ChatGPT4 outperforms endoscopists for determination of post-colonoscopy re-screening and surveillance recommendations.

BACKGROUND: Large language models (LLM) including ChatGPT4 improve access to artificial intelligence, but their impact on the clinical practice of gastroenterology is undefined. In this study, we aim to compare the accuracy, concordance and reliability of ChatGPT4 colonoscopy recommendations for colorectal cancer re-screening and surveillance to contemporary guidelines and real-world gastroenterology practice. METHODS: History of present illness, colonoscopy data and pathology reports from patients undergoing procedures at two large academic centers were entered into ChatGPT4 and it was queried for next recommended colonoscopy follow-up interval. Using McNemar's test and inter-rater reliability, we compared the recommendations made by ChatGPT4 with the actual surveillance interval provided in the endoscopist's procedure report (gastroenterology practice) and the appropriate USMSTF guidance. The latter was generated for each case by an expert panel using the clinical information and guideline documents as reference. RESULTS: Text input of de-identified data into ChatGPT4 from 505 consecutive patients undergoing colonoscopy between January 1st and April 30th, 2023 elicited a successful follow-up recommendation in 99.2% of the queries. ChatGPT4 recommendations were in closer agreement with the USMSTF Panel (85.7%) than gastroenterology practice recommendations with the USMSTF Panel (75.4%) (P<.001). Of the 14.3% discordant recommendations between ChatGPT4 and USMSTF Panel, recommendations were for later screening in 26 (5.1%) and earlier screening in 44 (8.7%) cases. The inter-rater reliability was good for ChatGPT4 vs. USMSTF Panel (Fleiss κ: 0.786, CI95%: 0.734-0.838, P<.001). CONCLUSIONS: Initial real-world results suggest that ChatGPT4 can accurately define routine colonoscopy screening intervals based on verbatim input of clinical data. LLM have potential for clinical applications, but further training is needed for broad use.

Isatuximab Monotherapy for Desensitization in Highly Sensitized Patients Awaiting Kidney Transplant.

SIGNIFICANCE STATEMENT: There is no standardized desensitization regimen for kidney transplant candidates. CD38, expressed by plasma cells, could be targeted for desensitization to deplete plasma cells producing alloantibodies and donor-specific antibodies. Few studies and case reports are available regarding the use of CD38 antibodies for desensitization in patients awaiting kidney transplant. This study shows that isatuximab, a CD38-targeting therapy, was well tolerated in kidney transplant candidates, with a durable decrease in anti-HLA antibodies and partial desensitization activity. The short treatment period and long follow-up of this study allowed for the understanding of the mechanism and timing for any antibody rebound. Isatuximab could be further investigated as an option for adjunct therapy to existing desensitization for patients on the kidney transplant waitlist. BACKGROUND: Patients with calculated panel reactive antibody (cPRA) ≥80.00%, particularly those with cPRA ≥99.90%, are considered highly sensitized and underserved by the Kidney Allocation System. Desensitization removes circulating reactive antibodies and/or suppresses antibody production to increase the chances of a negative crossmatch. CD38 is expressed highly on plasma cells, thus is a potential target for desensitization. METHODS: This was an open-label single-arm phase 1/2 study investigating the safety, pharmacokinetics, and preliminary efficacy of isatuximab in patients awaiting kidney transplantation. There were two cohorts, cohorts A and B, which enrolled cPRA ≥99.90% and 80.00% to <99.90%, respectively. RESULTS: Twenty-three patients (12 cohort A, 11 cohort B) received isatuximab 10 mg/kg weekly for 4 weeks then every 2 weeks for 8 weeks. Isatuximab was well tolerated with pharmacokinetic and pharmacodynamic profiles that indicated similar exposure to multiple myeloma trials. It resulted in decreases in CD38 + plasmablasts, plasma cells, and NK cells and significant reductions in HLA-specific IgG-producing memory B cells. Overall response rate, on the basis of a predefined composite desensitization end point, was 83.3% and 81.8% in cohorts A and B. Most responders had decreases in anti-HLA antibodies that were maintained for 26 weeks after the last dose. Overall, cPRA values were minimally affected, however, with only 9/23 patients (39%) having cPRA decreases to target levels. By study cutoff (median follow-up of 68 weeks), six patients received transplant offers, of which four were accepted. CONCLUSIONS: In this open-label trial, isatuximab was well tolerated and resulted in a durable decrease in anti-HLA antibodies with partial desensitization activity. CLINICAL TRIAL REGISTRATION NUMBER: NCT04294459 .

