COVID-19 significantly impacted initial consultation for idiopathic scoliosis.

INTRODUCTION: Since the outbreak of the COVID-19 pandemic, reduction of social activities and rapid adoption of telemedicine, decreasing face-to-face encounters seems to have negatively affected the timely Idiopathic Scoliosis (IS) referral with a spine specialist. We aim to document the progression of IS curves during COVID-19 pandemic reflected by the late presentation of patients at the initial visit with higher Cobb angles and to evaluate its influence on health-related quality of life scores. MATERIALS AND METHODS: All IS patients scheduled for surgery between April 2019 and September 2021 were recruited in a prospective cohort study. The patients were divided into five cohorts of 6 month duration each according to their booking date: 2 periods before the 1st COVID-19 wave, one period during and two periods afterwards. In each cohort, patients were divided into 3: those who were scheduled for posterior spinal fusion (PSF) at 1st visit, those booked for vertebral body tethering (VBT) at 1st visit, and those scheduled for surgery but who have failed brace treatment. Variables included age, gender, Risser grade and preoperative SRS-22 scores. Chi2 and ANOVA tests were used for comparison. RESULTS: 173 patients were analyzed. 33 patients (13.1 ± 3 y.o.) were scheduled between Apr and Sept 2019; 38 (13.1 y.o. ± 2) between Oct 2019 and Mar 2020; 31 (13.4 ± 3 y.o.) between Apr and Sept 2020; 30 (14.3 ± 2 y.o.) between Sept 2020 and Mar 2021; and 41 patients (13.8 ± 2 y.o.) between Apr and Sept 2021. Non-statistically significant differences were found between periods before, during or after the COVID-19 first wave regarding patients' age, gender, Risser grade and SRS-22 scores. Average Cobb angles of patients at their 1st visit after the beginning of the COVID-19 pandemic were significantly higher than those before COVID-19 (52.2° ± 7° and 56.6° ± 13° vs 47.8° ± 12° and 45.2° ± 13°; p = 0.0001). More patients were booked for PSF (p < 0.0000) through the five evaluated periods, while the indication of VBT or surgery in patients previously braced progressively decreased. CONCLUSION: Patients presented at the scoliosis clinic for the 1st time after the 1st COVID-19 wave with significantly larger Cobb angles, and likely contributed to an increased proportion of PSF, as the potential window for bracing or VBT was missed due to a delayed consultation.

Chronic treatment with ATR and CHK1 inhibitors does not substantially increase the mutational burden of human cells.

DNA replication stress (RS) entails the frequent slow down and arrest of replication forks by a variety of conditions that hinder accurate and processive genome duplication. Elevated RS leads to genome instability, replication catastrophe and eventually cell death. RS is particularly prevalent in cancer cells and its exacerbation to unsustainable levels by chemotherapeutic agents remains a cornerstone of cancer treatments. The adverse consequences of RS are normally prevented by the ATR and CHK1 checkpoint kinases that stabilize stressed forks, suppress origin firing and promote cell cycle arrest when replication is perturbed. Specific inhibitors of these kinases have been developed and shown to potentiate RS and cell death in multiple in vitro cancer settings. Ongoing clinical trials are now probing their efficacy against various cancer types, either as single agents or in combination with mainstay chemotherapeutics. Despite their promise as valuable additions to the anti-cancer pharmacopoeia, we still lack a genome-wide view of the potential mutagenicity of these new drugs. To investigate this question, we performed chronic long-term treatments of TP53-depleted human cancer cells with ATR and CHK1 inhibitors (ATRi, AZD6738/ceralasertib and CHK1i, MK8776/SCH-900776). ATR or CHK1 inhibition did not significantly increase the mutational burden of cells, nor generate specific mutational signatures. Indeed, no notable changes in the numbers of base substitutions, short insertions/deletions and larger scale rearrangements were observed despite induction of replication-associated DNA breaks during treatments. Interestingly, ATR inhibition did induce a slight increase in closely-spaced mutations, a feature previously attributed to translesion synthesis DNA polymerases. The results suggest that ATRi and CHK1i do not have substantial mutagenic effects in vitro when used as standalone agents.

The mutational impact of Illudin S on human cells.

Illudin S (ILS) is a fungal sesquiterpene secondary metabolite with potent genotoxic and cytotoxic properties. Early genetic studies and more recent genome-wide CRISPR screens showed that Illudin-induced lesions are preferentially repaired by transcription-coupled nucleotide excision repair (TC-NER) with some contribution from post-replication repair pathways. In line with these results, Irofulven, a semi-synthetic ILS analog was recently shown to be particularly effective on cell lines and patient-derived xenografts with impaired NER (e.g. ERCC2/3 mutations), raising hope that ILS-derived molecules may soon enter the clinic. Despite the therapeutic potential of ILS and its analogs, we still lack a global understanding of their mutagenic potential. Here, we characterize the mutational signatures associated with chronic exposure to ILS in human cells. ILS treatment rapidly stalls DNA replication and transcription, leading to the activation of the replication stress response and the accumulation of DNA damage. Novel single and double base substitution signatures as well as a characteristic indel signature indicate that ILS treatment preferentially alkylates purine residues and induces oxidative stress, confirming prior in vitro data. Many mutation contexts exhibit a strong transcriptional strand bias, highlighting the contribution of TC-NER to the repair of ILS lesions. Finally, collateral mutations are also observed in response to ILS, suggesting a contribution of translesion synthesis pathways to ILS tolerance. Accordingly, ILS treatment led to the rapid recruitment of the Y-family DNA polymerase kappa onto chromatin, supporting its preferential use for ILS lesion bypass. Altogether, our work provides the first global assessment of the genomic impact of ILS, demonstrating the contribution of multiple DNA repair pathways to ILS resistance and mutagenicity.

A Dangerous Curve: Impact of the COVID-19 Pandemic on Brace Treatment in Adolescent Idiopathic Scoliosis.

STUDY DESIGN: Observational Cohort study. OBJECTIVES: We aim to document the abandon and irregular compliance rate towards brace treatment during the COVID-19 pandemic and its impact on AIS progression. METHODS: We reviewed a database of AIS patients recruited between March and September 2020. We included AIS patients under brace treatment according to SRS criteria. The patients were divided in 2 cohorts: those with self-reported Good-Compliance (GC) to treatment and those who had a Bad-Compliance (BC). Data analysis included biometric and radiographic data at first visit and last follow-up and percentage of progression. Unpaired student-t tests and Chi2 were used for comparison. RESULTS: 152 patients met inclusion criteria. 89 patients (age:12.1y.o.±1.4) reported good adherence to treatment, while 63 patients (age:12.7y.o.±1.8) were not compliant. Within the BC group, 18 patients reported irregular brace wear, while 45 had completely abandoned treatment (abandon rate of 29%). The GC cohort started treatment with a mean main thoracic (MT) curve of 26° and finished with 27°. The mean difference between measurements was +.65°±7.5; mean progression rate was -4.6%. However, the BC cohort started with a mean MT curve of 27° and finished with 32°, with a mean increase of +5°±8 and a mean progression rate of -13%. The differences between the 2 cohorts were statistically significant (P = .0002). Six patients from the BC group progressed and were offered surgery. CONCLUSION: The abandon rate of brace treatment in AIS significantly increased during the first wave of COVID-19 pandemic. Patients who voluntarily discontinued treatment had significant increases in curve progression and surgical indication rates. LEVEL OF EVIDENCE: III.