and orally bioavailable degrader of mutant BRAF for the treatment of BRAF-driven cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3425.

OBJECTIVE To determine if women who newly met criteria for stage 1 hypertension in early pregnancy were at increased risk for adverse perinatal outcomes compared with normotensive women. STUDY DESIGN We conducted a retrospective cohort study of women who had prenatal care at a single institution and subsequently delivered a live infant between December 2017 and August 2019. Women with a singleton gestation who had at least two prenatal visits prior to 20 weeks of gestation were included. We excluded women with known chronic hypertension or other major maternal illness. Two groups were identified: (1) women newly diagnosed with stage 1 hypertension before 20 weeks of gestation (blood pressure [BP] 130-139/80-89 on at least two occasions) and (2) women with no known history of hypertension and normal BP (

Rapid automatized naming (RAN) tasks have been shown to be a strong correlate of reading abilities. RAN also predicts future reading across different ages, ability levels, and languages, and is often used in literacy screening. Thus, understanding the specific relations between early RAN and later reading difficulties is important. In this systematic review and meta-analysis (with N = 68 samples; k = 373 effect sizes; n = 10,513 participants), we test the extent to which measures of RAN assessed before grade school predict later reading performance in English-speaking children. We also test whether characteristics of the RAN tasks, reading measures, or sample demographics moderate this relationship. We found that kindergarten/preschool RAN is correlated with grade-school reading at r = -.38, similar in magnitude to previous meta-analyses that included various ages and languages. We found that alphanumeric RAN tasks are particularly strongly related to future reading, as compared with non-alphanumeric tasks (p = .01) but that other features of the RAN task, such as the number of items, do not alter its predictive significance. RAN predicts all types of reading measures, but more strongly predicts real word than nonword reading (p < .001). These results support a shared cognitive resource model in which the similarity between RAN and reading tasks accounts for their correlation. We provide practical guidelines based on these data for early screening for reading difficulties and dyslexia.

Purpose: Learning to read is a complex, multi-faceted process that relies on several speech and language-related subskills. Individual differences in word reading outcomes are indicated among children with inaccurate speech-sound productions, with inconsistent reports as to whether phonological deficits and/or weaknesses in oral language explain subsequent reading difficulties. Thus, it remains unclear how variability in speech production accuracy in early childhood may impact reading development. Therefore, the present longitudinal study seeks to clarify the relationship between speech-sound production accuracy in kindergarten and subsequent reading outcomes with a focus on additional potential mediating factors.Method: Speech accuracy, core pre-literacy skills (phonological awareness, rapid naming, letter-name knowledge) and additional potential mediators (oral language, nonverbal cognitive abilities, and socioeconomic status (SES) were characterized at the start of formal reading instruction. Word reading, decoding, reading fluency and comprehension were assessed at the end of second grade. Mediation analyses were conducted to examine factors that mediate the relationship between speech accuracy in kindergarten and subsequent reading outcomes.Results: Speech-sound production accuracy uniquely contributed to the prediction of word reading; whereas full mediation effects of core pre-literacy skills and SES were identified for decoding and fluency. For reading comprehension, full effects of pre-literacy and vocabulary skills were observed. Hierarchical regression models further revealed the relative contributions of each factor to respective reading outcomes.Conclusions: Findings carry implications for the importance of monitoring emergent literacy abilities among children with speech delays and assessing speech-sound production accuracy in multifactorial approaches to early identification of risk for reading difficulties.

