Breast cancer is the most diagnosed cancer in women. Women who are diagnosed early and who receive evidence-based guideline-adherent care have better outcomes. Previous studies have shown disparities in the receipt of appropriate care based on race and socioeconomic status. This study was designed to explore these disparities in women diagnosed with triple-negative breast cancer in the context of the receipt of National Comprehensive Cancer Network guideline-adherent care and its effects on outcomes using the California Cancer Registry. Our results show that racial minorities and members of lower socioeconomic groups are less likely to receive guideline-adherent care, and that this is associated with an increased risk of dying from breast cancer. Our study adds to the growing evidence of persistent healthcare disparities, suggesting that more work is needed to bridge the gaps in healthcare provision for racial minorities and members of lower socioeconomic groups.p < 0.0001) compared to White patients. Conclusions: A significant majority of breast cancer patients in California continue to receive non-guideline-adherent care. Non-Hispanic Black patients and patients from lower SES quintile groups were less likely to receive guideline-adherent care. Patients with non-adherent care had worse disease-specific survival compared to recipients of NCCN guideline-adherent care.Background: The National Comprehensive Cancer Network guidelines were designed to improve patient outcomes. Here, we examine factors that may contribute to outcomes and guideline adherence in patients with triple-negative breast cancer. Methods: This was a retrospective cohort study of women with triple-negative breast cancer using the California Cancer Registry. Adherent treatment was defined as the receipt of a combination of surgery, lymph node assessment, adjuvant radiation, and/or chemotherapy. A multivariable logistic regression was used to determine the effects of independent variables on adherence to the NCCN guidelines. Disease-specific survival was calculated using Cox regression analysis. Results: A total of 16,858 women were analyzed. Black and Hispanic patients were less likely to receive guideline-adherent care  compared to White patients. Hazard ratios adjusted for adherent care showed that Black patients had increased disease-specific mortality (HR 1.28, 95%CI 1.16–1.42,  Breast cancer remains the most commonly diagnosed cancer and the second-leading cause of cancer mortality in American women ,2. The lTriple-negative breast cancer is important because limited targeted therapies are currently available for its treatment. TNBC tends to be more aggressive and presents at an earlier age with more advanced disease. As such, it carries a worse short-term prognosis compared to receptor-positive breast cancers, and even more so when detected later in the disease course . DespitePrevious studies have shown that disparities in access to healthcare among Non-Hispanic Black and Hispanic women continue to be a barrier to receiving guideline-adherent care (GAC) . AdherenThis retrospective cohort study of adult women diagnosed with triple-negative breast cancer (TNBC) in California was carried out using data from the California Cancer Registry (CCR). Patients diagnosed between 2004 and 2015 (with follow-up through November 2018) were included in the study. This study was approved by the Institutional Review Board of the University of California, Irvine, as exempt.The CCR is California’s population-based cancer surveillance system, which collects information about almost all cancers diagnosed and treated in the state. Data include patient-level demographics, tumor-specific characteristics , and vital statistics such as time and cause of death. Treatment data obtained from the registry are limited to the first course of treatment.The inclusion criteria for the study were female patients who were 18 to 79 years old and diagnosed with triple-negative invasive carcinoma of the breast as the first or only cancer in their lifetime. Patients older than 80 years were excluded because comorbidity data were missing, and we believe that this may have influenced the decision to withhold guideline-recommended therapy. TNBC is defined as breast cancer that is estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and human epidermal growth factor receptor 2 (HER2)-negative. The following variables were collected for this study: age at diagnosis, year of diagnosis, race/ethnicity (Non-Hispanic White (NHW), Non-Hispanic Black (NHB), Asian (not including Pacific Islanders), and other or unknown), mutually exclusive insurance type , marital status (married vs. not married), neighborhood socioeconomic status (nSES), tumor stage and grade, and treatment variables . Neighborhood socioeconomic status (nSES) was determined using neighborhood census block data and was divided into five groups by quintiles  based on the Yost SES score or Yang SES index . The YosPatients with localized disease and up to 1–3 positive lymph nodes  with node-negative tumors ≤ 10 mm who received sentinel lymph node surgery and either a total mastectomy or breast-conserving surgery (BCS) plus radiation.Patients with localized disease and up to 1–3 positive lymph nodes  with node-negative tumors > 10 mm who underwent sentinel lymph node surgery, chemotherapy, and either a total mastectomy or BCS plus radiation.Patients with localized disease and up to 1–3 positive lymph nodes  with nodal micro-metastasis, tumor ≤ 10 mm, who received sentinel lymph node surgery and either a total mastectomy or BCS plus radiation.Patients with localized disease and up to 1–3 positive lymph nodes  with nodal micro-metastasis, tumor > 10 mm, who received sentinel lymph node surgery, chemotherapy and either a total mastectomy or BCS plus radiation.Patients with localized disease and up to 1–3 positive lymph nodes  with lymph-node-positive tumors of any size who received sentinel lymph node surgery and chemotherapy.Patients with stages IIIA, IIIB, or IIIC tumors who received sentinel lymph node surgery and chemotherapy.Patients with stage IV cancer who received chemotherapy.An algorithm based on the NCCN-recommended treatment approach for TNBC was applied according to the time of diagnosis 2004–2015) and is summarized in  and is sA subject was considered to have received adherent care if treatment