FANCI Regulates Recruitment of the FA Core Complex at Sites of DNA Damage Independently of FANCD2.

The Fanconi anemia (FA)-BRCA pathway mediates repair of DNA interstrand crosslinks. The FA core complex, a multi-subunit ubiquitin ligase, participates in the detection of DNA lesions and monoubiquitinates two downstream FA proteins, FANCD2 and FANCI (or the ID complex). However, the regulation of the FA core complex itself is poorly understood. Here we show that the FA core complex proteins are recruited to sites of DNA damage and form nuclear foci in S and G2 phases of the cell cycle. ATR kinase activity, an intact FA core complex and FANCM-FAAP24 were crucial for this recruitment. Surprisingly, FANCI, but not its partner FANCD2, was needed for efficient FA core complex foci formation. Monoubiquitination or ATR-dependent phosphorylation of FANCI were not required for the FA core complex recruitment, but FANCI deubiquitination by USP1 was. Additionally, BRCA1 was required for efficient FA core complex foci formation. These findings indicate that FANCI functions upstream of FA core complex recruitment independently of FANCD2, and alter the current view of the FA-BRCA pathway.

Evaluating the Short-term Environmental and Clinical Effects of a Radiation Oncology Department's Response to the COVID-19 Pandemic.

PURPOSE: During the COVID-19 pandemic, many radiation oncology departments worldwide adopted the use of shorter and more intense hypofractionated regimens. Hospital foot traffic was reduced through virtual care. This study's primary objective was to assess the collective environmental effect of these strategic changes by identifying sources of carbon dioxide equivalents (CO2e). The rate of radiation-related adverse events from the increased use of hypofractionated treatments was assessed. METHODS AND MATERIALS: All patients treated with external beam radiation therapy from April 1, 2019, to March 31, 2021, at our single institution were identified (n = 10,175) along with their radiation therapy visits (176,423 fractions) and unplanned visits to the radiation nursing clinic or emergency department. Out-patient hospital and virtual visits (n = 75,853) during this same period were also analyzed. Environmental effect measures, including linear accelerator power usage, patient travel distances, and personal protection equipment consumption were all converted into CO2e. RESULTS: The use of curative hypofractionated regimens increased from 17% to 27% during the pandemic year. Carbon footprint was reduced by 39% during the pandemic year (1,332,388 kg CO2e) compared with the prepandemic year (2,024,823 kg CO2e). Comparing patients in the prepandemic versus pandemic year, there was a significant reduction in the proportion of hypofractionated patients who needed a visit to either the radiation nursing clinic (39% vs 25%; P < .001) or emergency department (6% vs 2%; P < .001) during and within 90 days of radiation therapy. CONCLUSIONS: This is the first study to demonstrate the environmental benefits of increased use of hypofractionated regimens and virtual care, while assuring that there was no added acute radiation-related adverse event. Our findings support their continued use as one of many long-term strategies to reduce the environmental footprint of health care delivery.

Risk of Parkinson's disease in glaucoma patients: a systematic review and meta-analysis.

OBJECTIVE: To conduct a systematic review and meta-analysis to evaluate the relationship between glaucoma and the risk of Parkinson's disease. METHODS: A systematic search of databases including MEDLINE, EMBASE, and CINAHL were conducted. Grey literature search, including Dissertations and Theses databases and conference abstracts, was performed. Duplicates were removed, and two independent reviewers conducted the screening. We included any primary observational studies that examined the relationship between glaucoma and Parkinson's disease. Study characteristics along with relevant outcome measurements such as hazard ratio (HR), odds ratio (OR), and prevalence were extracted. Meta-analysis using STATA 15.0 was performed, and the presence of heterogeneity was determined using I2 statistics, Z-test, and p-value. RESULTS: A total of 746 citations were found through the databases and grey literature searches. After screening, five studies met the inclusion criteria, and three studies were included in the meta-analysis. There was a non-significant hazard of developing Parkinson's disease (Hazard Ratio = 1.13, 95% CI: [0.99, 1.29]) in patients with glaucoma compared to controls. DISCUSSION: The hazard of developing Parkinson's disease was non-significantly different for those with glaucoma compared to controls; however, there were not enough studies available to draw definitive conclusions.

Comparing the diagnostic accuracy of telemedicine utilization versus in-person clinical examination for retinopathy of prematurity in premature infants: a systematic review.