The BRAF kinase is a critical node in the MAPK signaling pathway and is mutated in approximately 8% of human cancers including melanoma (~60%), thyroid (~60%), and lung adenocarcinoma (~10%). The most common mutation in BRAF is V600E (Class I), occurring in half of malignant melanomas. This mutation hyperactivates ERK and signals as a RAF inhibitor-sensitive monomer. BRAF inhibitors including vemurafenib, dabrafenib and encorafenib have produced impressive responses in V600X patients, however resistance usually emerges within a year, including RAS mutation, BRAFV600E amplification, and BRAFV600E intragenic deletion or splice variants. These inhibitors are also ineffective against non-V600 BRAF mutants (Class II & III). To address some of these limitations we have developed CFT1946, a bifunctional degradation activating compound (BiDAC™) degrader comprising a BRAF kinase domain targeting ligand linked to a cereblon ligand. CFT1946 is capable of degrading BRAF V600E (Class I), G469A (Class II), G466V (Class III) mutations, and the p61-BRAFV600E splice variant while maintaining exquisite selectivity against the proteome including WT BRAF and CRAF. In A375 cells, CFT1946 potently degraded BRAFV600E (Emax = 26%; DC50 = 14nM at 24hr) and, inhibited ERK phosphorylation (IC50 = 11nM at 24hr) and cell growth (GI50 = 94nM at 96hr) while having no effect in the mutant KRAS driven cell line HCT116. In A375 xenografts, oral delivery of CFT1946 resulted in deeper tumor regressions when dosed at 10 mg/kg PO BID and compared favorably to a clinically relevant dose of encorafenib. We further evaluated CFT1946 in an engineered A375-BRAFV600E/NRASQ61K double mutant model of BRAF inhibitor resistance. CFT1946 was able to degrade BRAFV600E in these cells and was much more effective than encorafenib at inhibiting viability in vitro. In this model, in vivo dosing of single agent CFT1946 caused robust tumor growth inhibition and combination with the MEK inhibitor, trametinib, resulted in tumor regressions. The combination of encorafenib and trametinib showed no activity in the same model. Next, we demonstrated that CFT1946 was able to degrade additional BRAF mutant proteins including G469A (Class II), G466V (Class III), and the p61-BRAFV600E splice variant using heterologous expression in HEK293T cells. Additionally, we also showed that CFT1946, but not encorafenib, inhibited proliferation of the BRAFG466V heterozygous lung tumor cell line H1666. Based on its activity in preclinical models, including models of BRAF inhibitor resistance, and its drug-like properties we are progressing CFT1946 as a candidate for clinical development in patients with solid tumors bearing BRAF V600X mutations. Further, given CFT1946’s activity on non-V600 BRAF mutations, we are continuing to explore CFT1946 and related BiDAC degraders as therapeutic options for patients bearing Class II or Class III BRAF mutations. Citation Format: Mathew E. Sowa, Bridget Kreger, Joelle Baddour, Yanke Liang, Jeffrey R. Simard, Laura Poling, Ping Li, Robert Yu, Ashley Hart, Roman V. Agafonov, Grace Sarkissian, Joe Sahil Patel, Richard Deibler, Kyle S. Cole, Scott Eron, David Cocozziello, Fazlur Rahman, Moses Moustakim, Christopher G. Nasveschuk, Katrina L. Jackson, Mark Fitzgerald, Victoria Garza, Morgan O’Shea, Gesine Veits, Jeremy L. Yap, Andrew J. Phillips, Elizabeth Norton, Adam S. Crystal, Stewart L. Fisher, Roy M. Pollock. Preclinical evaluation of CFT1946 as a selective degrader of mutant BRAF for the treatment of BRAF driven cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2158.