was consistent with NCCN treatment guidelines for the tumor stage . Based op < 0.05 using 2-tailed tests. Statistical analyses were performed using SAS 9.4 .Descriptive statistics of the study population according to treatment adherence status were generated for the patients’ social–demographic variables and tumor characteristics. The chi-squared test was used to test for differences between the guideline-adherent and guideline-non-adherent groups. Univariate and multivariable logistic regression was fitted for the receipt of NCCN guideline-adherent care. NCCN guideline-adherent care was the dependent variable in this analysis. Independent variables were age, race, nSES, insurance type, marital status, and tumor characteristics. We conducted survival analyses using disease-specific survival. Patients who died from other causes or were alive at the end of the follow-up were censored. Kaplan–Meier estimates of survival probability and log-rank tests were performed to compare adherent and non-adherent groups. After checking proportional hazards assumptions, univariate and multivariate Cox proportional hazards regression models were fitted for disease-specific survival. Unadjusted and adjusted hazard ratios with 95% confidence intervals were calculated. Statistical significance was set at n = 3533 or 21.0%, p < 0.0001), while the age group 65+ was least likely to receive adherent care  compared to other age groups (Patient demographics are summarized in e groups .p < 0.0001). A similar association was seen among uninsured women , who were less likely to receive guideline-adherent care than women having managed care insurance (33.5%). Women in the lowest SES group  were least likely to receive guideline-adherent care compared to women with the highest SES (34.9%).When compared to Non-Hispanic White patients (34.0%), Non-Hispanic Black patients were the least likely to receive guideline-adherent care . Married women were more likely to receive guideline-adherent care compared to women who were not married . When compared to women with stage I cancer, those with stage IV cancer were the most likely to receive guideline-adherent care . Compared to women who had managed care insurance, having Medicare , Medicaid , other insurance , or no insurance  had no significant effect on the likelihood of receiving guideline-adherent care (Adjusted odds ratios for receiving NCCN guideline-adherent care are reported in ent care .p < 0.0001) . There was a trend toward statistically significantly higher mortality in uninsured women . The SES of women had a very strong effect on the risk of death from breast cancer. This effect was seen in the lowest SES , lower-middle SES , and middle SES  groups. Not surprisingly, having more advanced disease was associated with an increased risk of death, with the highest risk seen in stage IV tumors .The hazard ratios for breast-cancer-specific death according to age, race/ethnicity, insurance type, SES, marital status, tumor stage, and the receipt of NCCN guideline-adherent care using a Cox model are listed in This study reveals the persistence of significant disparities in the treatment and outcomes of breast cancer among U.S. women, as described in previous studies ,18,19,20Age has been recognized as an independent risk factor for poor health outcomes. As people get older, they develop cardiovascular, metabolic, and other comorbidities and physical frailty, which independently contribute to increased mortality risk ,22. OtheThe effect of the cancer stage at diagnosis on the likelihood of receiving NCCN guideline-adherent care was surprisingly strong in this study. When compared to women with stage I disease, stage IV disease patients were 7 times more likely to receive NCCN guideline-adherent care. Prior studies have shown that patients with no insurance or who have public insurance such as Medi-Cal tended to present at later stages of cancer compared to those with private insurance . DespiteSocioeconomic status (SES) is an important contributing factor to health outcomes in populations. Measures of SES can be at the level of the individual or their neighborhood . PreviouIn the U.S., the African American population is disproportionately poor, undereducated, unemployed, and more likely to live in poorer neighborhoods. Between 2014 and 2016, the average household income in the U.S. was USD 70,000 compared to USD 48,000 for African Americans ,27. LoweThe health insurance type revealed a significant correlation with health outcomes. Women with Medicaid insurance had a 29% increased risk of death compared to managed care recipients after adjusting for age, nSES, and disease stage. When we looked at the risk of death in NHB compared to NHW women, we adjusted for insurance type but observed a residual disparity. This is likely because having health insurance does not always equate to having access to good-quality healthcare. The residual disparity suggests that other factors are likely at play. These factors may include a lack of reliable transportation to appointments, language barriers, and difficulty navigating the healthcare system due to limited education . For exaLike our study, other authors have observed a residual disparity in disease outcomes in NHB women compared to NHW women, and differences in tumor biology have been implicated as contributory, independent of SES and access to healthcare . Breast Our study, being a retrospective population-based cohort study, has several limitations. We relied on registry data from the California Cancer Registry. California is the most racially diverse state in the U.S.  and reprIn conclusion, we observed that race/ethnic disparities in the receipt of NCCN guideline-adherent care and breast-cancer-specific mortality were attenuated but persisted after adjustment for socioeconomic status and insurance type. The demonstrated attenuation in the risk of adverse outcomes between NHB and NHW women by correcting for nSES and insurance type, even if not complete, demonstrates the need for concerted efforts aimed at improving socioeconomic conditions for NHB women; health policy changes that make health insurance available to all Americans; cultural sensitivity training within health systems to improve the quality of doctor–patient interactions; and funding for research into possible molecular/genetic bases for differences in tumor behavior.


