Large Clusters of Invasive emm49 Group A Streptococcus Identified within and across Arizona Healthcare Facilities through Statewide Genomic Surveillance System, 2019-2021.

A statewide genomic surveillance system for invasive Group A Streptococcus was implemented in Arizona in June 2019, resulting in 1,046 isolates being submitted for genomic analysis to characterize emm-types and identify transmission clusters. Eleven of the 32 identified distinct emm-types comprised >80% of samples, with 29.7% of all isolates being typed as emm49 (and its genetic derivative emm151). Phylogenetic analysis initially identified an emm49 genomic cluster of four isolates that rapidly expanded over subsequent months (June 2019-February 2020). Public health investigations identified epidemiologic links with three different long-term care facilities, resulting in specific interventions. Unbiased genomic surveillance allowed for identification and response to clusters that would have otherwise remained undetected.

Complex balanced intrachromosomal rearrangement involving PITX2 identified as a cause of Axenfeld-Rieger Syndrome.

Axenfeld-Rieger Syndrome (ARS) type 1 is a rare autosomal dominant condition characterized by anterior chamber anomalies, umbilical defects, dental hypoplasia, and craniofacial anomalies, with Meckel's diverticulum in some individuals. Here, we describe a clinically ascertained female of childbearing age with ARS for whom clinical targeted sequencing and deletion/duplication analysis followed by clinical exome and genome sequencing resulted in no pathogenic variants or variants of unknown significance in PITX2 or FOXC1. Advanced bioinformatic analysis of the genome data identified a complex, balanced rearrangement disrupting PITX2. This case is the first reported intrachromosomal rearrangement leading to ARS, illustrating that for patients with compelling clinical phenotypes but negative genomic testing, additional bioinformatic analysis are essential to identify subtle genomic abnormalities in target genes.

The Deterioration Risk Index: Developing and Piloting a Machine Learning Algorithm to Reduce Pediatric Inpatient Deterioration.

OBJECTIVES: Develop and deploy a disease cohort-based machine learning algorithm for timely identification of hospitalized pediatric patients at risk for clinical deterioration that outperforms our existing situational awareness program. DESIGN: Retrospective cohort study. SETTING: Nationwide Children's Hospital, a freestanding, quaternary-care, academic children's hospital in Columbus, OH. PATIENTS: All patients admitted to inpatient units participating in the preexisting situational awareness program from October 20, 2015, to December 31, 2019, excluding patients over 18 years old at admission and those with a neonatal ICU stay during their hospitalization. INTERVENTIONS: We developed separate algorithms for cardiac, malignancy, and general cohorts via lasso-regularized logistic regression. Candidate model predictors included vital signs, supplemental oxygen, nursing assessments, early warning scores, diagnoses, lab results, and situational awareness criteria. Model performance was characterized in clinical terms and compared with our previous situational awareness program based on a novel retrospective validation approach. Simulations with frontline staff, prior to clinical implementation, informed user experience and refined interdisciplinary workflows. Model implementation was piloted on cardiology and hospital medicine units in early 2021. MEASUREMENTS AND MAIN RESULTS: The Deterioration Risk Index (DRI) was 2.4 times as sensitive as our existing situational awareness program (sensitivities of 53% and 22%, respectively; p < 0.001) and required 2.3 times fewer alarms per detected event (121 DRI alarms per detected event vs 276 for existing program). Notable improvements were a four-fold sensitivity gain for the cardiac diagnostic cohort (73% vs 18%; p < 0.001) and a three-fold gain (81% vs 27%; p < 0.001) for the malignancy diagnostic cohort. Postimplementation pilot results over 18 months revealed a 77% reduction in deterioration events (three events observed vs 13.1 expected, p = 0.001). CONCLUSIONS: The etiology of pediatric inpatient deterioration requires acknowledgement of the unique pathophysiology among cardiology and oncology patients. Selection and weighting of diverse candidate risk factors via machine learning can produce a more sensitive early warning system for clinical deterioration. Leveraging preexisting situational awareness platforms and accounting for operational impacts of model implementation are key aspects to successful bedside translation.

Investigation of SARS-CoV-2 Transmission Associated With a Large Indoor Convention - New York City, November-December 2021.

