Nevin Manimala

Pediatrics. 2022 Apr 1;149(4):e2021052165. doi: 10.1542/peds.2021-052165.

ABSTRACT

BACKGROUND AND OBJECTIVES: Inappropriate vancomycin use is common in children’s hospitals. We report a quality improvement (QI) intervention to reduce vancomycin use in our tertiary care PICU.

METHODS: We retrospectively quantified the prevalence of infections caused by organisms requiring vancomycin therapy, including methicillin-resistant Staphylococcus aureus (MRSA), among patients with suspected bacterial infections. Guided by these data, we performed 3 QI interventions over a 3-year period, including (1) stakeholder education, (2) generation of a consensus-based guideline for empiric vancomycin use, and (3) implementation of this guideline through clinical decision support. Vancomycin use in days of therapy (DOT) per 1000 patient days was measured by using statistical process control charts. Balancing measures included frequency of bacteremia due to an organism requiring vancomycin not covered with empiric therapy, 30-day mortality, and cardiovascular, respiratory, and renal organ dysfunction.

RESULTS: Among 1276 episodes of suspected bacterial infection, a total of 19 cases of bacteremia (1.5%) due to organisms requiring vancomycin therapy were identified, including 6 MRSA bacteremias (0.5%). During the 3-year QI project, overall vancomycin DOT per 1000 patient days in the PICU decreased from a baseline mean of 182 DOT per 1000 patient days to 109 DOT per 1000 patient days (a 40% reduction). All balancing measures were unchanged, and all cases of MRSA bacteremia were treated empirically with vancomycin.

CONCLUSION: Our interventions reduced overall vancomycin use in the PICU without evidence of harm. Provider education and consensus building surrounding indications for empiric vancomycin use were key strategies.

PMID:35362066 | DOI:10.1542/peds.2021-052165

Pediatrics. 2022 Apr 1;149(4):e2021050197. doi: 10.1542/peds.2021-050197.

ABSTRACT

BACKGROUND AND OBJECTIVES: Family-centered rounds (FCR) can lead to improved communication, satisfaction, and care delivery. However, FCR are variable in practice. Our primary goal was to implement and sustain consistent communication practices during FCR (a subset of all rounds in which parents were present) for patients on a pediatric hospital medicine service. We aimed to achieve 80% reliability for the following FCR practices: (1) discussion of risk factors and prevention strategies for hospital-acquired conditions (HACs), (2) discussion of discharge planning, and (3) asking families for questions.

METHODS: Research assistants observed FCR on a pediatric acute care unit at an academic medical center and recorded if the rounding team discussed HAC risk factors, discussed discharge, or asked families for questions. Using the Model for Improvement, we performed multiple plan-do-study-act cycles to test and implement interventions, including (1) standardized note templates, (2) education via peer-led group discussions and team e-mails, and (3) routine provider feedback about performance. Data were analyzed by using statistical process control charts.

RESULTS: From October 2017 to April 2019, reliability increased to >80% and sustained for (1) discussion of HAC risk factors (increased from 11% to 89%), (2) discussion of discharge planning (from 60% to 92%), and (3) asking families for questions (from 61% to 87%). Peer-led physician education, reminder e-mails, and physician engagement were the most impactful interventions corresponding to centerline shifts.

CONCLUSIONS: Using multiple interventions, we achieved and sustained improvements in key communication-related elements of FCR. Future work will focus on determining if improved practices impact clinical outcomes.

PMID:35362064 | DOI:10.1542/peds.2021-050197

Interact Cardiovasc Thorac Surg. 2022 Mar 31;34(4):584-589. doi: 10.1093/icvts/ivab295.

ABSTRACT

OBJECTIVES: Our goal was to evaluate the effect of thymectomy on the progression of thymolipomatous myasthenia gravis.