Facilitation by nurse plants increases understorey diversity and supports ecological communities. In turn, biodiversity shapes ecological networks and enhances ecosystem functioning. However, whether and how facilitation and increased biodiversity jointly influence community structure and ecosystem functioning remains unclear.We performed a field experiment disentangling the relative contribution of nurse plants and increasing understorey plant diversity in driving pollination interactions. Both the presence of nurse shrubs as well as increased understorey plant diversity increased pollinator diversity and visitation rates. While nurse and understorey diversity effects on pollinator visitation rates did not interact, the effects of increasing understorey plant diversity on pollinator diversity were stronger in the absence than in the presence of shrubs, meaning that nurse shrubs attenuated the effects of high understorey diversity and buffered the effects of low understorey diversity.We also found positive complementarity effects among understorey species as well as complementarity between nurse plants and understorey species at high diversity. Results also indicate negative selection effects, suggesting that species with generally few pollinators benefit the most in the polyculture, while a species (possibly the nurse plant) with generally lots of pollinators does not. The corresponding changes in pollination networks with the experimental treatments were due to both changes in the frequency of visits and turnover in pollinator community composition.Synthesis Plant–plant facilitative systems, where a nurse plant increases understorey plant diversity, are common in stressful environments. Here, we show that these facilitative systems positively influence mutualistic interactions with pollinators via both direct nurse effects and indirect positive effects of increasing plant diversity.Conserving and supporting nurse plant systems is crucial not only for maintaining plant diversity but also for supporting ecosystem functions and services.

Contact networks can provide useful insights into animal behaviour and have the potential to quantify the spread of disease. Successful control of livestock diseases requires an understanding of how they spread amongst animals and between premises. Whilst movement records can provide valuable data on potential between-farm spread, the within-group dynamics of livestock are not well quantified; without this knowledge it is difficult to fully exploit knowledge about one-to-one transmission (such as insights gained from small scale experiments). Here the physical contact structure of domestic sheep (Ovis Aries) flocks is determined for different stages in the breeding cycle. Three observational studies were carried out on conventionally managed flocks, consisting of approximately thirty Dorset/cross sheep grazing a large paddock: a flock with young (newborn) lambs and their mothers; the flock when the lambs were older (nearly weaned); and a flock of ewes outside of the lambing season. Networks were constructed and key centrality measures calculated for all direct physical and proximal contacts. Proximity networks with conventional sheep flocks appear to be dense, but physical contacts have a more complex structure with strong variations determined by stages in the breeding cycle. There was a significant difference in the level of physical contact within those flocks with lambs and those without, and also as a result of the age of lambs. A clear reduction in between-ewe contact was observed amongst individuals with young, but there was an overall increase in connectivity in such flocks as a result of contacts involving lambs. Results are considered applicable to different sized flocks, given the known social behaviour of sheep and the experimental protocol used.

An international study about implementation of the World Health Organization Surgical Safety Checklist showed that use of the checklist reduced complication and death rates in adult surgical patients. Clinicians at Children's Hospital Boston, Massachusetts, modified the Surgical Safety Checklist for pediatric populations. We pilot tested the Pediatric Surgical Safety Checklist and created a large checklist poster for each OR to allow the entire surgical team to view the checklist simultaneously and to promote shared responsibility for conducting the time out. Results of the pilot test showed improvements in teamwork, communication, and adherence to process measures. Parallel efforts were made in other areas of the hospital where invasive procedures are performed. Compliance with the checklist at our facility has been good, and team members have expressed satisfaction with the flow and content of the checklist.

Importance Although seroepidemiological studies indicate that greater than 50% of the population has been infected with John Cunningham virus (JCV), the sites of JCV persistence remain incompletely characterized. Objective To determine sites of JCV persistence in immunologically healthy individuals. Design, Setting, and Participants Tissue specimens from multiple sites including brain, renal, and nonrenal tissues were obtained at autopsy performed in the Department of Pathology at the University of Kentucky from 12 immunologically healthy patients between February 9, 2011, and November 27, 2012. Quantitative polymerase chain reaction was performed on the tissue specimens and urine. Serum JCV antibody status was determined by enzyme-linked immunosorbent assay. Main Outcomes and Measures The detection and quantification of JCV from the tissues by quantitative polymerase chain reaction illuminated sites of viral persistence. These results were correlated with JCV antibody levels. Results Autopsies were performed on 12 individuals, 10 men and 2 women, ranging in age from 25 to 75 years (mean, 55.3 years). Seven of 12 individuals were JCV antibody seropositive based on absorbance units. Serostatus was associated with amounts of JCV DNA in urine and its tissue distribution. John Cunningham virus DNA was found in 75% of genitourinary tissue samples from donors (18 of 24) with high JCV antibody levels, 13.3% of donors with low levels i(4 of 30), and 0% of seronegative persons (0 of 32). In nongenitourinary tissues, JCV DNA was detected in 45.1% of tissue samples of donors (32 of 71) with high JCV, 2.2% of donors with low JCV serostatus (2 of 93), and 0% of seronegative persons (0 of 43). Genitourinary tissues had higher copy numbers than other sites. John Cunningham virus DNA was detected in urine of seronegative individuals in a research-grade assay. Conclusions and Relevance Persistent (latent or actively replicating) JCV infection mostly predominates in genitourinary tissues but distributes in other tissues at low copy number. The distribution and copy numbers of the virus appear to correlate with urinary JCV shedding and serostatus.