A Preliminary Controlled Trial of Endoscopic Ultrasound-guided Fiducial Markers to Guide Pancreas Surgery.

OBJECTIVE: Endoscopic ultrasound (EUS) is routinely used for fiducial marker placement (FMP) to guide stereotactic radiation of pancreatic tumors, but EUS-FMP explicitly to guide surgery has not been studied in a prospective, controlled manner. Multipurpose EUS systems have been developed that facilitate simultaneous EUS-FMP at the time of biopsy. We aimed to evaluate the feasibility of EUS-FMP to guide pancreatic resection. METHODS: In this prospective trial, we enrolled patients with resectable pancreas masses undergoing tissue sampling and placed preloaded fiducials immediately after biopsy. Intraprocedure confirmation of carcinoma, neuroendocrine, and nonlymphomatous neoplasia by rapid on-site evaluation and lesion size <4 cm was required. The main outcomes were the feasibility and ease of preoperative placement and intraoperative detection of the markers using predefined Likert scales. RESULTS: In 20 patients, EUS-FMP was successful before planned surgery and placement was technically straightforward (Likert Scale: 9.1 ± 1.3; range: 1, most challenging to 10, most facile). Intraoperative detection was feasible and improved when compared with a pre-established comparator of 5 representing an equivalent lesion without a marker (Likert Scale: 7.8 ± 2.2; range: 1, most difficult to 10, most facile; P = 0.011). The mean tumor size on EUS was 1.7 ± 0.9 (range: 0.5 to 3.6) cm. CONCLUSION: EUS-FMP is feasible and safe for resectable pancreatic tumors before surgery and may assist in perioperative detection. Preloaded fiducials may be considered for placement at the time of initial referral for EUS-fine needle biopsy.

Underwater versus conventional endoscopic mucosal resection for colorectal lesions: An updated meta-analysis of randomized controlled trials.

Background and study aims Colorectal malignancy is a leading cause of death. Conventional endoscopic mucosal resection (CEMR) is a strategy used to resect precancerous lesions that involves injecting fluid beneath a polyp to create a gap for resection. Underwater endoscopic mucosal resection (UEMR) is a newer method that forgoes injection, instead filling the intestinal cavity with water to facilitate polyp resection. Our aim was to compare the safety and efficacy of these approaches by synthesizing the most contemporary evidence. Methods PubMed, Embase, and Cochrane libraries were searched from inception through November 11, 2022 for randomized controlled trials (RCTs) comparing UEMR and CEMR for resection of colorectal lesions. The primary outcome was the rate of en bloc resection and secondary outcomes included recurrence, procedure time, and adverse events (AEs). Results A total of 2539 studies were identified through our systematic literature search. After screening, seven RCTs with a total of 1581 polyps were included. UEMR was associated with significantly increased rates of en bloc resection (RR 1.18 [1.03, 1.35]; I 2 = 76.6%) versus conventional approaches. No significant differences were found in procedure time, recurrence, or AEs. Conclusions UEMR is a promising effective technique for removal of colorectal lesions. The most contemporary literature indicates that it improves en bloc resection rate without increasing procedure time, recurrence, or AEs (PROSPERO ID CRD42022374935).

Assessing the safety of deep sedation in outpatient pediatric oral health care.

BACKGROUND: Children are the patient subgroup with the lowest error tolerance regarding deep sedation (DS)-supported care. This study assessed the safety of DS-supported pediatric dental treatment carried out in an outpatient setting through retrospective review of patient charts. METHODS: An automated script was developed to identify charts of pediatric patients who underwent DS-supported dental procedures from 2017 through 2019 at a dental clinic. Charts were assessed for the presence of sedation-related adverse events (AEs). A panel of experts performed a second review and confirmed or refuted the designation of AE (by the first reviewer). AEs were classified with the Tracking and Reporting Outcomes of Procedural Sedation system. RESULTS: Of the 175 DS cases, 19 AEs were identified in 15 cases (8.60%). Using the Tracking and Reporting Outcomes of Procedural Sedation classification system, 7 (36.84%) events were related to the airway and breathing category, 9 (47.37%) were related to sedation quality (including a dizzy patient who fell at the checkout desk and sustained a head laceration), and 3 (15.79%) were classified as an allergy. CONCLUSION: This study suggests an AE (whether relatively minor or of potentially major consequence) occurs in 1 of every 12 DS cases involving pediatric patients, performed at an outpatient dental clinic. Larger studies are needed, in addition to root cause analyses. PRACTICAL IMPLICATIONS: As dentists increasingly pivot in the use of DS services from in-hospital to outpatient settings, patients expect comparable levels of safety. This work helps generate evidence to drive targeted efforts to improve the safety and reliability of pediatric outpatient sedation.