PURPOSE: To synthesize the literature assessing the diagnostic accuracy of telemedicine evaluation compared with clinical examination for retinopathy of prematurity (ROP) in premature infants. METHODS: Covidence software was used to conduct a systematic literature search from September 14, 2020, through September 27, 2020, on MEDLINE (Ovid), EMBASE (Ovid), CINAHL, and the gray literature to identify studies relevant to telemedicine utilization for ROP detection. After duplicate removal and two-levels of screening, studies comparing telemedicine evaluation with binocular indirect ophthalmoscopic examination were included. Risk of bias assessment was conducted for the included studies following data extraction. A qualitative review was performed to summarize estimates of accuracy of ROP evaluation by telemedicine. RESULTS: A total of 507 studies were reviewed, of which 323 were found in EMBASE, 115 in MEDLINE, and 79 in CINAHL. Three possibly relevant conference abstracts were found. Following duplicate removal, 410 studies were reviewed based on titles and abstracts. Subsequently, 19 articles were thoroughly examined, and 14 studies (2,655 participants) were included. Most studies found that telemedicine performance for detecting ROP was comparable to ophthalmic examination, especially with regard to identifying treatment-requiring ROP. CONCLUSIONS: Telemedicine evaluation can reliably detect ROP. Incorporation of telemedicine into conventional neonatal care has the potential to improve access to ROP care.

Diagnostic accuracy of current machine learning classifiers for age-related macular degeneration: a systematic review and meta-analysis.

BACKGROUND AND OBJECTIVE: The objective of this study was to systematically review and meta-analyze the diagnostic accuracy of current machine learning classifiers for age-related macular degeneration (AMD). Artificial intelligence diagnostic algorithms can automatically detect and diagnose AMD through training data from large sets of fundus or OCT images. The use of AI algorithms is a powerful tool, and it is a method of obtaining a cost-effective, simple, and fast diagnosis of AMD. METHODS: MEDLINE, EMBASE, CINAHL, and ProQuest Dissertations and Theses were searched systematically and thoroughly. Conferences held through Association for Research in Vision and Ophthalmology, American Academy of Ophthalmology, and Canadian Society of Ophthalmology were searched. Studies were screened using Covidence software and data on sensitivity, specificity and area under curve were extracted from the included studies. STATA 15.0 was used to conduct the meta-analysis. RESULTS: Our search strategy identified 307 records from online databases and 174 records from gray literature. Total of 13 records, 64,798 subjects (and 612,429 images), were used for the quantitative analysis. The pooled estimate for sensitivity was 0.918 [95% CI: 0.678, 0.98] and specificity was 0.888 [95% CI: 0.578, 0.98] for AMD screening using machine learning classifiers. The relative odds of a positive screen test in AMD cases were 89.74 [95% CI: 3.05-2641.59] times more likely than a negative screen test in non-AMD cases. The positive likelihood ratio was 8.22 [95% CI: 1.52-44.48] and the negative likelihood ratio was 0.09 [95% CI: 0.02-0.52]. CONCLUSION: The included studies show promising results for the diagnostic accuracy of the machine learning classifiers for AMD and its implementation in clinical settings.

The Prevalence of Occupational Burnout Among Ophthalmologists: A Systematic Review and Meta-Analysis.

OBJECTIVE: To investigate the prevalence of occupational burnout among ophthalmologists in order to better understand the mental and physical well-being of eye physicians and surgeons in the professional workplace. STUDY DESIGN: A systematic review and meta-analysis. METHODS: Online computer databases MEDLINE, EMBASE, CINAHL, and ProQuest Dissertations and Theses were searched systematically and thoroughly. Conferences held through Association for Research in Vision and Ophthalmology, American Academy of Ophthalmology, and Canadian Society of Ophthalmology were searched. Studies were screened using Covidence software. Data on reported burnout prevalence was extracted. STATA 15.0 was used to conduct meta-analysis.Synthesis: Our search strategy identified 318 records from online databases and 11 records from grey literature search, which were screened at 2-levels. Title and abstracts of each record were screened resulting in 24 records moving to full-text screening. Total of 9 records were utilized for quantitative analysis in the data extraction stage. Our results indicated significant professional burnout among ophthalmologists (ES = 0.41; CI: [0.26, 0.56]) with significant emotional exhaustion (ES = 0.43; CI: [0.33, 0.53]), depersonalization (ES = 0.29; CI: [0.13, 0.46]), and a low sense of personal accomplishment (ES = 0.36; CI: [0.08, 0.63]). CONCLUSIONS: Significant occupational burnout among ophthalmologists is concerning because burnout can have a negative effect on the physical and mental health of eye physicians and surgeons. It could impact productivity, cutbacks in work hours, or lead to early retirement from the profession. Contributing factors in ophthalmologist burnout including work overload need to be addressed in a timely manner.