In conclusion, TG-LASIK might yield less postoperative trefoil in high-myopia patients and higher QoV in the general population compared to the WFO-LASIK procedure.We aimed to investigate high-order aberration (HOA) change between topography-guided (TG) and wavefront-optimized (WFO) laser in situ keratomileusis (LASIK) in patients with different degrees of myopia. A non-randomized clinical trial was conducted, in which 40 eyes of 20 patients aged 20–50 years old were included. Participants received TG-LASIK in one eye and WFO-LASIK on the alternate eye. Corneal topography and HOAs including coma, trefoil, spherical aberration (SA), and contrast sensitivity (CS) were collected. Moreover, a quality of vision (QoV) questionnaire was completed by each participant. Non-parametric tests were used to infer the difference in HOAs and CS between the TG-LASIK and WFO-LASIK groups, and subgroup analyses stratified by myopia degree were performed. The high-myopia patients with TG-LASIK showed more coma and SA compared to low-myopia individuals , and subjects who received WFO-LASIK exhibited more SA in high-myopia status (both 95% CI lower limits > 0). The TG-LASIK group showed lower postoperative trefoil compared to the WFO-LASIK group in the high-myopia population . The TG-LASIK group yielded less surgically induced haze, better clarity at night, and better total quality scores (all  Laser in situ keratomileusis (LASIK) has been established as an effective treatment for refractive errors such as myopia, hyperopia, and astigmatism in recent decades . In a prThe field of refractive surgery has since shifted to custom correction tailored to the patient’s HOA refractive error, such as wavefront-optimized (WFO) LASIK . HoweverA review of the literature comparing the performance of different LASIK profiles reveals that most patients in these studies have low- or middle-level of myopia ,7,8,9. TAccordingly, the aim of our study is to analyze and compare outcomes between TG-LASIK and WFO-LASIK in terms of visual performance and the change in different types of HOA, including coma, trefoil, and SA, in patients with high myopia. We also administered a subjective quality of vision (QoV) questionnaire to confirm whether the alleged superiority of TG-LASIK has translated to real-life scenarios and is noticeable to patients.The inclusion criteria for this study were as follows: age between 20 and 50 years old, corrected distance visual acuity (CDVA) of both eyes reaching a 0.1 logarithm of the minimum angle of resolution (log MAR), and eyes wit stable refractive errors of myopia and astigmatism within the last 6 months. The exclusion criteria were as follows: cataracts; corneal opacities or irregularities; dry eye ; amblyopia; coexisting ocular pathologies; glaucoma; non-dilating pupils; history of intraocular surgery, laser therapy, or retinopathy; optic nerve or macular diseases; estimated postoperative cornea residual stromal thickness less than 250 μm; pregnancy or under lactation; uncontrolled diabetic mellitus or systemic immune disease; or refusal or inability to maintain follow-up. This study included 20 patients and 40 eyes, among which 20 eyes received TG ablation and the other contralateral 20 eyes received WFO ablation.All LASIK surgeries were performed by one of two experienced surgeons (C.K.C. and E.L.C.M.) using an identical technique. In all the operated eyes, a 9.0 mm diameter flap was created using a femtosecond laser  with a hinge on the superior and flap the thickness set to 110 μm; refractive laser ablation was performed utilizing an excimer laser WaveLight EX500 with Contoura Vision software input  in all cases. We designated a Contoura-based TG ablation profile to the dominant eye and a WFO ablation profile to the non-dominant eye in all patients. The treatment target was based on manifest refraction with adjustment using Alcon’s nomogram of LASIK, with both eyes corrected to emmetropia. In the TG group, adjusted manifest refractions were used, which were based on corneal topography images obtained from a WaveLight Topolyzer VARIO device and then transferred to Contoura Vision software to correct the HOA; at least three consistent images were acquired for all eyes according to the manufacturer’s protocol.The patients were examined preoperatively, as well as on post-op day 1, the 1st week, 1st month, and 3rd month after surgery. During each visit, we performed a thorough ophthalmologic examination that included tests for UCVA and CDVA, manifest refraction, biomicroscopy, and pneumotonometry. Fundus examination and cycloplegic refraction were performed before surgery. Ocular dominance was evaluated preoperatively by the hole-in-the-card method described in the literature . The folp < 0.05.Rasch analysis was used to evaluate the QoV questionnaire and determine whether all items measured a single underlying construct . The rawp > 0.05)  .p > 0.05). As shown in The amounts of all HOAs, including the surgically induced and postoperative types, are shown in p = 0.0215), clarity at night , and total scores  than patients who received WFO-LASIK ablation. The current study shows similar results with respect to UDVA, CDVA, and SE between the TG-LASIK group and the WFO-LASIK group. TG-LASIK induced less trefoil than WFO-LASIK in the high-myopia group, while other HOAs were similar between the two groups. Moreover, the TG-LASIK group reported higher postoperative satisfaction and QoV.The overall rating of TG-LASIK on the postoperative adverse symptom questionnaire was more satisfactory than that of WFO-LASIK, particularly for the items “haze” and “clarity at night”. A previous study showed that postoperative higher-order aberrations could negatively affect QoV and may cause visual disturbance, especially with coma and spherical aberration . This isp = 0.0001), and TG-LASIK yielded more surgically induced comas in the high-myopia group. The induction of SA could be due to the ablation-induced change in corneal asphericity and may be positively correlated with the amount of refraction correction. The induction of coma aberration may also result from subclinical decentrations or asymmetry from wound healing [The postoperative SA in both groups significantly increased  in which the ocular trefoil was reported to be significantly lower after topography-guided ablation than at baseline . HoweverThis study is subject to several limitations. First, the number of patients included was limited, with less than 30 eyes in each group, which may have contributed to statistical bias; however, the contralateral eye design with pairwise data comparison might overcomes this shortcoming. Second, the design of the ablation profile was based on ocular dominance but not randomized, which may have caused bias in estimating subjective questionnaire outcomes. Moreover, different wavefront programs may have different effects on HOAs, some of which may have showed better HOA reductions than the TG program. Nevertheless, we cannot compare the TG program of our device to the wavefront program in other devices since we have only one excimer laser device in our institution.In conclusion, TG-LASIK might contribute to less trefoil in high-myopia patients compared to WFO-LASIK. Our study shows that high-myopia patients correlate exhibit numerically higher SA and coma, regardless of TG or WFO-LASIK profiles, as compared to low-myopia patients. Moreover, our subjective QoV questionnaire shows higher patient satisfaction in the TG-LASIK group.