Oral Health Behaviors for Young Low-Income Urban Children during the COVID-19 Pandemic: A Mixed Methods Analysis.

This research assessed oral health behaviors changes in urban families with young children during the stay-at-home period of the COVID-19 pandemic (Nov 2020-August 2021). Survey data on oral health behaviors were collected in homes at three points before COVID-19, and via phone during COVID-19. A subset of parents and key informants from clinics and social service agencies completed in-depth interviews via video/phone. Of the 387 parents invited, 254 completed surveys in English or Spanish (65.6%) during COVID-19. Fifteen key informant interviews (25 participants) and 21 family interviews were conducted. The mean child age was 4.3 years. Children identified as mainly Hispanic (57%) and Black race (38%). Parents reported increased child tooth brushing frequency during the pandemic. Family interviews highlighted changes in family routines that impacted oral health behaviors and eating patterns, suggesting less optimal brushing and nutrition. This was linked to changed home routines and social presentability. Key informants described major disruptions in oral health services, family fear, and stress. In conclusion, the stay-at-home period of the COVID-19 pandemic was a time of extreme routine change and stress for families. Oral health interventions that target family routines and social presentability are important for families during times of extreme crisis.

Association between neighborhood disadvantage and children's oral health outcomes in urban families in the Chicago area.

Purpose: The prevalence of childhood caries in urban Chicago, compared with national and state data, indicates that neighborhood context influences oral health. Our objective was to delineate the influence of a child's neighborhood on oral health outcomes that are predictive of caries (toothbrushing frequency and plaque levels). Methods: Our study population represents urban, Medicaid-enrolled families in the metropolitan Chicago area. Data were obtained from a cohort of participants (child-parent dyads) who participated in the Coordinated Oral Health Promotion (CO-OP) trial at 12 months of study participation (N = 362). Oral health outcomes included toothbrushing frequency and plaque levels. Participants' neighborhood resource levels were measured by the Area Deprivation Index (ADI). Linear and logistic regression models were used to measure the influence of ADI on plaque scores and toothbrushing frequency, respectively. Results: Data from 362 child-parent dyads were analyzed. The mean child age was 33.6 months (SD 6.8). The majority of children were reported to brush at least twice daily (n = 228, 63%), but the mean plaque score was 1.9 (SD 0.7), classified as "poor." In covariate-adjusted analyses, ADI was not associated with brushing frequency (0.94, 95% CI 0.84-1.06). ADI was associated with plaque scores (0.05, 95% CI 0.01-0.09, p value = 0.007). Conclusions: Findings support the hypothesis that neighborhood-level factors influence children's plaque levels. Because excessive plaque places a child at high risk for cavities, we recommend the inclusion of neighborhood context in interventions and policies to reduce children's oral health disparities. Existing programs and clinics that serve disadvantaged communities are well-positioned to support caregivers of young children in maintaining recommended oral health behaviors.

Oral health behaviors for young low-income urban children during the COVID-19 pandemic: a mixed methods analysis.

This research assessed oral health behaviors changes in urban families with young children during the stay-at-home period of the COVID-19 pandemic. Survey data on oral health behaviors were collected in homes at three points over one year before COVID-19, and then via phone during COVID-19. Multivariate logistic regression was used to model tooth brushing frequency. A subset of parents completed in-depth interviews via video/phone that expanded on oral health and COVID-19. Key informant interviews via video/phone were also conducted with leadership from 20 clinics and social service agencies. Interview data were transcribed and coded, and themes were extracted. COVID-19 data collection went from Nov 2020 - August 2021. Of the 387 parents invited, 254 completed surveys in English or Spanish (65.6%) during COVID-19. Fifteen key informant (25 participants) and 21 parent interviews were conducted. The mean child age was approximately 4.3 years. Children identified as mainly Hispanic (57%) and Black race (38%). Parents reported increased child tooth brushing frequency during the pandemic. Parent interviews highlighted significant changes in family routines that impacted oral health behaviors and eating patterns, suggesting less optimal brushing and nutrition. This was linked to changed home routines and social presentability. Key informants described major disruptions in their oral health services and significant family fear and stress. In conclusion, the stay-at-home period of the COVID-19 pandemic was a time of extreme routine change and stress for families. Oral health interventions that target family routines and social presentability are important for families during times of extreme crisis.