Prevalence of Obstructive Sleep Apnea in Glaucoma Patients: A Systematic Review and Meta-analysis.

AIM AND OBJECTIVE: Obstructive sleep apnea (OSA) is a known systemic risk factor associated with glaucoma. The purpose of the study was to determine the overall prevalence of sleep apnea among patients with glaucoma. DESIGN: A systematic review and meta-analysis. PARTICIPANTS: Not applicable. MATERIALS AND METHODS: A systematic literature search was performed through MEDLINE, EMBASE, and CINAHL and gray literature using Clinical Trials.gov, and ProQuest Dissertations and Theses and conferences held through the Association for Research in Vision and Ophthalmology, American Academy of Ophthalmology, and Canadian Society of Ophthalmology was done until June 10, 2020. Eligible articles were identified by reviewing the retrieved results. Data extracted included the total number of patients with glaucoma and the proportion of glaucoma patients with a co-occurring diagnosis of OSA. STATA 15.0 was used to perform the meta-analysis. RESULTS: 544 articles were gathered from the databases and 40 records were collected via the gray literature search. Ten studies with 956 subjects were included for analysis. The results of the meta-analysis demonstrated a significant rate of OSA among glaucoma patients (ES = 0.17; CI: [0.08, 0.25]). CONCLUSION: We examine the prevalence of OSA in glaucoma patients and conclude that the prevalence of OSA in glaucoma patients is higher. CLINICAL SIGNIFICANCE: The findings in the ongoing investigation on the link between glaucoma and OSA continue to be unclear. The results from this study contribute to evidence of an association between the two diseases. HOW TO CITE THIS ARTICLE: Yu BE, Cheung R, Hutnik C, et al. Prevalence of Obstructive Sleep Apnea in Glaucoma Patients: A Systematic Review and Meta-analysis. J Curr Glaucoma Pract 2021;15(3):109-116.

CTDP1 regulates breast cancer survival and DNA repair through BRCT-specific interactions with FANCI.

BRCA1 C-terminal domains are found in a specialized group of 23 proteins that function in the DNA damage response to protect genomic integrity. C-terminal domain phosphatase 1 (CTDP1) is the only phosphatase with a BRCA1 C-terminal domain in the human proteome, yet direct participation in the DNA damage response has not been reported. Examination of the CTDP1 BRCA1 C-terminal domain-specific protein interaction network revealed 103 high confidence interactions enriched in DNA damage response proteins, including FANCA and FANCI that are central to the Fanconi anemia DNA repair pathway necessary for the resolution of DNA interstrand crosslink damage. CTDP1 expression promotes DNA damage-induced FANCA and FANCD2 foci formation and enhances homologous recombination repair efficiency. CTDP1 was found to regulate multiple aspects of FANCI activity, including chromatin localization, interaction with γ-H2AX, and SQ motif phosphorylations. Knockdown of CTDP1 increases MCF-10A sensitivity to DNA interstrand crosslinks and double-strand breaks, but not ultraviolet radiation. In addition, CTDP1 knockdown impairs in vitro and in vivo growth of breast cancer cell lines. These results elucidate the molecular functions of CTDP1 in Fanconi anemia interstrand crosslink repair and identify this protein as a potential target for breast cancer therapy.

Percutaneous cholecystostomy for high-risk patients with acute cholangitis.

Percutaneous cholecystostomy (PC) is a well-established treatment for acute cholecystitis. We investigate the performance and role of PC in managing acute cholangitis.Retrospective review on all patients who underwent PC for acute cholangitis between January 2012 and June 2017 at a major regional hospital in Hong Kong.Thirty-two patients were included. The median age was 84 years and median American Society of Anaesthesiologists (ASA) physical status was Class III (severe systemic disease). All fulfilled Tokyo Guidelines 2013 (TG13) diagnostic criteria for moderate or severe cholangitis. Eighty-four percent of the patients were shown to have lower common bile duct stones on imaging. The majority had previously failed intervention by endoscopic retrograde cholangiopancreatography (38%), percutaneous transhepatic biliary drainage (38%), or both (13%)The technical success rate for PC was 100% with no procedure-related mortality. The overall 30-day mortality was 9%. Rest of the patients (91%) had significant improvement in clinical symptoms and could be discharged with median length of stay of 14 days. Significant postprocedural biochemical improvement was observed in terms of white cell count (P < .001), serum bilirubin (P < .001), alkaline phosphatase (P = .001), and alanine transaminase levels (P < .001). Time from admission to PC was associated with excess mortality (P = .002).PC is an effective treatment for acute cholangitis in high-risk elderly patients. Early intervention is associated with lower mortality. PC is particularly valuable as a temporising measure before definitive treatment in critical patients or as salvage therapy where other methods endoscopic retrograde cholangiopancreatography/percutaneous transhepatic biliary drainage (ERCP/PTBD) have failed.