Klebsiella pneumoniae (CRKP) has become a critical public healthcare concern due to treatment challenges and high mortality. In recent years, there has been an increase in cases of CRKP co-producing New Delhi metallo-β-lactamases (NDM) and oxacillinase 48 (OXA-48)-like carbapenemases in the US. The aim of this study was to correlate the clinical and genomic characteristics of CRKP co-producing NDM and OXA-48-like carbapenemases isolated from patients in Southern California since 2016. Whole-genome sequencing was performed on clinical isolates obtained from various sources, including blood, abdominal fluid, wounds, and urine. Genetic diversity was observed in these CRKP, including ST-14, ST-16, ST-167, ST-437, ST-2096, and ST-2497 lineages. Phylogenetic analysis revealed two closely related clusters (ST-14 and ST-2497), with single nucleotide polymorphism (SNP) differences ranging from 0 to 36, suggesting a possible local spread of these CRKP. Significant antimicrobial resistance (AMR) genes were identified in these CRKP, including NDM-1bla, NDM-5bla, OXA-232bla, OXA-181bla, CTX-M-15bla, armA, tet(A), and tet(D). Moreover, pColKP3-type and Inc-type plasmids known to harbor AMR genes were also detected in these isolates. Most of the patients infected with this rare type of CRKP died, although their severe comorbidities also played important roles in their demise. Our study highlighted the extremely limited treatment options and poor clinical outcomes associated with these dual-carbapenemase-producing CRKP. Real-time genomic surveillance of these unusual and deadly CRKP can provide critical information for infection prevention and treatment guidance.The global emergence of carbapenem-resistant  Enterobacteriaceae are Gram-negative bacteria that can cause community- and healthcare-acquired infections (HAIs) in the bloodstream, respiratory tract, and urinary tract [Enterobacteriaceae were found to be the cause of 23–31% of HAIs in patients that were in the adult, pediatric, and oncology wards of acute care hospitals in the United States [Escherichia coli, Klebsiella, and Enterobacter species were the most frequent pathogens associated with HAIs [Enterobacteriaceae infections were treated with cephalosporins; however, as antibiotic resistance due to extended-spectrum β-lactamase (ESBL) production became more prevalent, their use fell out of favor [Enterobacteriaceae (CRE) [The members of ry tract ,2. In a ith HAIs . Formerlof favor . Carbapeof favor ,7. Howevae (CRE) ,9.Klebsiella pneumoniae carbapenemases (KPC), members of Ambler Class A, hydrolyze carbapenems, thus allowing bacterial cell wall synthesis [Resistance to carbapenems arises from carbapenemase production (carbapenemase-producing CRE) and/or changes to the membrane proteins/production of other β-lactamases (non-carbapenemase-producing CRE) . Carbapeynthesis . Ambler ynthesis . Lastly,ynthesis . The acqynthesis ,16.Due to this myriad of resistance mechanisms, CRE infections pose a unique and worrisome challenge for infectious disease practitioners to treat. Moreover, carbapenem resistance is often associated with resistance to multiple other antimicrobial agents, further complicating an already challenging situation . CertainKlebsiella pneumoniae carbapenemase (KPC) led to an increase in the prevalence of CRE in the 1990s [K. pneumoniae (CRKP) co-producing NDM and OXA-48-like carbapenems, especially in the Arabian Peninsula [In the United States, the spread of the he 1990s . Other che 1990s ,23. Receeninsula ,25. Giveeninsula ,27. In tClinical CRKP isolates were worked up in the UCLA Clinical Microbiology Laboratory, from 4 patients admitted to UCLA Medical Center, and 2 patients from outside hospitals. The specimens included blood, hematoma, penile, peritoneal cavity fluid, expectorated sputum, tissue , and urine. Genomic DNA was extracted from the clinical isolates using the EZ1 Blood and Tissue Kit and the EZ1 Advanced XL instrument . The Qubit 1xdsDNA HS assay was used to quantify the extracted DNA via the Qubit 3.0 Fluorometer . The sequencing library was created using the Nextera DNA Flex Library Prep Kit  based on the manufacturer’s instructions. Sequencing was performed using MiSeq  with a 2 × 300 bp v3 protocol. The metrics for sequencing quality control included having a Q30 score of ≥85% and a cluster PF of ≥60%. At least 1 million reads were acquired for each isolate. AMR gene profiles and core genome MLST (cgMLST) were analyzed using the 1928 Diagnostics  cloud-based analytical service . Single The patient’s clinical history was retrospectively reviewed. This study was reviewed by the UCLA Human Research Protection Program and received an institutional review board exemption.Our limited cohort consisted of six patients from 2016 to 2022, with distinct medical histories and clinical manifestations. Four were directly treated at our hospital facility, whereas two received treatments at outside centers but utilized our laboratory facility for assistance in susceptibility testing and genetic analysis. Five out of the six of our cohort died during their respective hospitalizations. The patient information of five out of the six patients was available for complete chart review, and their detailed clinical histories are described here.K. pneumoniae. Unfortunately, no additional history was available for inclusion due to the patient being located outside our treatment center. He did unfortunately pass away during this hospitalization.A 75-year-old male who received treatment at an outside facility for a urinary tract infection. Our laboratory facility was asked to assist in susceptibility testing after his urine culture returned positive for CRE A 74-year-old male originally from India with a history of ischemic cardiomyopathy, chronic kidney disease, and non-insulin-dependent type II diabetes mellitus who presented to our facility from an outside hospital for management of complex cardiogenic shock and incidental bacterial parotitis. His history was significant due to frequent travel between India and the United States. Three months prior to admission to our facility, he was noted to be in relatively stable condition by his family and outside of chronic diabetes mellitus management. However, he experienced two bouts of acute decompensated heart failure while in India and required hospitalization. One admission did require treatment in an intensive care unit equivalent in India. A month prior to the admission at our facility, he returned from India and was subsequently admitted at a facility in Central California. He was medically optimized and discharged with a wearable defibrillator. One week prior to admission at our facility, he was readmitted to the outside hospital in cardiogenic shock and was found to have a cardiorenal acute kidney injury (AKI). He was started on inotropic agents at this time and an intra-aortic balloon pump (IABP) was placed, at which point he was transferred to our facility for a higher level of care.Upon arrival, he was found to have an elevated white blood cell count (WBC), which