During November 19-21, 2021, an indoor convention (event) in New York City (NYC), was attended by approximately 53,000 persons from 52 U.S. jurisdictions and 30 foreign countries. In-person registration for the event began on November 18, 2021. The venue was equipped with high efficiency particulate air (HEPA) filtration, and attendees were required to wear a mask indoors and have documented receipt of at least 1 dose of a COVID-19 vaccine.* On December 2, 2021, the Minnesota Department of Health reported the first case of community-acquired COVID-19 in the United States caused by the SARS-CoV-2 B.1.1.529 (Omicron) variant in a person who had attended the event (1). CDC collaborated with state and local health departments to assess event-associated COVID-19 cases and potential exposures among U.S.-based attendees using data from COVID-19 surveillance systems and an anonymous online attendee survey. Among 34,541 attendees with available contact information, surveillance data identified test results for 4,560, including 119 (2.6%) persons from 16 jurisdictions with positive SARS-CoV-2 test results. Most (4,041 [95.2%]), survey respondents reported always wearing a mask while indoors at the event. Compared with test-negative respondents, test-positive respondents were more likely to report attending bars, karaoke, or nightclubs, and eating or drinking indoors near others for at least 15 minutes. Among 4,560 attendees who received testing, evidence of widespread transmission during the event was not identified. Genomic sequencing of 20 specimens identified the SARS-CoV-2 B.1.617.2 (Delta) variant (AY.25 and AY.103 sublineages) in 15 (75%) cases, and the Omicron variant (BA.1 sublineage) in five (25%) cases. These findings reinforce the importance of implementing multiple, simultaneous prevention measures, such as ensuring up-to-date vaccination, mask use, physical distancing, and improved ventilation in limiting SARS-CoV-2 transmission, during large, indoor events.†.

Impact of integrated translational research on clinical exome sequencing.

PURPOSE: Exome sequencing often identifies pathogenic genetic variants in patients with undiagnosed diseases. Nevertheless, frequent findings of variants of uncertain significance necessitate additional efforts to establish causality before reaching a conclusive diagnosis. To provide comprehensive genomic testing to patients with undiagnosed disease, we established an Individualized Medicine Clinic, which offered clinical exome testing and included a Translational Omics Program (TOP) that provided variant curation, research activities, or research exome sequencing. METHODS: From 2012 to 2018, 1101 unselected patients with undiagnosed diseases received exome testing. Outcomes were reviewed to assess impact of the TOP and patient characteristics on diagnostic rates through descriptive and multivariate analyses. RESULTS: The overall diagnostic yield was 24.9% (274 of 1101 patients), with 174 (15.8% of 1101) diagnosed on the basis of clinical exome sequencing alone. Four hundred twenty-three patients with nondiagnostic or without access to clinical exome sequencing were evaluated by the TOP, with 100 (9% of 1101) patients receiving a diagnosis, accounting for 36.5% of the diagnostic yield. The identification of a genetic diagnosis was influenced by the age at time of testing and the disease phenotype of the patient. CONCLUSION: Integration of translational research activities into clinical practice of a tertiary medical center can significantly increase the diagnostic yield of patients with undiagnosed disease.

Comparison of live birth rates after IVF-embryo transfer with and without preimplantation genetic testing for aneuploidies.

RESEARCH QUESTION: Does the use of preimplantation genetic testing for aneuploidies (PGT-A) result in higher live birth rates when compared with both fresh and frozen embryo transfers (FET) not utilizing PGT-A? DESIGN: Retrospective cohort study at a single tertiary centre using inverse probability of treatment weighting (IPTW) to adjust for differences in baseline characteristics between groups. RESULTS: A total of 107 FET using PGT-A from 74 patients, along with 321 fresh and 286 FET not using PGT-A from 381 patients met the inclusion criteria for this study. In the IPTW-adjusted analysis of transfer-level data, PGT-A transfers resulted in a significantly higher live birth rate when compared with both non-PGT-A fresh (49.5% versus 38.6%, P = 0.036) and FET (50.6% versus 35.8%, P = 0.016). When data were analysed per retrieval level, the live birth rate was similar and acceptably high with or without PGT-A (63.7% versus 52.3%, P = 0.09). CONCLUSION: When comparing PGT-A to non-PGT-A fresh and FET, PGT-A embryo transfers have a significantly higher live birth rate. However, this difference did not persist at a per-retrieval level. Further investigation is needed to understand in what scenarios PGT-A has clinical significance and whether differences in the number of available embryos for transfer negates the benefit of PGT-A.

