The Finger Wrecker / words by Bert Dixon

Cover: description reads novelty piano solo; Publisher: Jack Mills Inc. (New York)https://egrove.olemiss.edu/sharris_d/1031/thumbnail.jp

Nebulized heparin in burn patients with inhalation trauma : safety and feasibility

Background: Pulmonary hypercoagulopathy is intrinsic to inhalation trauma. Nebulized heparin could theoretically be beneficial in patients with inhalation injury, but current data are conflicting. We aimed to investigate the safety, feasibility, and effectiveness of nebulized heparin. Methods: International multicenter, double-blind, placebo-controlled randomized clinical trial in specialized burn care centers. Adult patients with inhalation trauma received nebulizations of unfractionated heparin (25,000 international unit (IU), 5 mL) or placebo (0.9% NaCl, 5 mL) every four hours for 14 days or until extubation. The primary outcome was the number of ventilator-free days at day 28 post-admission. Here, we report on the secondary outcomes related to safety and feasibility. Results: The study was prematurely stopped after inclusion of 13 patients (heparin N = 7, placebo N = 6) due to low recruitment and high costs associated with the trial medication. Therefore, no analyses on effectiveness were performed. In the heparin group, serious respiratory problems occurred due to saturation of the expiratory filter following nebulizations. In total, 129 out of 427 scheduled nebulizations were withheld in the heparin group (in 3 patients) and 45 out of 299 scheduled nebulizations were withheld in the placebo group (in 2 patients). Blood-stained sputum or expected increased bleeding risks were the most frequent reasons to withhold nebulizations. Conclusion: In this prematurely stopped trial, we encountered important safety and feasibility issues related to frequent heparin nebulizations in burn patients with inhalation trauma. This should be taken into account when heparin nebulizations are considered in these patients

Total knee replacement after high tibial osteotomy: Time-to-event analysis and predictors

© 2021 Joule Inc. or its licensors. BACKGROUND: An important aim of high tibial osteotomy (HTO) is to prevent or delay the need for total knee replacement (TKR). We sought to estimate the frequency and timing of conversion from HTO to TKR and the factors associated with it. METHODS: We prospectively evaluated patients with osteoarthritis (OA) of the knee who underwent medial opening wedge HTO from 2002 to 2014 and analyzed the cumulative incidence of TKR in July 2019. The presence or absence of TKR on the HTO limb was identified from the orthopedic surgery reports and knee radiographs contained in the electronic medical records for each patient at London Health Sciences Centre. We used cumulative incidence curves to evaluate the primary outcome of time to TKR. We used multivariable Cox proportional hazards analysis to assess potential preoperative predictors including radiographic disease severity, malalignment, correction size, pain, sex, age, body mass index (BMI) and year of surgery. RESULTS: Among 556 patients who underwent 643 HTO procedures, the cumulative incidence of TKR was 5% (95% confidence interval [CI] 3%–7%) at 5 years and 21% (95% CI 17%–26%) at 10 years. With the Cox proportional hazards multivariable model, the following preoperative factors were significantly associated with an increased rate of conversion: radiographic OA severity (adjusted hazard ratio [HR] 1.96, 95% CI 1.12–3.45), pain (adjusted HR 0.85, 95% CI 0.75–0.96)], female sex (adjusted HR 1.67, 95% CI 1.08–2.58), age (adjusted HR 1.50 per 10 yr, 95% CI 1.17–1.93) and BMI (adjusted HR 1.31 per 5 kng/m2, 95% CI 1.12–1.53). INTERPRETATION: We found that 79% of knees did not undergo TKR within 10 years after undergoing medial opening wedge HTO. The strongest predictor of conversion to TKR is greater radiographic disease at the time of HTO

Extending the allelic spectrum at noncoding risk loci of orofacial clefting

Genome-wide association studies (GWAS) have generated unprecedented insights into the genetic etiology of orofacial clefting (OFC). The moderate effect sizes of associated noncoding risk variants and limited access to disease-relevant tissue represent considerable challenges for biological interpretation of genetic findings. As rare variants with stronger effect sizes are likely to also contribute to OFC, an alternative approach to delineate pathogenic mechanisms is to identify private mutations and/or an increased burden of rare variants in associated regions. This report describes a framework for targeted resequencing at selected noncoding risk loci contributing to nonsyndromic cleft lip with/without cleft palate (nsCL/P), the most frequent OFC subtype. Based on GWAS data, we selected three risk loci and identified candidate regulatory regions (CRRs) through the integration of credible SNP information, epigenetic data from relevant cells/tissues, and conservation scores. The CRRs (total 57 kb) were resequenced in a multiethnic study population (1061 patients; 1591 controls), using single-molecule molecular inversion probe technology. Combining evidence from in silico variant annotation, pedigree- and burden analyses, we identified 16 likely deleterious rare variants that represent new candidates for functional studies in nsCL/P. Our framework is scalable and represents a promising approach to the investigation of additional congenital malformations with multifactorial etiology

Breakpoint mapping and haplotype analysis of translocation t(1;12)(q43;q21.1) in two apparently independent families with vascular phenotypes