triggered an infectious workup and empiric therapy with piperacillin-tazobactam. Of note, he had had an ongoing left-sided cheek mass for three years with some associated numbness that had not been evaluated until admission at our facility. He denied any history of head or neck cancer or past infections. Two days after admission, respiratory cultures were found to be positive for CRKP. Fine needle aspiration (FNA) of the left parotid gland was performed and returned positive two days later for CRKP again. Blood and urine cultures remained negative at this time; thus, empiric antibiotic therapy was discontinued.Four days after admission, he underwent percutaneous coronary intervention (PCI). At day 5 post-admission, he developed bloody bowel movements. Given the ongoing concern regarding a systemic infection secondary to the patient’s own normal flora, the decision was made to initiate therapy with polymyxin B and meropenem, with the latter being renally dosed due to ongoing AKI. On day 7 post-admission, the bleed was determined to be secondary to a duodenal dieulafoy lesion, which was treated with electrocautery and epinephrine. The following day, IABP was discontinued due to hemodynamic stability. However, over the next 24 h the patient steadily decompensated with declining venous oxygen levels, hypotension, and respiratory rates at 30 s and 40 s. At that time, it was unclear if this acute change was secondary to septic (patient was found to have rising WBC count) vs. cardiogenic shock; so, the IABP was replaced with increased inotropic and vasopressor support. There was no improvement in hemodynamics after these interventions. Ten days after admission to our facility, the patient went into pulseless electrical activity (PEA) and expired.Staphylococcus aureus infection of her arteriovenous fistula, but no other infection-related complications; she had not traveled in over a year. The donor graft was sourced from Nevada and had no prior travel history within the previous year. No CRE cases had been sourced at the originating facility in 2.5 years.A 68-year-old female with a past medical history that was significant due to breast cancer , stable meningioma, type II diabetes mellitus complicated by right-sided retinal detachment, and end-stage renal disease, on hemodialysis for 8 years prior to admission, who originally presented to our facility for a dead-donor renal transplant. Prior to this admission, the patient had a remote history of a methicillin-resistant The post-transplant period was complicated by sudden pulseless electrical activity of an unknown etiology with the return of spontaneous circulation (ROSC), though the patient had been started on ECMO and continuous veno-venous hemodialysis. Two days post-transplant, the patient developed an allograft hematoma and required an exploratory laparotomy for removal. Fourteen days post-transplant, the patient remained in critical condition, anuric, and on multiple vasopressors. At this time, the culture of her peritoneal dialysis drain and her blood cultures returned positive for CRKP, though she remained afebrile. She was started on ceftazidime-avibactam, aztreonam, and daptomycin at this time. She developed a fever over the next day, with subsequent augmentation of therapy with plazomicin. The renal allograft was removed 16 days post-admission, with no evidence of gross graft infection, but some poor wound healing. A recurrent hematoma developed, requiring repeat washout 21 days post-admission. Investigational antibiotic cefiderocol was started at this time. The patient developed a persistent gastrointestinal (GI) bleed 23 days post-admission, with a colonoscopy showing diffuse colitis and severe ulcerations; in addition, there was a concern regarding ischemic vs. infectious etiology. Due to ongoing pressor requirements, continuous renal replacement therapy, and newfound feculent output in one of her Jackson–Pratt (JP) drains, the patient’s family decided to transition to comfort care. She expired the following day.Staphylococcus haemolyticus and Enterococcus faecium central venous catheter (CVC)-associated bacteremia, as well as ventilator-associated pneumonia (VAP), with sputum cultures positive for CRKP, Acinetobacter baumanii and Aspergillus flavus. His CVC was removed at that facility and replaced with a peripherally inserted central catheter (PICC). At the time of arrival at our facility, his antimicrobial regimen included cefepime/sulbactam, tigecycline, inhaled colistin, and voriconazole, and his PICC was replaced with a femoral CVC.An 89-year-old male with history of coronary artery disease (CAD) and coccidiomycosis who was transferred to our facility from India one month after cardiac arrest with ROSC, with cervical spinal cord compression/hyperextension injury secondary to a fall during the arrest. He was originally managed conservatively at a hospital in India but deteriorated and required intubation and eventual decompression and fixation of C3-4 with tracheostomy as well. His hospitalization in India was complicated by Elizabethkingae bacteremia, and he was started on minocycline. He remained relatively stable on pressors and with an ongoing ventilator requirement for the following week, with the eventual removal of his CVC due to a concern regarding central line-associated bacteremia. Two weeks after his admission, he developed increased tracheal secretions, which were found to be positive for Candida parapsilosis, and he was started on caspofungin. At that time, he also developed purulent discharge from his urethra; the culture of this discharge returned positive for CRKP; CKRP was also detected in the patient’s blood three days later. He did improve over the next two weeks with ongoing antibiotic therapy and continuous renal replacement therapy (CRRT), though he continued to have evidence of systemic bacterial infection. However, he spontaneously developed severe right upper lung mucus plugging and atelectasis 1.5 months post-admission, with worsening renal failure and increasing ventilator requirements with ongoing severe leukocytosis despite constantly updated antibiotic regimens. Due to no improvement with ongoing maximal medical therapy, the decision was made by the family to palliate the patient, and he expired two months after his transfer to our facility.Unfortunately, one day after arrival, his course was further complicated by A 64-year-old male with a past medical history that was significant due to chronic obstructive pulmonary disease (COPD), pulmonary hypertension, CAD, diverticulitis, recurrent pneumothorax with bronchopleural fistula, history of hepatitis C (negative status post-therapy), and latent tuberculosis with a distant history of approximately 6 months of treatment; regarding his status, he had a bilateral lung transplant 3 months prior to admission; he presented to the emergency department with new onset hemoptysis and pleuritic chest pain. The patient was born and raised in New York but had moved to California nearly thirty years previously. He had a history of