Citations

Abstract Background In predynamic or dynamic scapholunate (SL) instability, standard diagnostic imaging may not identify SL interosseous ligament (SLIL) injury, leading to delayed detection and intervention. This study describes the use of four-dimensional computed tomography (4DCT) in identifying early SLIL injury and following injured wrists to 1-year postoperatively. Description of Technique 4DCT acquires a series of three-dimensional volume data with high temporal resolution (66 ms). 4DCT-derived arthrokinematic data can be used as biomarkers of ligament integrity. Patients and Methods This study presents the use of 4DCT in a two-participant case series to assess changes in arthrokinematics following unilateral SLIL injury preoperatively and 1-year postoperatively. Patients were treated with volar ligament repair with volar capsulodesis and arthroscopic dorsal capsulodesis. Arthrokinematics were compared between uninjured, preoperative injured, and postoperative injured (repaired) wrists. Results 4DCT detected changes in interosseous distances during flexion-extension and radioulnar deviation. Generally, radioscaphoid joint distances were greatest in the uninjured wrist during flexion-extension and radioulnar deviation, and SL interval distances were smallest in the uninjured wrist during flexion-extension and radioulnar deviation. Conclusion 4DCT provides insight into carpal arthrokinematics during motion. Distances between the radioscaphoid joint and SL interval can be displayed as proximity maps or as simplified descriptive statistics to facilitate comparisons between wrists and time points. These data offer insight into areas of concern for decreased interosseous distance and increased intercarpal diastasis. This method may allow surgeons to assess whether (1) injury can be visualized during motion, (2) surgery repaired the injury, and (3) surgery restored normal carpal motion. Level of Evidence Level IV, Case series.

Introduction: The long-term effects of interventional treatment (with surgery, stereotactic radiosurgery, or endovascular embolization) for unruptured brain arteriovenous malformations (uBAVM) are uncertain. We address this in a large multi-center international cohort study comparing risk of intracranial hemorrhage (ICH) in the treated and untreated course of uBAVM patients. Methods: We pooled individual patient data (n=3,291) from 10 cohorts and imputed missing data. Survival analysis was performed from time of uBAVM diagnosis to intracranial hemorrhage (ICH) using Cox models, stratified by cohort, censoring at death or last follow-up, and including BAVM interventional treatment as a time-varying covariate. We tested for an interaction of treatment with follow-up time, then estimated the association of interventional treatment with ICH, adjusting for propensity quintile. Individual treatment propensity scores were calculated using logistic regression with Spetzler-Martin grade, sex, diagnosis age and year, cohort, and presence of presenting symptoms (seizures, headaches, and/or deficits). Results: Median cohort age was 36 years, 48% were female, and 77% received ≥1 treatment modality for uBAVM during follow-up. 373 ICH occurred during 32,054 person-years of follow-up (median=6.6y), for an ICH rate of 1.16 per 100 P-Y. Overall, treatment was not associated with risk of ICH (HR=1.12, 95% CI=0.89-1.51, p=0.33). However, we observed a strong interaction between treatment and follow-up time (p<0.001): between 0-1 year, treatment was associated with higher risk of ICH (HR=3.48, 95% CI: 2.26-5.37, p<0.001); between 1-10 years, we found no association between treatment and risk of ICH (HR=1.02, 95% CI: 0.73-1.45, p=0.87); after 10 years, treatment was associated with a lower risk of ICH (HR=0.46, 95% CI: 0.30-0.70, p<0.001). Survival curves for untreated and treated courses crossed around 17 years. Conclusion: After accounting for treatment propensity for uBAVM, we found an initial increased risk of ICH in the treated relative to untreated course, which continually declined over time with survival curves crossing around 17 years. These results require confirmation in a randomized controlled trial of uBAVM with long-term follow-up.

Abstract Background: Multifocal hepatocellular carcinoma (MF-HCC) accounts for >40% of HCCs, demonstrating a poor prognosis than single primary HCCs. Characterizing the dynamic changes of mutation signature along with clonal evolution, quantifying intrahepatic metastatic timing, and investigating the genetic structure in the preneoplastic stage underlying different subtypes of MF-HCC are important for understanding their molecular evolution and developing a precision management strategy. Methods: We conducted whole-exome sequencing in 74 tumor samples from spatially distinct regions in 35 resected tumor lesions and adjacent non-cancerous tissues in 11 patients with synchronous MF-HCCs, 15 histologically confirmed preneoplastic lesions and six samples from peripheral blood mononuclear cell. We also used the previously published MF-HCC cohorts (n=9) as an independent validation dataset. Results: We classified MF-HCCs into three subtypes, including intrahepatic metastasis, multicentric occurrence, and mixed intrahepatic metastasis and multicentric occurrence. The dynamic changes in mutation signatures between tumor subclonal expansions demonstrated varied etiologies underlying the clonal progression in different MF-HCC subtypes, especially the contribution of aristolochic acid exposure decreased along with subclonal expansions. The clonal evolution in intrahepatic metastasis exhibited an early metastatic seeding that occurred at 10-4–0.01 cm3 in primary tumor volume, below the limitation in clinical detection. These findings were validated in another independent cohort. In addition, for multicentric occurrence MF-HCC, mutational footprints in the preneoplastic lesions revealed common preneoplastic arising clones, evidently being ancestors of different tumor sites. Conclusion: Our study comprehensively characterized the dynamic mutational signature, early metastatic timing, and common preneoplastic clones in multicentric occurrence that characterized the varied tumor clonal evolutionary history underlying different subtypes of MF-HCC, and provided important implications for optimizing personalized clinical management for MF-HCC.