Interactions between MYC and transforming growth factor alpha alter the growth and tumorigenicity of liver progenitor cells.

The MYC oncogene induces both cell proliferation and apoptosis. The apoptotic function of MYC is thought to inhibit carcinogenesis; thus, when disrupted, tumorigenic potential is increased. Both MYC and transforming growth factor alpha (TGFalpha) are commonly over-expressed in hepatocellular carcinomas, and transgenic mice expressing these genes rapidly develop tumors via the suppression of MYC-induced apoptosis by the growth factor. However, the nature of the interactions between MYC and TGFalpha are not well understood. Specifically, it is unclear whether TGFalpha acts only as an anti-apoptotic factor in its interactions with MYC or whether it has substantial effects on cell growth. We investigated whether TGFalpha can provide additional mitogenic signals if it is not required to act as an anti-apoptotic factor. We demonstrate that expression of MYC and TGFalpha in liver progenitor cells (known as oval cells) results in enhanced cell proliferation in culture and the generation of poorly differentiated tumors after inoculation into nude mice. We further demonstrate that while the apoptosis-deficient T58A and S71F alleles of MYC retain their ability to promote oval cell proliferation, they have opposite growth interactions with TGFalpha. The T58A allele has a stimulatory effect on both proliferation and tumorigenicity. In contrast, co-expression of the S71F allele reduces proliferation and slows tumor development. We conclude that the tumorigenic growth effects of MYC in TGFalpha-expressing liver progenitor cells are not solely dependent on its apoptotic activity.

Recent insights into the molecular basis of Fanconi anemia: genes, modifiers, and drivers.

Fanconi anemia (FA), the most common form of inherited bone marrow failure, predisposes to leukemia and solid tumors. FA is caused by the genetic disruption of a cellular pathway that repairs DNA interstrand crosslinks. The impaired function of this pathway, and the genetic instability that results, is considered the main pathogenic mechanism behind this disease. The identification of breast cancer susceptibility genes (for example, BRCA1/FANCS and BRCA2/FANCD1) as being major players in the FA pathway has led to a surge in molecular studies, resulting in the concept of the FA-BRCA pathway. In this review, we discuss recent advances in the molecular pathogenesis of FA from three viewpoints: (a) new FA genes, (b) modifier pathways that influence the cellular and clinical phenotypes of FA and (c) non-canonical functions of FA genes that may drive disease progression independently of deficient DNA repair. Potential therapeutic approaches for FA that are relevant to each will also be proposed.

Ubiquitination-Linked Phosphorylation of the FANCI S/TQ Cluster Contributes to Activation of the Fanconi Anemia I/D2 Complex.

Repair of interstrand crosslinks by the Fanconi anemia (FA) pathway requires both monoubiquitination and de-ubiquitination of the FANCI/FANCD2 (FANCI/D2) complex. In the standing model, the phosphorylation of six sites in the FANCI S/TQ cluster domain occurs upstream of, and promotes, FANCI/D2 monoubiquitination. We generated phospho-specific antibodies against three different S/TQ cluster sites (serines 556, 559, and 565) on human FANCI and found that, in contrast to the standing model, distinct FANCI sites were phosphorylated either predominantly upstream (ubiquitination independent; serine 556) or downstream (ubiquitination-linked; serines 559 and 565) of FANCI/D2 monoubiquitination. Ubiquitination-linked FANCI phosphorylation inhibited FANCD2 de-ubiquitination and bypassed the need to de-ubiquitinate FANCD2 to achieve effective interstrand crosslink repair. USP1 depletion suppressed ubiquitination-linked FANCI phosphorylation despite increasing FANCI/D2 monoubiquitination, providing an explanation of why FANCD2 de-ubiquitination is important for function of the FA pathway. Our work results in a refined model of how FANCI phosphorylation activates the FANCI/D2 complex.