intravenous (IV) drug use but had stopped using all drugs 20 years prior to admission. He had previously been diagnosed with tuberculosis (TB) in the 1980s and endorsed treatment at that time. Since his transplant, he had been on chronic immunosuppressive therapy with tacrolimus and prednisone.Pseudomonas aeruginosa and CRKP, though it was unclear whether either of these organisms were contributing to his illness given drastic improvement on the previously mentioned anticoagulants and antibiotic therapies. Due to his history of bilateral lung transplant and the ongoing use of immunosuppressing agents, the patient was started on polymyxin B as a prophylaxis with continued piperacillin/tazobactam; treatment with vancomycin was discontinued. Eleven days after admission, the patient’s vitals were stable, with no symptoms reported, and he was discharged on a 14-day course of ciprofloxacin.At the time of admission, he was incidentally found to be positive for COVID-19. He was started on vancomycin and piperacillin-tazobactam empirically in the emergency department. Due to a concern regarding pulmonary embolism (PE), a computerized tomography (CT) pulmonary angiogram was performed and showed a right lower lobe segmental PE, which was likely secondary to the bilateral popliteal deep vein thromboses in the lower extremities found later via ultrasound; he was started on heparin with eventual transition to apixaban. Two days post-admission, the sputum cultures returned positive for A 73-year-old man with a history of hypertension presented with several months of progressive dyspnea and back pain. Three days prior to presentation he was hospitalized in Cambodia, where he had resided for the previous four years. There, he received IV antibiotics and was discharged with cefixime directly to the airport. He reported dyspnea for several months, which had become acutely worse prior to presentation, and he reported ambulating with a walker for the previous three months due to progressive back pain but denied focal neurologic deficits. He was originally from Central California and denied intravenous drug use and animal exposures.E. coli, and he was discharged to a nursing facility with a plan for six weeks of therapy.On presentation, he was found to have acute bilateral pulmonary emboli and magnetic resonance imaging (MRI) changes, with concerns regarding thoracic vertebral osteomyelitis at T9-T10, acute T10 compression fracture, and an acute right 10th rib fracture. A biopsy of the vertebral lesion was terminated due to accidental entry into the intercostal artery. After the failed biopsy, vancomycin was started empirically. The antibiotics were changed to ertapenem after PCR testing of the blood showed One week later he presented with altered mental status and was found to have COVID-19 and a loculated left pleural effusion. A repeat MRI noted decreased phlegmonous changes in the ventral space with progressive T9-10 destructive changes. When his mental status did not improve, concern was raised regarding carbapenem neurotoxicity, and the ertapenem was held. After four days, his mental status improved, and ceftriaxone and trimethoprim-sulfamethoxazole were started. A week later, he was transferred to the intensive care unit (ICU) with worsening agitation and delirium. The antibiotics were switched back to ertapenem and daptomycin. His clinical status worsened; he was intubated and required pressor support. His sputum culture grew CRKP, and his antibiotics were switched to cefiderocol. The cultures of the pleural fluid were negative. Over the next five days, he had a continuous fever and worsening multiorgan failure; ultimately, he died.The multilocus sequence typing (MLST) analysis demonstrated genetic diversity within the CRKP isolates: ST-14, ST-16, ST-437, ST-2096, and ST-2497 . There wA phylogenetic analysis was also performed to further analyze the genomic epidemiology of these CRKP A. The cgK. pneumoniae, especially in the health care setting. Nevertheless, we did observe that ST-14, 16, and 2497 were the most frequently encountered CRKP genotypes in our institution.We further compared these isolates with a few other representative single carbapenemase-producing CRKP isolated at our institution in the past 10 years, including three isolates producing NDM-1 (NDM Ctrl#1-3), two isolates producing KPC-3 (KPC Ctrl#1-2), and two isolates producing OXA-232 (OXA Ctrl#1-2). pColKP3-type plasmids and Inc-type plasmids, including pIncFII  of the cases had CRKP co-producing NDM-1 and OXA-232. Case 1 had CRKP co-producing NDM-5 and OXA-232. Case 6 had CRKP co-producing NDM-4 and OXA-181. Interestingly, in Case 6 the patient had two CRKP isolates: one producing dual carbapenemase (NDM-1 and OXA-232) and another solely expressing OXA-232 , and tet(D), which conferred resistance to extended spectrum beta-lactams, aminoglycosides, and tetracyclines. These CRKP also possessed multiple mutations and AMR genes that confer additional antimicrobial resistance to sulphamethoxazole/trimethoprim, chloramphenicol, fluroquinolones, and macrolides , though the patients’ demise was likely multifactorial in nature. Severe comorbidities were noted in four/five cases available for review, and this likely contributed to the poor patient outcomes. Additionally, several old generation antibiotics, such as polymyxin B and colistin, which were used to treat these patients, have since been found to have deleterious effects on kidney function and were found to worsen mortality in several randomized controlled trials . Two of Case 5, were uniformly poor despite variances in antibiotic therapies, infection source, time to diagnosis, and preexisting comorbidities. Case 5′s good outcome appears to have been due to their CRKP infection representing an incidental finding during treatment for COVID-19, which improved with treatment. Cases 2, 3, and 4 originally presented to our facility for the treatment of non-infectious issues , but ultimately suffered severe infectious complications that likely contributed to their ultimate demise. Case 6′s illness appears to have been a primary infection which eventually resulted in the patient’s death, though whether this was E. coli, K. pneumoniae, or another infection is unclear. Notably, 75% of the patients that received polymyxin B, which has since been dropped from the Infectious Diseases Society of America’s (IDSA) guidelines due to increased mortality and excess nephrotoxicity, had poor outcomes, with kidney dysfunction noted on the chart review; however, it is unclear whether poor renal function was related to the treatment or other ongoing comorbidities during their respective admissions [The treatment outcomes for all the patients, excluding missions .The current guidelines suggest either ceftazidime-avibactam combined with aztreonam or cefiderocol alone for NDM-producing infections and ceftazidime-avibactam alone for OXA-48-producing infections outside of the urinary tract . The treThe genomic surveillance of these unusual CRKP can therefore provide critical information for