Background Despite mounting evidence that use of surgical checklists improves patient morbidity and mortality, compliance among surgical teams in executing required elements of checklists has been low. Recognizing that clinicians' receptivity is a major determinant of checklist use, we conducted a survey to investigate how mandated use of a surgical checklist impacts its operating room clinicians' attitudes about and perceptions of operating room safety, efficiency, teamwork, and prevention of medical errors. Methods Operating room clinicians at 1 pediatric hospital were surveyed on their attitudes and perception of the novel Pediatric Surgical Safety Checklist and the impact the checklist had on efficiency, teamwork, and prevention of medical errors 1 year after its implementation. The survey responses were compared and classified by multidisciplinary perioperative clinical staff. Results Most responses reflected positive attitudes toward checklist use. The respondents felt that the checklist reduced complications and errors and improved patient safety, communication among team members, teamwork in complex procedures, and efficiency in the operating room. Many operating room staff also reported that checklist use had prevented or averted an error or a complication. Perceptions varied according to perioperative clinical discipline, reflecting differences in perspectives. For example, the nurses perceived a higher rate of consent-related errors and site marking errors than did the physicians; the surgeons reported more antibiotic timing and equipment errors than did others. Conclusions The surgical staff at 1 pediatric hospital who responded viewed the novel Pediatric Surgical Safety Checklist as potentially beneficial to operative patient safety by improving teamwork and communication, reducing errors, and improving efficiency. Responses varied by discipline, indicating that team members view the checklist from different perspectives.

Infection of glial cells by the human polyomavirus JC (JCV) causes progressive multifocal leukoencephalopathy (PML). JCV Encephalopathy (JCVE) is a newly identified disease characterized by JCV infection of cortical pyramidal neurons. The virus JCVCPN associated with JCVE contains a unique 143 base pair deletion in the agnogene. Contrary to most JCV brain isolates, JCVCPN has an archetype-like regulatory region (RR) usually found in kidney strains. This provided us with the unique opportunity to determine for the first time how each of these regions contributed to the phenotype of JCVCPN. We characterized the replication of JCVCPN compared to the prototype virus JCVMad-1 in kidney, glial and neuronal cell lines. We found that JCVCPN is capable of replicating viral DNA in all cell lines tested, but is unable to establish persistent infection seen with JCVMad-1. JCVCPN does not have an increased ability to replicate in the neuronal cell line tested. To determine whether this phenotype results from the archetype-like RR or the agnogene deletion, we generated chimeric viruses between JCVCPN of JCVMad-1. We found that the deletion in the agnogene is the predominant cause of the inability of the virus to maintain a persistent infection, with the introduction of a full length agnogene, either with or without agnoprotein expression, rescues the replication of JCVCPN. Studying this naturally occurring pathogenic variant of JCV provides a valuable tool for understanding the functions of the agnogene and RR form in JCV replication.