An immediate way to lower pandemic risk: (not) seizing the low-hanging fruit (bat).

What is the least that humanity can do to mitigate the risks of future pandemics, to prevent worldwide surges in human deaths, illness, and suffering-and more waves of multitrillion US dollar impacts on the global economy? The issues around our consumption and trading of wildlife are diverse and complex, with many rural communities being dependent on wild meat for their nutritional needs. But bats might be one taxonomic group that can be successfully eliminated from the human diet and other uses, with minimal costs or inconvenience to the vast majority of the 8 billion people on Earth. The order Chiroptera merits genuine respect given all that these species contribute to human food supplies through pollination services provided by the frugivores and to disease risk mitigation delivered by insectivorous species. The global community missed its chance to stop SARS-CoV and SARS-CoV-2 from emerging-how many more times will humanity allow this cycle to repeat? How long will governments ignore the science that is in front of them? It's past time for humans to do the least that can be done. A global taboo is needed whereby humanity agrees to leave bats alone, not fear them or try to chase them away or cull them, but to let them have the habitats they need and live undisturbed by humans.

Toddlers at Elevated Likelihood for Autism: Exploring Sensory and Language Treatment Predictors.

Baseline child characteristics may predict treatment outcomes in children with or at elevated likelihood of developing autism (EL-ASD). Little is known about the role of child sensory and language features on treatment outcome. Participants were randomly assigned to a parent-mediated intervention or control condition. Analyses explored the relationship between baseline child sensory and language characteristics and changes in ASD symptoms over approximately 9 months. Higher baseline sensory hyporeactivity was significantly related to less improvement in social communication (SC) for the treatment group only. More baseline atypical vocalizations were significantly related to less improvement on SC across treatment and control groups. This work provides an initial framework to encourage the tailoring of interventions for EL-ASD children, suggesting sensory reactivity and atypical vocalizations may be useful behaviors to consider in treatment planning.

Scoping review of behavioral coding measures used to evaluate parent responsiveness of children with autism or elevated risk of autism.

LAY ABSTRACT: The topic of how parents react (e.g., how they talk and act) to their child with autism or elevated likelihood of autism, often called parent responsiveness, has been studied by researchers for over 50 years. Many methods for measuring behaviors around parent responsiveness have been created depending on what researchers were interested in discovering. For example, some include only the behaviors that the parent does/says in reacting to something the child does/says. Other systems look at all behaviors in a period of time between child and parent (e.g., who talked/acted first, how much the child or parent said/did). The purpose of this article was to provide a summary of how and what researchers looked at around parent responsiveness, describe the strengths and barriers of these approaches, and suggest a "best practices" method of looking at parent responsiveness. The model suggested could make it more possible to look across studies to compare study methods and results. The model could be used in the future by researchers, clinicians, and policymakers to provide more effective services to children and their families.

Diversity, equity, and inclusion within the Society for Pediatric Anesthesia: A mixed methods assessment.