better infection prevention in order to create treatment algorithms to help with patient management. Our results indicated that the most common CRKP in our cohort were the ST-14 isolates that co-produced NDM-1 and OXA-232; this has also been reported in several countries ,46,47,48pColKP3-type and Inc-type plasmids, which are known to carry a range of carbapenemases and other AMR genes [CTX-M-15bla was identified in all the isolates. CTX-M-15 is the most predominant extended spectrum beta-lactamase (ESBL) that confers resistance to later generation cephalosporins [tet(A) or tet(D) [armA or rmtB1, which confer high-level resistance to aminoglycosides, including a newer drug, plazomycin [All the isolates carried MR genes ,51,52,53osporins . Resistar tet(D) . Furtherazomycin .An SNP analysis was performed to further assess the genetic relatedness among our isolates. There were 10 SNP differences among the ST-2497 isolates collected in 2018 and 2020, and only 36 SNP differences among the ST-14 isolates collected from 2016 to 2018, indicating that these CRKP strains were most likely circulating in a specific population sharing similar epidemiological exposures and risk factors . Given that the patients had differences in travel history and disease presentation, these data would suggest that some of these CRKP strains could be spreading in the Southern California community, most likely in hospitals and long-term care facilities.The genetic surveillance of CRE co-producing dual carbapenemases is essential to monitor and control the spread within our community. Our results revealed that patients could harbor an assortment of CRKP genotypes with different carbapenemase(s) and AMR genes. By understanding the resistance mechanisms involved, we can provide critical information to enhance patient care and control the spread of infection. Our findings highlight the importance of the real-time genetic surveillance of CRKP co-producing NDM and OXA-48-like carbapenemases in Southern California.


Type I and type II diabetes mellitus, characterized by increased blood glucose levels, affect almost half a billion people around the world. Diabetes is caused either by an inability to produce enough insulin or insufficient insulin action. Regardless of diabetes type, its complications involve microvascular, macrovascular, and neuropathic issues . MicrovaSeveral molecules, such as flavones, isoflavone, and chalcones, have shown promising activity as inhibitors against drug targets, i.e., PTP1B, α-glucosidase, DPP-4, aldose reductase, SGLT-2, etc., in type 2 diabetes ,4,5. TheThis Special Issue covers new pathways and mechanisms in diabetes mellitus, investigating new approaches for the management of organ fibrosis in diabetes. In addition, the Special Issue helps to identify new management strategies for the disease using new therapeutic approaches.We broadly focused on two major sections.Endothelial cells function by maintaining vascular integrity, homeostasis, and barrier function, and by arresting inflammation through regulating their interactions with immune cells. Endothelial cell dysfunction is the predominant pathology of pre-thrombotic complications in diabetes. Endothelial-to-mesenchymal transition (EndMT) is one of the mechanisms by which endothelial cells acquire the characteristics of mesenchymal phenotypes . AlteratGlomerular fibrosis is one key feature of DKD that is poorly understood . It is cIn this Special Issue, Pandey et al. described the implication of various microRNAs and long non-coding RNAs in diabetes and delineated non-coding RNAs (ncRNAs) and their biological networks in diabetes. The authors discussed the clinical trials on diabetes-associated ncRNAs, as well as the functional relevance of the dysregulated ncRNA interactome in diabetes. This knowledge will facilitate the identification of putative biomarkers for the therapeutic management of diabetes and its comorbidities .The Epidemiology of Diabetes Interventions and Complications study describes how poor initial glycemic control is linked with a higher prevalence of diabetic complications . This ph2, and possibly even 15 mL/min/1.73 m2, while reinforcing the importance of dose adjustment and the frequent monitoring of eGFR [In this Special Issue, the authors analyze real-word data from a population-based cohort including 96,643 patients with Type II Diabetes observed for 0.7 million person-years. The authors estimated the risks associated with metformin, and its dose relationship with ESKD, in a propensity-score overlap-weighting cohort using eGFR categories. These data underscore the major benefits and low risk of lactic acidosis with metformin use down to an eGFR of 30 mL/min/1.73 m of eGFR . In another study, the authors evaluated the clinical efficacy of continuous subcutaneous insulin infusion (CSII) therapy combined with six classes of oral glucose-lowering drugs (TZDs/metformin/acarbose/GLP-1 receptor agonist/SGLT-2 inhibitor/DPP-4 inhibitor) and carried out their analysis using a network meta-analysis to provide an evidence-based reference for making clinical decisions regarding CSII combined with drugs in the management of type II diabetes (REF). A more outstanding performance was seen with insulin infusion (CSII) combined with metformin, which had the best clinical effect in controlling blood sugar and improving insulin resistance .In this Special Issue, a study by Weber et al. demonstrated the use of the rosiglitazone and its associated increased risk of myocardial infarction. The data suggest that the chronic administration of rosiglitazone does not result in major hidden cardiotoxic effects in myocardial I/R injury models and the inhibition of the antiarrhythmic effects of ischemic preconditioning may have some clinical relevance that needs to be further explored .Cardiovascular disease (CVD) morbidity and mortality are directly associated with diabetes. Individuals with diabetes experience worse clinical outcomes due to heart failure than non-diabetic patients. Hyperglycemia is the main cause that activates the oxidative damage, inflammation, fibrosis, and apoptosis pathways that aggravate diabetic CVD progression. In this Special Issue, Sapian et al. reviewed the phytochemical-based nutraceutical product anthocyanin for diabetic treatment. In preclinical and clinical studies, plants rich in anthocyanin have been reported to attenuate diabetic CVD. The authors unveiled the potential of anthocyanin to be developed as a nutraceutical for therapeutic strategies in the management of CVD associated with diabetes .It is important to understand the underlying mechanisms of diabetes-induced organ damage. In this Special Issue, we have discussed potent therapeutic regimens for the management of diabetes mellitus, tissue/cell/specific novel biological mechanistic approaches, and clinical data sets. We speculate that this Special Issue will provide basic essential information that could be used in the design of potential therapeutic agents and could help in the management of patients with diabetes mellitus.