METHODS: An electronic search performed across PubMed, MEDLINE and Web of Science databases included all article types. We included 15 series comprising 36 cases that met specific criteria, including case reports or case series related to thymolipoma with a myasthenia gravis association, where thymectomy was cited as the primary intervention with postoperative reporting of the prognosis and articles written in the English language.

RESULTS: Our study included 17 men (47.2%) and 19 women (52.8%). Tumour sizes varied between 34 × 18 × 7 cm and 2.8 × 2.3 × 1.9 cm; the weight of the tumours ranged between 38 and 1780 g (mean 190, standard deviation 341). The surgical approaches were a median sternotomy in 29 patients (80.6%), a thoracotomy in 1 patient (2.8%), video-assisted thoracoscopic surgery in 2 patients (5.6%) and unreported approaches in 4 (11.1%) patients. The disease was entirely resolved with complete, stable remission in 5 patients (13.9%); symptoms were improved in 19 (52.8%) and stable in 10 patients (27.7%). We identified 2 groups of patients according to their improvement post-thymectomy (improved group and group with no change).

CONCLUSIONS: Although the cases were uncontrolled and did not demonstrate strong associations, they do support some hypotheses. We found a significant statistical difference between the 2 groups in terms of age, because younger patients tended to improve to a greater degree post-thymectomy. Also, we found that female patients with thymoma visible on the imaging scans were significantly associated with post-thymectomy myasthenia gravis improvement.

REGISTRATION NUMBER IN PROSPERO: CRD42020173229.

PMID:35362060 | DOI:10.1093/icvts/ivab295

Cell Death Differ. 2022 Mar 31. doi: 10.1038/s41418-022-00982-5. Online ahead of print.

ABSTRACT

Mutations in genes encoding general transcription factors cause neurological disorders. Despite clinical prominence, the consequences of defects in the basal transcription machinery during brain development are unclear. We found that loss of the TATA-box binding protein-associated factor TAF8, a component of the general transcription factor TFIID, in the developing central nervous system affected the expression of many, but notably not all genes. Taf8 deletion caused apoptosis, unexpectedly restricted to forebrain regions. Nuclear levels of the transcription factor p53 were elevated in the absence of TAF8, as were the mRNAs of the pro-apoptotic p53 target genes Noxa, Puma and Bax. The cell death in Taf8 forebrain regions was completely rescued by additional loss of p53, but Taf8 and p53 brains failed to initiate a neuronal expression program. Taf8 deletion caused aberrant transcription of promoter regions and splicing anomalies. We propose that TAF8 supports the directionality of transcription and co-transcriptional splicing, and that failure of these processes causes p53-induced apoptosis of neuronal cells in the developing mouse embryo.

PMID:35361962 | DOI:10.1038/s41418-022-00982-5

Eye (Lond). 2022 Mar 31. doi: 10.1038/s41433-022-01992-w. Online ahead of print.

ABSTRACT

BACKGROUND/OBJECTIVES: Retinoblastoma is a common childhood intraocular malignancy, the bilateral form of which most commonly results from a de novo germline pathogenic variant in the RB1 gene. Both advanced maternal age and decreasing birth order are known to increase the risk of de novo germline pathogenic variants, while the influence of national wealth is understudied. This cohort study aimed to retrospectively observe whether these factors influence the ratio of bilateral retinoblastoma cases compared to unilateral retinoblastoma, thereby inferring an influence on the development of de novo germline pathogenic variants in RB1.

SUBJECTS/METHODS: Data from 688 patients from 11 centres in 10 countries were analysed using a series of statistical methods.

RESULTS: No associations were found between advanced maternal age, birth order or GDP per capita and the ratio of bilateral to unilateral retinoblastoma cases (p values = 0.534, 0.201, 0.067, respectively), indicating that these factors do not contribute to the development of a de novo pathogenic variant.

CONCLUSIONS: Despite a lack of a definitive control group and genetic testing, this study demonstrates that advanced maternal age, birth order or GDP per capita do not influence the risk of developing a bilateral retinoblastoma.