BACKGROUND: Leadership of the Society for Pediatric Anesthesia created the Diversity, Equity, and Inclusion committee in 2018 to prioritize diversity work. The Society for Pediatric Anesthesia-Diversity, Equity, and Inclusion committee implemented a baseline survey of the Society for Pediatric Anesthesia membership in 2020 to assess demographics, equity in leadership, inclusivity, and attitudes toward diversity work. The Society for Pediatric Anesthesia plays a significant role in shaping the future of pediatric anesthesiology and in supporting our diverse pediatric patients. METHODS: This study is an IRB-exempt, cross-sectional survey of the Society for Pediatric Anesthesia membership. Quantitative analysis provided descriptive statistics of demographics, practice characteristics, and involvement within the Society for Pediatric Anesthesia. Qualitative thematic analysis provided an in-depth assessment of perceptions of diversity, challenges faced, and prioritization of Diversity, Equity, and Inclusion efforts within the Society for Pediatric Anesthesia. RESULTS: Out of 3 242 Society for Pediatric Anesthesia members, 1 232 completed the survey representing 38% of overall membership. Respondents were 89.2% United States members, 52.7% female, 55.7% non-Hispanic White, 88.6% heterosexual, 95.7% non-military, 59.2% religious, and 2.1% have an Americans with Disabilities Act recognized disability. All major United States geographical areas were represented equally with 71% practicing in urban areas and 67% in academic settings. Ethnic/racial minorities were more likely to be international medical graduates (p < .001). Among United States members, 41.5% report being fluent in a language other than English, and 23.5% of those fluent in another language are certified to interpret. Compared to men, women are less likely to be in leadership roles (p < .003), but we found no difference in participation and leadership when stratified by race/ethnicity, geography, international medical graduate status, or sexuality. Racial/ethnic minorities (p < .028), women (p < .001), and lesbian, gay, bisexual, transgender, and queer members (p < .044) more frequently hold lower academic rank positions when compared to white, heterosexual, and male members. Half of respondents were unsure whether diversity, equity, and inclusion challenges existed within the Society for Pediatric Anesthesia while the other half demonstrated opposing views. Among those who reported diversity, equity, and inclusion challenges, the themes centered around persistent marginalization, the need for more inclusive policies and increased psychological safety, and lack of leadership diversity. CONCLUSIONS: Compared to the diversity of the pediatric population we serve, there are still significant gaps in demographic representation within the Society for Pediatric Anesthesia. As well, there is no consensus among Society for Pediatric Anesthesia membership regarding perceptions of diversity, equity, and inclusion in pediatric anesthesia in the United States. Among those who reported diversity challenges, opportunities for the Society for Pediatric Anesthesia and Anesthesiology Departments to better support minoritized members included bolstering workforce diversity efforts and awareness via more inclusive policies, improved psychological safety, and increasing diversity in leadership. If pediatric anesthesiology is like other specialties, gaining consensus and improving diversity in the workforce might advance pediatric anesthesia innovation, quality, and safety for children of all backgrounds in the United States.

Evaluating the Women's Empowerment and Leadership Initiative: Supporting mentorship, career satisfaction, and well-being among pediatric anesthesiologists.

The Society for Pediatric Anesthesia launched the Women's Empowerment and Leadership Initiative (WELI) in 2018 to empower highly productive women pediatric anesthesiologists to achieve equity, promotion, and leadership. WELI is focused on six career development domains: promotion and leadership, networking, conceptualization and completion of projects, mentoring, career satisfaction, and sense of well-being. We sought feedback about whether WELI supported members' career development by surveys emailed in November 2020 (baseline), May 2021 (6 months), and January 2022 (14 months). Program feedback was quantitatively evaluated by the Likert scale questions and qualitatively evaluated by extracting themes from free-text question responses. The response rates were 60.5% (92 of 152) for the baseline, 51% (82 of 161) for the 6-month, and 52% (96 of 185) for the 14-month surveys. Five main themes were identified from the free-text responses in the 6- and 14-month surveys. Members reported that WELI helped them create meaningful connections through networking, obtain new career opportunities, find tools and projects that supported their career advancement and promotion, build the confidence to try new things beyond their comfort zone, and achieve better work-life integration. Frustration with the inability to connect in-person during the coronavirus-19 pandemic was highlighted. Advisors further stated that WELI helped them improve their mentorship skills and gave them insight into early career faculty issues. Relative to the baseline survey, protégés reported greater contributions from WELI at 6 months in helping them clarify their priorities, increase their sense of achievement, and get promoted. These benefits persisted through 14 months. Advisors reported a steady increase in forming new meaningful relationships and finding new collaborators through WELI over time. All the members reported that their self-rated mentoring abilities improved at 6 months with sustained improvement at 14 months. Thus, programs such as WELI can assist women anesthesiologists and foster gender equity in career development, promotion, and leadership.

Community health worker intervention to improve tooth brushing in young children: Results from a cluster randomized controlled trial.