Background The risk of serious congenital anomaly for de novo balanced translocations is estimated to be at least 6%. We identified two apparently independent families with a balanced t(1;12)(q43;q21.1) as an outcome of a ''Systematic Survey of Balanced Chromosomal Rearrangements in Finns. ''In the first family, carriers (n=6) manifest with learning problems in childhood, and later with unexplained neurological symptoms (chronic headache, balance problems, tremor, fatigue) and cerebral infarctions in their 50s. In the second family, two carriers suffer from tetralogy of Fallot, one from transient ischemic attack and one from migraine. The translocation cosegregates with these vascular phenotypes and neurological symptoms. Methods and Results We narrowed down the breakpoint regions using mate pair sequencing. We observed conserved haplotypes around the breakpoints, pointing out that this translocation has arisen only once. The chromosome 1 breakpoint truncates a CHRM3 processed transcript, and is flanked by the 5 end of CHRM3 and the 3 end of RYR2. TRHDE, KCNC2, and ATXN7L3B flank the chromosome 12 breakpoint. Conclusions This study demonstrates a balanced t(1;12)(q43;q21.1) with conserved haplotypes on the derived chromosomes. The translocation seems to result in vascular phenotype, with or without neurological symptoms, in at least two families. We suggest that the translocation influences the positional expression of CHRM3, RYR2,TRHDE, KCNC2, and/or ATXN7L3B.Peer reviewe

Use of Yttrium-90 Microspheres in Patients with Advanced Hepatocellular Carcinoma and Portal Vein Thrombosis

Patients with portal vein thrombosis (PVT) and hepatocellular carcinoma (HCC) have limited treatment options due to increased disease burden and diminished hepatic perfusion. 90Y-microspheres may be better tolerated than chemoembolization in these patients. Here we review the safety and efficacy of 90Y-microsphere use for HCC with major PVT

Identification of de novo variants in nonsyndromic cleft lip with/without cleft palate patients with low polygenic risk scores

[Background]: Nonsyndromic cleft lip with/without cleft palate (nsCL/P) is a congenital malformation of multifactorial etiology. Research has identified >40 genome-wide significant risk loci, which explain less than 40% of nsCL/P heritability. Studies show that some of the hidden heritability is explained by rare penetrant variants. [Methods]: To identify new candidate genes, we searched for highly penetrant de novo variants (DNVs) in 50 nsCL/P patient/parent-trios with a low polygenic risk for the phenotype (discovery). We prioritized DNV-carrying candidate genes from the discovery for resequencing in independent cohorts of 1010 nsCL/P patients of diverse ethnicities and 1574 population-matched controls (replication). Segregation analyses and rare variant association in the replication cohort, in combination with additional data (genome-wide association data, expression, protein–protein-interactions), were used for final prioritization. [Conclusion]: In the discovery step, 60 DNVs were identified in 60 genes, including a variant in the established nsCL/P risk gene CDH1. Re-sequencing of 32 prioritized genes led to the identification of 373 rare, likely pathogenic variants. Finally, MDN1 and PAXIP1 were prioritized as top candidates. Our findings demonstrate that DNV detection, including polygenic risk score analysis, is a powerful tool for identifying nsCL/P candidate genes, which can also be applied to other multifactorial congenital malformations.The present study was supported by the German Research Foundation (DFG)-Grants BE 3828/8-1, LU 1944/2-1, MA 2546/5-1, and LU1944/3-1

Brain ultrasonography findings in neonates with exposure to cocaine during pregnancy

Background: Cocaine exposure during pregnancy has been reported to have detrimental effects on the fetus. Objective: To describe the findings on cranial ultrasonography (CUS) as part of a neonatal screening programme for exposed neonates. Materials and methods: The study was a semiprospective analysis of a 12-year cohort of neonates born to mothers who had used cocaine during their pregnancy and who had follow-up according to a strict clinical protocol. Results: In total, 154 neonates (78 boys, 76 girls) were included, of whom 29 (19%) were born preterm, and 125 (81%) were born full-term. Abnormalities on CUS were seen in 37 neonates (24%; 95% CI 18-31%). The abnormalities were classified as minor in 20 (13%; 95% CI 9-19%) and mildly abnormal in 17 (11%; 95% CI 7-17%). None of the infants showed severe abnormalities. The abnormalities were not associated with the duration or maximum amount of cocaine use during pregnancy. Conclusion: None of the infants had severe abnormalities. Detected abnormalities were not correlated with the duration or maximum amount of cocaine use. Given these findings, we feel that routine cranial ultrasonography in this population is not warranted

Epigenetic reprogramming at estrogen-receptor binding sites alters 3D chromatin landscape in endocrine-resistant breast cancer

Endocrine therapy resistance frequently develops in estrogen receptor positive (ER+) breast cancer, but the underlying molecular mechanisms are largely unknown. Here, we show that 3-dimensional (3D) chromatin interactions both within and between topologically associating domains (TADs) frequently change in ER+ endocrine-resistant breast cancer cells and that the differential interactions are enriched for resistance-associated genetic variants at CTCF-bound anchors. Ectopic chromatin interactions are preferentially enriched at active enhancers and promoters and ER binding sites, and are associated with altered expression of ER-regulated genes, consistent with dynamic remodelling of ER pathways accompanying the development of endocrine resistance. We observe that loss of 3D chromatin interactions often occurs coincidently with hypermethylation and loss of ER binding. Alterations in active A and inactive B chromosomal compartments are also associated with decreased ER binding and atypical interactions and gene expression. Together, our results suggest that 3D epigenome remodelling is a key mechanism underlying endocrine resistance in ER+ breast cancer