Examining career shadowing in genetic counseling: Perspectives of shadowees, program directors, and genetic counselors.

Career shadowing can be a valuable opportunity for individuals to experience the daily activities of a working professional. However, there is no published research regarding the impact of shadowing for individuals hoping to pursue a career as a genetic counselor (GC) (termed 'shadowees'). Additionally, little is known about the impact of shadowing on practicing GCs, nor the value of shadowing in the application and admission process for genetic counseling graduate programs. For this study, three independent surveys were developed and sent to three stakeholder groups: shadowees in the Minnesota Genetic Counseling Experience Program, program directors within the Association of Genetic Counseling Program Directors, and members of the National Society of Genetic Counselors. Quantitative and qualitative analyses were performed on responses. The survey of shadowees (n = 55) found that the majority believed that shadowing had either a 'very' or 'somewhat positive' impact on their decision to become a GC and on their application to a genetic counseling graduate program (81.8% and 91.3%, respectively). Of the participating program director respondents (n = 43), the majority indicated that having shadowing experience was either 'moderately' or 'extremely important' in offering an interview or for acceptance into a graduate program (63% and 56%, respectively). While programs differ in evaluation of shadowing experiences, most program directors indicated that an applicant's ability to speak to their shadowing experience was the most important factor in admissions consideration (71%). Among the GCs surveyed (n = 325), 69.2% have hosted shadowees; of these, 82.7% indicated that hosting a shadowee decreases their efficiency at work. Despite this drawback, the majority of respondents expressed a willingness and motivation to host shadowees to help the shadowee (64.8%) and to promote the genetic counseling profession (32.6%). These findings suggest the need for additional research and the development of resources for GCs to increase access of career shadowing.

Fetal glycosylation defect due to ALG3 and COG5 variants detected via amniocentesis: Complex glycosylation defect with embryonic lethal phenotype.

INTRODUCTION: Congenital disorders of glycosylation (CDG) are inborn errors of glycan metabolism with high clinical variability. Only a few antenatal cases have been described with CDG. Due to a lack of reliable biomarker, prenatal CDG diagnostics relies primarily on molecular studies. In the presence of variants of uncertain significance prenatal glycosylation studies are very challenging. CASE REPORT: A consanguineous couple had a history of second-trimester fetal demise with tetralogy of Fallot and skeletal dysplasia. In the consecutive pregnancy, the second trimester ultrasonography showed skeletal dysplasia, vermian hypoplasia, congenital heart defects, omphalocele and dysmorphic features. Prenatal chromosomal microarray revealed a large region of loss of heterozygosity. Demise occurred at 30 weeks. Fetal whole exome sequencing showed a novel homozygous likely pathogenic variant in ALG3 and a variant of uncertain significance in COG5. METHODS: Western blot was used to quantify ALG3, COG5, COG6, and the glycosylation markers ICAM-1 and LAMP2. RT-qPCR was used for ALG3 and COG5 expression in cultured amniocytes and compared to age matched controls. RESULTS: ALG3 and COG5 mRNA levels were normal. ICAM-1, LAMP2, ALG3 and COG5 levels were decreased in cultured amniocytes, suggesting the possible involvement of both genes in the complex phenotype. CONCLUSION: This is the first case of successful use of glycosylated biomarkers in amniocytes, providing further options of functional antenatal testing in CDG.

Counseling Close to Home: Genetic Counselors' Experiences with their own Family Members.

