Transient genomic instability drives tumorigenesis through accelerated clonal evolution.

Abnormal numerical and structural chromosome content is frequently found in human cancer. To test the role of aneuploidy in tumor initiation and progression, we generated mice with random aneuploidies by transient induction of polo-like kinase 4 (Plk4), a master regulator of centrosome number. Short-term chromosome instability (CIN) from transient Plk4 induction resulted in formation of aggressive T-cell lymphomas in mice with heterozygous inactivation of one p53 allele and accelerated tumor development in the absence of p53. Transient CIN increased the frequency of lymphoma-initiating cells with a specific karyotype profile, including trisomy of chromosomes 4, 5, 14, and 15 occurring early in tumorigenesis. Tumor development in mice with chronic CIN induced by an independent mechanism (through inactivation of the spindle assembly checkpoint) gradually trended toward a similar karyotypic profile, as determined by single-cell whole-genome DNA sequencing. Overall, we show how transient CIN generates cells with random aneuploidies from which ones that acquire a karyotype with specific chromosome gains are sufficient to drive cancer formation, and that distinct CIN mechanisms can lead to similar karyotypic cancer-causing outcomes.

Evaluation of the efficacy of commercial and noncommercial tourniquets for extremity hemorrhage control in a perfused cadaver model.

BACKGROUND: Tourniquets are a critical tool in the immediate response to life-threatening extremity hemorrhage; however, the optimal tourniquet type and effectiveness of noncommercial devices remain unclear. Our aim was to evaluate the efficacy of five tourniquets in a perfused-cadaver model. METHODS: This prospective study used a perfused-cadaver model with standardized superficial femoral artery injury bleeding at 700 mL/min. Five tourniquets were tested: combat application tourniquet; rapid application tourniquet system; Stretch, Wrap, And Tuck Tourniquet; an improvised triangle bandage windlass; and a leather belt. Forty-eight medical students underwent a practical hands-on demonstration of each tourniquet. Using a random number generator, they placed the tourniquets on the bleeding cadaver in random order. Time to hemostasis, time to secure devices, estimated blood loss, and difficulty rating were assessed. A one-way repeated measures analysis of variance was used to compare efficacy between the tourniquets in achieving the outcomes. RESULTS: The mean ± SD participant age was 25 ± 2.6 years, and 29 (60%) were male. All but one tourniquet was able to stop bleeding, but the rapid application tourniquet system had a 4% failure rate. Time to hemostasis and estimated blood loss did not differ significantly (p > 0.05). Stretch, Wrap, And Tuck Tourniquet required the longest time to be secured (47.8 ± 17.0 seconds), whereas the belt was the fastest (15.2 ± 6.5 seconds; p < 0.001). The improvised windlass was rated easiest to learn and apply, with 22 participants (46%) assigning a score of 1. CONCLUSION: Four of five tourniquets evaluated, including both noncommercial devices, effectively achieved hemostasis. A standard leather belt was the fastest to place and was able to stop the bleeding. However, it required continuous pressure to maintain hemostasis. The improvised windlass was as effective as the commercial devices and was the easiest to apply. In an emergency setting where commercial devices are not available, improvised tourniquets may be an effective bridge to definitive care.

Discontinuing involuntary mental health holds for children: Does psychiatrist specialty matter? A pilot study.

BACKGROUND: Involuntary mental health detainments should only be utilized when less restrictive alternatives are unavailable and should be discontinued as soon as safety can be ensured. The study objective was to determine if child and adolescent psychiatrists discontinue a greater proportion of involuntary holds than general psychiatrists for similar pediatric patients. METHODS: Retrospective analysis of consecutive patients under 18 years placed on an involuntary hold in the prehospital setting presenting over a 1-year period to one high-volume emergency department (ED) where youth on involuntary holds are seen by child and adolescent psychiatrists when available and general psychiatrists otherwise. The primary outcome of interest was hold discontinuation after initial psychiatric consultation. The key predictor of interest was psychiatrist specialty (child and adolescent vs. general). We conducted multivariate logistic regression modeling adjusting for patient characteristics and time of arrival. RESULTS: Child and adolescent psychiatrists discontinued 27.4% (51/186) of prehospital holds while general psychiatrists discontinued only 10.6% (22/207). After adjusting for observable confounders, holds were over 3 times as likely to be discontinued in patients evaluated by child and adolescent psychiatrists rather than general emergency psychiatrists (adjusted OR 3.2, 95% CI 1.7-5.9, p < 0.001). CONCLUSIONS: Child and adolescent psychiatrists are much more likely to discontinue prehospital involuntary mental health holds compared with general emergency psychiatrists. While inappropriate hold discontinuation places patients at risk of harm, prolonged hold continuation limits patients' rights and potentially increases psychiatric boarding in EDs. Earlier access to child and adolescent psychiatry may facilitate early hold discontinuation and standardize patient care.