Abstract Background Crohn’s disease (CD) and ulcerative colitis (UC), together known as inflammatory bowel diseases (IBD), affect approximately seven million people globally. The continuous rise in IBD prevalence and the aging of populations will inevitably lead to an increasing use of health care resources. In parallel with these trends, continuing innovations in IBD therapeutics, diagnostics, and preventatives are creating more options for IBD patients seeking to reduce their disease burden. These trends pose an imminent burden on health care systems and require that we identify modifiable cost drivers in IBD care and develop strategies for delivering equitable and affordable care for all patients. Methods This Lancet Gastroenterology & Hepatology Commission, consisting of a diverse faculty of health care professionals with expertise in the field of IBD and health economists, was formed to deliver an extensive summary of the literature and discuss key topics on the costs and cost-effectiveness of treating IBD in the present, and how this is likely to look in the future. Furthermore, it offers suggestions for how to deliver affordable IBD care in the coming years. The report’s focus was on high-income countries in Europe, North America, Australia and New Zealand, and Asia. Results The Commission drew together a wide range of expertise to discuss the current costs of IBD care, the drivers of increasing costs, as well as how to deliver affordable care for IBD in the future. The key conclusions are that (i) increases in health care costs must be evaluated against improved disease control and reductions in indirect costs, and (ii) that overarching systems for data interoperability, registries, and big data approaches must be established for continuous assessment of effectiveness, costs, and cost-effectiveness of care. International collaborations should be sought in order to evaluate novel models of care (such as value-based health care, including integrated health care and participatory health care models), as well as to improve the education and training of clinicians, patients, and policymakers. Measures to reduce the costs of IBD care are summarised in Table 1. Conclusion Increases in health care costs must be evaluated against improved disease control and reductions in indirect costs. Evaluations should be systematically aligned between countries and regions. Detailed analysis of the current epidemiology and the likely effects of changing IBD management on disease course and socioeconomic outcomes is essential; and will become even more imperative in the era of precision medicine, where complex biotechnologies will require expensive analyses, highly skilled personnel, and drug development for what may sometimes be relatively small patient groups.

Sonic hedgehog signaling regulates processes of embryonic development across multiple tissues, yet factors regulating context-specific Shh signaling remain poorly understood. Exome sequencing of families with polymicrogyria (disordered cortical folding) revealed multiple individuals with biallelic deleterious variants in TMEM161B , which encodes a multi-pass transmembrane protein of unknown function. Tmem161b null mice demonstrated holoprosencephaly, craniofacial midline defects, eye defects, and spinal cord patterning changes consistent with impaired Shh signaling, but were without limb defects, suggesting a CNS-specific role of Tmem161b. Tmem161b depletion impaired the response to Smoothened activation in vitro and disrupted cortical histogenesis in vivo in both mouse and ferret models, including leading to abnormal gyration in the ferret model. Tmem161b localizes non-exclusively to the primary cilium, and scanning electron microscopy revealed shortened, dysmorphic, and ballooned ventricular zone cilia in the Tmem161b null mouse, suggesting that the Shh-related phenotypes may reflect ciliary dysfunction. Our data identify TMEM161B as a regulator of cerebral cortical gyration, as involved in primary ciliary structure, as a regulator of Shh signaling, and further implicate Shh signaling in human gyral development.

AbstractBackgroundThere has been conflicting reports on the effect of new trainees on clinical outcomes at teaching hospitals in the first training month (July in the United States of America). We sought to assess this “July effect” in a contemporary acute myocardial infarction (AMI) population.MethodsAdult (>18 years) AMI hospitalizations in May and July in urban teaching and urban nonteaching hospitals in the United States were identified from the HCUP‐NIS database (2000–2017). In‐hospital mortality was compared between May and July admissions. A difference‐in‐difference analysis comparing a change in outcome from May to July in teaching hospitals to a change in outcome from May to July in nonteaching hospitals was also performed.ResultsA total of 1,312,006 AMI hospitalizations from urban teaching (n = 710,593; 54.2%) or nonteaching (n = 601,413; 45.8%) hospitals in the months of May and July were evaluated. May admissions in teaching hospitals, had greater comorbidity, higher rates of acute multiorgan failure (10.6% vs. 10.2%, p < 0.001) and lower rates of cardiac arrest when compared to July admissions. July AMI admissions had lower in‐hospital mortality compared to May (5.6% vs. 5.8%; adjusted odds ratio 0.94 [95% confidence interval 0.92–0.97]; p < 0.001) in teaching hospitals. Using the difference‐in‐difference model, there was no evidence of a July effect for in‐hospital mortality (p = 0.19).ConclusionsThere was no July effect for in‐hospital mortality in this contemporary AMI population.