Genetic counselors are trained to provide personalized genetic information and support to clients and their families. When requests for counseling comes from the counselor's own family member, should that counselor still provide service? There is a paucity of literature regarding genetic counselors counseling their own family members and no specific recommendations regarding how to reply to requests for genetic information from relatives. The purpose of this mixed methods study was to report genetic counselors' and genetic counseling students' perspectives and experiences providing genetic counseling to relatives. In the present study, 423 genetic counselors and genetic counseling students completed a 70-item web-based survey that explored genetic counselors' experiences counseling family members outside of a clinic setting. The majority (73%; n = 301/410) of respondents have been asked to provide genetic counseling. Over half (57%; n = 257/423) provided counseling, personalized genetic information or risk assessment to family members. Only a small fraction of respondents (11%; n = 45/420) responded that they received any formal training in their graduate education, or in any other capacity that addressed the issue of how genetic counselors should respond to genetic counseling requests made family members. Those who have were less likely to provide genetic counseling to a family member (p < 0.05). Respondents who provided genetic counseling to relatives were significantly more likely to think their colleagues would do the same. Those who never provided genetic counseling to relatives were more likely to think their colleagues would refer to an unrelated genetic counselor (p < 0.0001). We highlight how our results have clinical and professional implications and provide suggestions to generate discussion among genetic counselors on how they might respond to requests for counseling from family members.

Development and implementation of an electronic health record generated surgical handoff and rounding tool.

Electronic health records (EHR) have been adopted across the nation at tremendous effort and expense. The purpose of this study was to assess improvements in accuracy, efficiency, and patient safety for a high-volume pediatric surgical service with adoption of an EHR-generated handoff and rounding list. The quality and quantity of errors were compared pre- and post-EHR-based list implementation. A survey was used to determine time spent by team members using the two versions of the list. Perceived utility, safety, and quality of the list were reported. Serious safety events determined by the hospital were also compared for the two periods. The EHR-based list eliminated clerical errors while improving efficiency by automatically providing data such as vital signs. Survey respondents reported 43 min saved per week per team member, translating to 372 work hours of time saved annually for a single service. EHR-based list users reported higher satisfaction and perceived improvement in efficiency, accuracy, and safety. Serious safety events remained unchanged. In conclusion, creation of an EHR-based list to assist with daily handoffs, rounding, and patient management demonstrated improved accuracy, increased efficiency, and assisted in maintaining a high level of safety.

Notes at your fingertips: Open note considerations regarding pediatric and adolescent care.

The clinician's note serves an increasing number of audiences, the most recent addition being the patient and, in the case of pediatrics, the parent/guardian. The early work of the OpenNotes initiative followed by the recently enacted 21st Century Cures Act Information Blocking Rule has mandated easy and timely electronic access to notes involving their clinical care. While many benefits have already been described and most drawbacks unrealized, the care of pediatric and adolescent patients brings unique challenges to enable this functionality while preserving patient, parent, and family confidentiality. Given statewide variability in affording these protections, there remains a technological gap in uniformly assisting clinicians to do the right thing while remaining compliant with the law. More research is needed on the impact and new workflow considerations for using an open notes approach across care settings and within academic institutions. Additional education and training are needed to adapt note writing to accommodate patient understanding and encourage patient engagement while conveying the complexity of medical decision making. As transparency and shared medical decision-making become more prevalent within medicine, clinicians' communication and documentation styles need to evolve to meet that challenge.

The Vitals Risk Index-Retrospective Performance Analysis of an Automated and Objective Pediatric Early Warning System.

INTRODUCTION: Pediatric in-hospital cardiac arrests and emergent transfers to the pediatric intensive care unit (ICU) represent a serious patient safety concern with associated increased morbidity and mortality. Some institutions have turned to the electronic health record and predictive analytics in search of earlier and more accurate detection of patients at risk for decompensation. METHODS: Objective electronic health record data from 2011 to 2017 was utilized to develop an automated early warning system score aimed at identifying hospitalized children at risk of clinical deterioration. Five vital sign measurements and supplemental oxygen requirement data were used to build the Vitals Risk Index (VRI) model, using multivariate logistic regression. We compared the VRI to the hospital's existing early warning system, an adaptation of Monaghan's Pediatric Early Warning Score system (PEWS). The patient population included hospitalized children 18 years of age and younger while being cared for outside of the ICU. This dataset included 158 case hospitalizations (102 emergent transfers to the ICU and 56 "code blue" events) and 135,597 control hospitalizations. RESULTS: When identifying deteriorating patients 2 hours before an event, there was no significant difference between Pediatric Early Warning Score and VRI's areas under the receiver operating characteristic curve at false-positive rates ≤ 10% (pAUC10 of 0.065 and 0.064, respectively; P = 0.74), a threshold chosen to compare the 2 approaches under clinically tolerable false-positive rates. CONCLUSIONS: The VRI represents an objective, simple, and automated predictive analytics tool for identifying hospitalized pediatric patients at risk of deteriorating outside of the ICU setting.