PMID:35361938 | DOI:10.1038/s41433-022-01992-w

Nat Methods. 2022 Mar 31. doi: 10.1038/s41592-022-01445-y. Online ahead of print.

ABSTRACT

Variant calling has been widely used for genotyping and for improving the consensus accuracy of long-read assemblies. Variant calls are commonly hard-filtered with user-defined cutoffs. However, it is impossible to define a single set of optimal cutoffs, as the calls heavily depend on the quality of the reads, the variant caller of choice and the quality of the unpolished assembly. Here, we introduce Merfin, a k-mer based variant-filtering algorithm for improved accuracy in genotyping and genome assembly polishing. Merfin evaluates each variant based on the expected k-mer multiplicity in the reads, independently of the quality of the read alignment and variant caller’s internal score. Merfin increased the precision of genotyped calls in several benchmarks, improved consensus accuracy and reduced frameshift errors when applied to human and nonhuman assemblies built from Pacific Biosciences HiFi and continuous long reads or Oxford Nanopore reads, including the first complete human genome. Moreover, we introduce assembly quality and completeness metrics that account for the expected genomic copy numbers.

PMID:35361932 | DOI:10.1038/s41592-022-01445-y

Nat Methods. 2022 Mar 31. doi: 10.1038/s41592-022-01440-3. Online ahead of print.

ABSTRACT

Advances in long-read sequencing technologies and genome assembly methods have enabled the recent completion of the first telomere-to-telomere human genome assembly, which resolves complex segmental duplications and large tandem repeats, including centromeric satellite arrays in a complete hydatidiform mole (CHM13). Although derived from highly accurate sequences, evaluation revealed evidence of small errors and structural misassemblies in the initial draft assembly. To correct these errors, we designed a new repeat-aware polishing strategy that made accurate assembly corrections in large repeats without overcorrection, ultimately fixing 51% of the existing errors and improving the assembly quality value from 70.2 to 73.9 measured from PacBio high-fidelity and Illumina k-mers. By comparing our results to standard automated polishing tools, we outline common polishing errors and offer practical suggestions for genome projects with limited resources. We also show how sequencing biases in both high-fidelity and Oxford Nanopore Technologies reads cause signature assembly errors that can be corrected with a diverse panel of sequencing technologies.

PMID:35361931 | DOI:10.1038/s41592-022-01440-3

Nat Rev Genet. 2022 Mar 31. doi: 10.1038/s41576-022-00482-9. Online ahead of print.

NO ABSTRACT

PMID:35361926 | DOI:10.1038/s41576-022-00482-9

Sci Rep. 2022 Mar 31;12(1):5458. doi: 10.1038/s41598-022-09544-8.

ABSTRACT

Type III interferons (IFNs) play an important role in respiratory viral infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. This study aimed to determine whether the expression of serum type III IFNs predicted disease severity among patients with the coronavirus disease (COVID-19). A retrospective cohort study was conducted of patients admitted to a single hospital between March 21, 2020, and March 31, 2021. Patients were divided into mild to moderate I (MM) and moderate II to severe (MS) groups based on the COVID-19 severity classification developed by the Japanese Ministry of Health, Labor and Welfare. A total of 257 patients were included in the analysis. Human interleukin-28A (IL-28A/IFN-λ2) expression was significantly lower, and interleukin (IL)-6 expression was significantly higher in the MS group than in the MM group (both p < 0.001). In addition, IL-28A/IFN-λ2 was statistically significantly inversely correlated with the time from disease onset to negative SARS-CoV-2 PCR results (p = 0.049). Multivariable logistic regression analysis showed that IL-28A/IFN-λ2 was an independent predictor of disease severity (p = 0.021). The low expression of IL-28A/IFN-λ2 may serve as a serum biomarker that predicts the severity of COVID-19, possibly through the mechanism of delayed viral elimination.

PMID:35361913 | DOI:10.1038/s41598-022-09544-8