OBJECTIVES: Coordinated Oral health Promotion (CO-OP) Chicago is a cluster randomized controlled trial testing the efficacy of a community health worker (CHW) intervention to improve tooth brushing in low-income children. METHODS: Four hundred twenty children under 3 years old (mean 21.5 months) were recruited from 20 sites in or near Chicago, IL. Children were identified mainly as Black race (41.9%) or Hispanic ethnicity (53.8%) and most (85.2%) had Medicaid. Intervention families were offered four CHW home visits over 1 year. Brushing frequency was self-reported. Plaque score was determined from images collected in homes using disclosing solution. Analyses used GEE logistic models with variable selection at p < .05. RESULTS: At enrolment, 45.0% of families reported twice a day or more child brushing frequency, and child plaque scores were poor (mean of 1.9, SD: 0.6). Data were obtained from 87.1% of children at 6 months and 86.2% at 12 months. In the CHW intervention arm (10 sites, N = 211), 23.7% received 4 visits, 12.8% 3 visits, 21.3% 2 visits, 23.2% 1 visit and 19% no visits from CHWs. No intervention effect was seen for brushing frequency or plaque score. Child brushing frequency improvement over time was associated with a range of child and caregiver factors. The only factor associated with a change in plaque score over time was parent involvement in brushing. CONCLUSIONS: Oral-health-specific CHW services were not associated with improved brushing behaviours in these young children. However, caregiver involvement with brushing supported more quality brushing. More robust interventions are needed to support families during this critical developmental period.

Supratherapeutic Infliximab Levels Do Not Predict Risk of Short-term Complications in Adults With Crohn's Disease.

BACKGROUND: It is uncertain if higher infliximab trough levels (TLs) confer a greater risk of infectious/noninfectious complications (IC/NIC). We aimed to assess the risk of IC and NIC in patients with different TLs. METHODS: We retrospectively evaluated a cohort of Crohn's disease (CD) patients treated with infliximab who underwent therapeutic drug monitoring (TDM), at a tertiary inflammatory bowel disease center, between January 1, 2010, and December 1, 2019. TDM was defined as checking of infliximab trough and antibody levels within a 48-hour period before administration. Patients with a minimum of 3-month assessment pre-TDM and post-TDM were included. In the case of multiple TDMs, the highest TL was considered, and patients were distributed across 4 predefined TL groups (A: <5 µg/mL, B: 5 to 10 µg/mL, C: 10 to 15 µg/mL, and D: ≥15 µg/mL). Rates of IC and NIC during the 3-month prior and following TDM were compared across the groups. In addition, duration of exposure, in terms of months up to TDM, was collected to analyze differences in rates of IC and NIC. RESULTS: Our study included 341 CD patients (median age: 35 y, 58% men). IC and NIC occurred in 52 (15%) and 30 (9%) patients, respectively. Rates of IC and NIC were similar across the 4 TL groups ( P =0.9 and 0.7, respectively for IC and NIC). On multivariable analysis, exposure to infliximab >40 months (as determined by receiver operating characteristic curve analysis) was associated with decreased odds for IC (adjusted odds ratio=0.51, P =0.04), but not NIC (adjusted odds ratio=0.72, P =0.46). CONCLUSIONS: In this large CD cohort, there was no association between infliximab TL and risk of short-term IC or NIC. Interestingly, a shorter duration of exposure predicted higher rates of IC. This supports the safety of targeting higher infliximab TLs when necessary and greater vigilance during the early stages of treatment.

Epidemiology and genomics of a slow outbreak of methicillin-resistant Staphyloccus aureus (MRSA) in a neonatal intensive care unit: Successful chronic decolonization of MRSA-positive healthcare personnel.

OBJECTIVE: To describe the genomic analysis and epidemiologic response related to a slow and prolonged methicillin-resistant Staphylococcus aureus (MRSA) outbreak. DESIGN: Prospective observational study. SETTING: Neonatal intensive care unit (NICU). METHODS: We conducted an epidemiologic investigation of a NICU MRSA outbreak involving serial baby and staff screening to identify opportunities for decolonization. Whole-genome sequencing was performed on MRSA isolates. RESULTS: A NICU with excellent hand hygiene compliance and longstanding minimal healthcare-associated infections experienced an MRSA outbreak involving 15 babies and 6 healthcare personnel (HCP). In total, 12 cases occurred slowly over a 1-year period (mean, 30.7 days apart) followed by 3 additional cases 7 months later. Multiple progressive infection prevention interventions were implemented, including contact precautions and cohorting of MRSA-positive babies, hand hygiene observers, enhanced environmental cleaning, screening of babies and staff, and decolonization of carriers. Only decolonization of HCP found to be persistent carriers of MRSA was successful in stopping transmission and ending the outbreak. Genomic analyses identified bidirectional transmission between babies and HCP during the outbreak. CONCLUSIONS: In comparison to fast outbreaks, outbreaks that are "slow and sustained" may be more common to units with strong existing infection prevention practices such that a series of breaches have to align to result in a case. We identified a slow outbreak that persisted among staff and babies and was only stopped by identifying and decolonizing persistent MRSA carriage among staff. A repeated decolonization regimen was successful in allowing previously persistent carriers to safely continue work duties.