Dominant effects of the diet on the microbiome and the local and systemic immune response in mice.

Outside the nutrition community the effects of diet on immune-mediated diseases and experimental outcomes have not been appreciated. Investigators that study immune-mediated diseases and/or the microbiome have overlooked the potential of diet to impact disease phenotype. We aimed to determine the effects of diet on the bacterial microbiota and immune-mediated diseases. Three different laboratory diets were fed to wild-type mice for 2 weeks and resulted in three distinct susceptibilities to dextran sodium sulfate (DSS)-induced colitis. Examination of the fecal microbiota demonstrated a diet-mediated effect on the bacteria found there. Broad-spectrum antibiotics disturbed the gut microbiome and partially eliminated the diet-mediated changes in DSS susceptibility. Dietary changes 2 days after DSS treatment were protective and suggested that the diet-mediated effect occurred quickly. There were no diet-mediated effects on DSS susceptibility in germ-free mice. In addition, the diet-mediated effects were evident in a gastrointestinal infection model (Citrobacter rodentium) and in experimental autoimmune encephalomyelitis. Taken together, our study demonstrates a dominant effect of diet on immune-mediated diseases that act rapidly by changing the microbiota. These findings highlight the potential of using dietary manipulation to control the microbiome and prevent/treat immune-mediated disease.

Determinants for HPV vaccine uptake in the Netherlands: A multilevel study.

In March 2009, a HPV catch-up vaccination campaign was implemented in the Netherlands for girls born between 1993 and 1996. We performed a multilevel study to investigate determinants for HPV vaccination uptake. National coverage for the first dose was 49.9%, with regional uptakes ranging from 31% to 61%. Data was gathered from individual to regional level. Our results suggest that organizing information meetings at schools and communicating with gynaecologists might be beneficial. Lower uptake among various ethnic groups and in areas with higher proportion of voters for Religious Political Parties indicate that communication on HPV vaccine should be adapted to religious and ethnic communities. Furthermore, lower uptake in areas with lower socioeconomic status needs attention since participation to cervical screening is also lower in these areas.

Barriers to implementing infection prevention and control guidelines during crises: experiences of health care professionals.

BACKGROUND: Communicable disease crises can endanger the health care system and often require special guidelines. Understanding reasons for nonadherence to crisis guidelines is needed to improve crisis management. We identified and measured barriers and conditions for optimal adherence as perceived by 4 categories of health care professionals. METHODS: In-depth interviews were performed (n = 26) to develop a questionnaire for a cross-sectional survey of microbiologists (100% response), infection preventionists (74% response), public health physicians (96% response), and public health nurses (82% response). The groups were asked to appraise barriers encountered during 4 outbreaks (severe acute respiratory syndrome [SARS], Clostridium difficile ribotype 027, rubella, and avian influenza) according to a 5-point Likert scale. When at least 33% of the participants responded "strongly agree," "agree," or "rather agree than disagree," a barrier was defined as "often experienced." The common ("generic") barriers were included in a univariate and multivariate model. Barriers specific to the various groups were studied as well. RESULTS: Crisis guidelines were found to have 4 generic barriers to adherence: (1) lack of imperative or precise wording, (2) lack of easily identifiable instructions specific to each profession, (3) lack of concrete performance targets, and (4) lack of timely and adequate guidance on personal protective equipment and other safety measures. The cross-sectional study also yielded profession-specific sets of often-experienced barriers. CONCLUSION: To improve adherence to crisis guidelines, the generic barriers should be addressed when developing guidelines, irrespective of the infectious agent. Profession-specific barriers require profession-specific strategies to change attitudes, ensure organizational facilities, and provide an adequate setting for crisis management.