Abstract Myeloid cells comprising up to 50% of total tumor mass in glioblastoma (GBM) contribute to tumor progression and immunosuppression. Restraining glioma-induced myeloid cell infiltration increases functional T cells within the tumors, improves the efficacy of checkpoint blockade, and significantly extends mouse survival. Here, we focus on an ion channel, voltage-gated proton channel Hv1, which is mainly expressed in myeloid cells and shapes the physiological functions of myeloid cells. Our bioinformatics analysis demonstrated that elevated Hv1 expression in the tumor mass correlates with poor disease prognosis in patients. Using the leading immunocompetent model of GBM in mice, we showed that Hv1 knockout mice (Hv1−/−) exhibit slower glioma progression and prolonged survival. Using in vivo two-photon imaging, we found that myeloid cells infiltrate into tumor mass since early time points and have intimate interaction with tumor cells. Notably, by full-spectrum flow cytometry, we found that Hv1−/− mice have reduced monocyte/macrophage infiltration, and increased PD-1+ CD4+ T cells in the tumor-burdened hemisphere. As a result, we combined anti-PD-1 treatment with Hv1 knockout in the middle stage of glioma, and found that approximately 30% of Hv1−/− mice were cured. Together, our results demonstrated that Hv1 controls myeloid infiltration and could be a novel therapeutic target for the treatment of GBM. Supported by R01NS110825, R01NS088627

Leukemia cells accumulate DNA damage but altered DNA repair mechanisms protect them from apoptosis. We showed here that formaldehyde generated by serine/one-carbon cycle metabolism contributed to accumulation of toxic DNA-protein crosslinks (DPCs) in leukemia cells, especially in driver clones harboring oncogenic tyrosine kinases [OTKs: FLT3(ITD), JAK2(V617F), BCR/ABL1]. To counteract this effect, OTKs enhanced the expression of DNA polymerase theta (POLq) by ERK1/2 serine/threonine kinase-dependent inhibition of c-CBL E3 ligase-mediated ubiquitination of POLq and its proteasomal degradation. Overexpression of POLq in OTK-positive cells resulted in efficient repair of DPC-containing DNA double-strand breaks (DSBs) by POLq-mediated end-joining (TMEJ). Transforming activity of OTKs and other leukemia-inducing oncogenes, especially of those causing inhibition of BRCA1/2 -mediated homologous recombination (HR) with and without concomitant inhibition of DNA-PK -dependent non-homologous end-joining (D-NHEJ), was abrogated in Polq-/- murine bone marrow cells. Genetic and pharmacological targeting of POLq polymerase and helicase activities revealed that both activities are promising targets in leukemia cells. Moreover, OTK inhibitor or DPC-inducing drug etoposide enhanced anti-leukemia effect of POLq inhibitor (POLqi) in vitro and in vivo. In conclusion, we demonstrated that POLq plays an essential role in protecting leukemia cells from metabolically induced toxic DNA lesions triggered by formaldehyde and that it can be targeted to achieve therapeutic effect.

The United States has one of the highest cumulative mortalities of coronavirus disease 2019 (COVID-19) and has reached 1 million deaths as of May 19th, 2022. Understanding which community and hospital factors contributed to disparities in COVID-19 mortality is important to inform public health strategies. This study aimed to explore the potential relationship between hospital service area (1) community (ie, health professional shortage areas, market competition, and uninsured percentage) and (2) hospital (ie, teaching, system, and ownership status) characteristics (2013–2018) on publicly available COVD-19 (February to October 2020) mortality data. The study included 2514 health service areas and used multilevel mixed-effects linear model to account for the multilevel data structure. The outcome measure was the number of COVID-19 deaths. This study found that public health, as opposed to acute care provision, was associated with community health and, ultimately, COVID-19 mortality. The study found that population characteristics including more uninsured greater proportion of those over 65 years, more diverse populations, and larger populations were all associated with a higher rate of death. In addition, communities with fewer hospitals were associated with a lower rate of death. When considering region in the United States, the west region showed a higher rate of death than all other regions. The association between some community characteristics and higher COVID-19 deaths demonstrated that access to health care, either for COVID-19 infection or worse health from higher disease burden, is strongly associated with COVID-19 deaths. Thus, to be better prepared for potential future pandemics, a greater emphasis on public health infrastructure is needed.