Natalizumab, a monoclonal antibody directed against α4 integrins, has, to date, been associated with 399 cases of progressive multifocal leukoencephalopathy (PML) worldwide in patients receiving treatment for multiple sclerosis (MS). Because of the limited number of histologic studies, the possible interplay between MS and PML lesions has not been investigated. We report the clinical, radiologic, and histologic findings of an MS patient who developed PML after 32 months of natalizumab monotherapy. After withdrawal of natalizumab, she received plasma exchange, mefloquine, and mirtazapine but died soon thereafter. Postmortem examination was restricted to examination of the brain and spinal cord. Extensive PML lesions, characterized by the presence of JC virus DNA were found in the cerebral white matter and neocortex. Sharply demarcated areas of active PML lesions contained prominent inflammatory infiltrates composed of approximately equal numbers of CD4-positive and CD8-positive T cells, consistent with an immune reconstitution inflammatory syndrome. Conversely, all MS lesions identified were hypocellular, long-standing inactive plaques characterized by myelin loss, relative axonal preservation, and gliosis and, importantly, were devoid of JC virus DNA and active inflammation. Chronic inactive MS lesions were separate and distinct from nearby PML lesions. This case demonstrates the coexistence and apparent lack of interplay between chronic inactive MS and PML lesions, and that immune reconstitution inflammatory syndrome seems to affect the shape and appearance of PML but not MS lesions.

Background Mass cytometry has recently emerged as a promising tool for clinical research. However, few studies have demonstrated its benefit for patient stratification and biomarker identification. Primary Sjogren's syndrome (pSS) is a prototype of chronic autoimmune disease, the pathogenesis of which remains unclear and for which treatment does not exist. Objective This observational case-control study was designed to discover new cellular biomarkers and therapeutic targets in patients with pSS. Methods Forty-nine patients with pSS and 45 control subjects were enrolled for clinical evaluation and mass cytometry quantification of 34 protein markers in blood. For a third of these subjects, matched labial salivary gland biopsy specimens were also analyzed by mass cytometry and immunohistochemistry. Results In salivary gland biopsy specimens from patients with pSS, we identified a high number of activated CD8 + T cells, terminally differentiated plasma cells, and activated epithelial cells, pointing to new pathogenic mechanisms for future clinical intervention. In blood, we identified a 6-cell disease signature defined by decreased numbers of CD4 and memory B lymphocytes, decreased plasmacytoid dendritic cell numbers, and increased representation of activated CD4 and CD8 T cells and plasmablasts. These blood cellular components correlated with clinical parameters and, when taken together, clustered patients into subsets with distinct disease activity and glandular inflammation. Conclusion This first application of mass cytometry to a well-stratified clinical cohort and small biopsy tissues establishes the benefits of such an approach for the discovery of new biomarkers and therapeutic targets. Similar high-dimensional immunophenotyping strategies could be implemented in longitudinal and interventional clinical settings in this and other disease areas.

During the 2007 meeting of the Child Health Corporation of America Operating Room Director's Forum, members identified two major discrepancies in surgical count policies among the member hospitals: variations for instrument counts in pediatrics and exceptions to radiographic verification when needle counts were incorrect. The group agreed to collaboratively develop a pediatric count policy based on directors' expertise and current literature to help improve count practices. The task force members reviewed the literature as well as count policies from 30 member hospitals to identify and combine best practices and to create a single, standardized count policy. The project exemplifies a successful nurse-led, national group effort. The outcome is a policy that represents best practice in pediatrics and is a first step toward future opportunities to improve patient safety.

Retained surgical items were the most frequently reported sentinel event in 2010, according to The Joint Commission. Perioperative nurse leaders at Children's Hospital Boston, a pediatric teaching hospital, conducted a quality improvement initiative to reduce or eliminate incorrect counts and count discrepancies, which increase the risk of an item being unintentionally retained after surgery. Work included educating the perioperative staff members, standardizing count practices, formally reviewing every reported count discrepancy with the nursing team, and reviewing and revising the count policy for prevention of retained surgical items. The initiative reduced the number of incorrect counts and count discrepancies by 50% between 2009 to 2010. These initiatives continue to be expanded, and the results have been sustained on an ongoing basis.