Use of heparin to rescue immunosuppressive monocyte reprogramming by glioblastoma-derived extracellular vesicles.

OBJECTIVE: The profound immunosuppression found in glioblastoma (GBM) patients is a critical barrier to effective immunotherapy. Multiple mechanisms of tumor-mediated immune suppression exist, and the induction of immunosuppressive monocytes such as myeloid-derived suppressor cells (MDSCs) is increasingly appreciated as a key part of this pathology. GBM-derived extracellular vesicles (EVs) can induce the formation of MDSCs. The authors sought to identify the molecular consequences of these interactions in myeloid cells in order to identify potential targets that could pharmacologically disrupt GBM EV-monocyte interaction as a means to ameliorate tumor-mediated immune suppression. Heparin-sulfate proteoglycans (HSPGs) are a general mechanism by which EVs come into association with their target cells, and soluble heparin has been shown to interfere with EV-HSPG interactions. The authors sought to assess the efficacy of heparin treatment for mitigating the effects of GBM EVs on the formation of MDSCs. METHODS: GBM EVs were collected from patient-derived cell line cultures via staged ultracentrifugation and cocultured with monocytes collected from apheresis cones from healthy blood donors. RNA was isolated from EV-conditioned and unconditioned monocytes after 72 hours of coculture, and RNA-sequencing analysis performed. For the heparin treatment studies, soluble heparin was added at the time of EV-monocyte coculture and flow cytometry analysis was performed 72 hours later. After the initial EV-monocyte coculture period, donor-matched T-cell coculture studies were performed by adding fluorescently labeled and stimulated T cells for 5 days of coculture. RESULTS: Transcriptomic analysis of GBM EV-treated monocytes demonstrated downregulation of several important immunological and metabolic pathways, with upregulation of the pathways associated with synthesis of cholesterol and HSPG. Heparin treatment inhibited association between GBM EVs and monocytes in a dose-dependent fashion, which resulted in a concomitant reduction in MDSC formation (p < 0.01). The authors further demonstrated that reduced MDSC formation resulted in a partial rescue of immune suppression, as measured by effects on activated donor-matched T cells (p < 0.05). CONCLUSIONS: The authors demonstrated that GBM EVs induce broad but reproducible reprogramming in monocytes, with enrichment of pathways that may portend an immunosuppressive phenotype. The authors further demonstrated that GBM EV-monocyte interactions are potentially druggable targets for overcoming tumor-mediated immune suppression, with heparin inhibition of EV-monocyte interactions demonstrating proof of principle.

Sequence-specific capture and concentration of viral RNA by type III CRISPR system enhances diagnostic.

Type-III CRISPR-Cas systems have recently been adopted for sequence-specific detection of SARS-CoV-2. Here, we repurpose the type III-A CRISPR complex from Thermus thermophilus (TtCsm) for programmable capture and concentration of specific RNAs from complex mixtures. The target bound TtCsm complex generates two cyclic oligoadenylates (i.e., cA3 and cA4) that allosterically activate ancillary nucleases. We show that both Can1 and Can2 nucleases cleave single-stranded RNA, single-stranded DNA, and double-stranded DNA in the presence of cA4. We integrate the Can2 nuclease with type III-A RNA capture and concentration for direct detection of SARS-CoV-2 RNA in nasopharyngeal swabs with 15 fM sensitivity. Collectively, this work demonstrates how type-III CRISPR-based RNA capture and concentration simultaneously increases sensitivity, limits time to result, lowers cost of the assay, eliminates solvents used for RNA extraction, and reduces sample handling.