Prevalence of at least one potential SSc-related symptom (other than RP) was 8.7%; 23.5% in subjects with RP and 7.1% without RP (p < 0.001). Subjects with RP and additional SSc-related symptoms more frequently reported dyspnea at rest, dyspnea after exertion, and self-reported pulmonary fibrosis, and had the lowest mean forced vital capacity compared to the other groups . In multivariate regression, dyspnea at rest/on exertion remained associated with an increased risk of SSc-related symptoms in subjects with RP (both p < 0.001). SAF was higher in subjects with RP and SSc-related symptoms compared to the other groups (p < 0.001), but this difference was not significant after correction for potential confounders. The prevalence of SSc-related symptoms was approximately three-fold higher in subjects with RP. Pulmonary symptoms are more prevalent in subjects with RP who also reported additional potential SSc-related symptoms. This might suggest that (suspected) early SSc develops more insidiously than acknowledged. According to this study, SAF is no marker for early detection of SSc.Puffy fingers and Raynaud’s phenomenon (RP) are important clinical predictors of the development of systemic sclerosis (SSc). We aim to assess the prevalence of SSc-related symptoms, explore pulmonary symptoms, and test the usefulness of skin autofluorescence (SAF) as a non-invasive marker for Advanced Glycation Endproducts (AGEs). Subjects from the Lifelines Cohort Study with known connective tissue disease (CTD) were excluded. Patient characteristics, SAF, self-reported pulmonary symptoms, and spirometry were obtained. Subjects ( Despite many efforts, the exact underlying pathology of systemic sclerosis (SSc) remains unknown, and effective disease-modifying treatment is currently unavailable ,2. AlthoIt was previously reported that the presence of Raynaud’s phenomenon (RP), puffy fingers, and positive Antinuclear Antibody (ANA) should be considered important predictors of an underlying SSc . A previPulmonary involvement, consisting of pulmonary arterial hypertension (PAH) and interstitial lung disease (ILD), is the leading cause of death in patients with SSc . HemodynHigher oxidative stress levels are associated with pulmonary involvement in SSc ,23,24. OWe aimed to assess the prevalence of SSc-related symptoms and SAF levels in the general population and in subjects with RP, without a known history of connective tissue disease (CTD), therefore attempting to estimate those at risk of developing or already suffering from undiagnosed SSc. Second, we focused on the pulmonary involvement (based on self-reported symptoms and pulmonary function tests) in subjects with self-reported RP and the possible association with SSc-related symptoms. Thirdly, we explored the role of SAF as a potential early biomarker for pulmonary involvement in patients with RP.We analyzed data from the Lifelines Cohort Study. Lifelines is a multi-disciplinary prospective population-based cohort study examining in a unique three-generation design the health and health-related behaviors of 167,729 persons living in the North of the Netherlands. It employs a broad range of investigative procedures in assessing the biomedical, socio-demographic, behavioral, physical, and psychological factors which contribute to the health and disease of the general population, with a special focus on multi-morbidity and complex genetics . Before For the present analysis, subjects were ≥18 years old. Subjects were excluded with self-reported underlying CTD including systemic lupus erythematosus, primary Sjögren syndrome, and systemic sclerosis (self-reported), or if the CTD screening questionnaire was missing. In accordance with the terms of Lifelines, numbers <10 were not reported to increase privacy (and decrease traceability of the participant).During the first visit to the Lifelines outpatient clinic, all subjects underwent a general clinical examination, followed by blood and urine collection. Body mass index (BMI) was calculated. Pulmonary function was measured with spirometry (Welch Allyn device version 1.6.0.489) according to standard operating procedures. The forced vital capacity (FVC) was used as a measure of lung function. Predicted FVC was calculated according to the following equations :FVCmen= is divided by the average excitation light intensity per nm (range 300 to 420 nm) and multiplied by 100 to calculate SAF (expressed in arbitrary units (AU)). A previous study found that when repeated SAF measurements were taken over one day the error was approximately 5%  of at least one SSc-related symptom (other than RP) was observed. Additionally, a prevalence of 7.1% [95% CI 5.9–6.2] of any SSc-related symptoms was observed in the non-RP group compared to 23.5% [95% CI 22.2–24.8] in the RP group . Univariate analysis showed that SAF was significantly associated with SSc-related complaints. In multivariate analysis, this association was no longer statistically significant after correcting for known potential confounders, including age, gender, BMI, self-reported heart failure, current smoking, diabetes, hypertension, hypercholesterolemia, and heart failure . In addition, subjects with RP and SSc-related symptoms had the lowest FVC mean (p = 0.009)  . Univari= 0.009) .In this large cohort of individuals from the general population without a known history of CTD, we found a three-fold higher prevalence of self-reported potential SSc-related symptoms in subjects with RP compared to those without RP. In addition, pulmonary symptoms, as a putative proxy of early pulmonary involvement, were more prevalent in subjects with self-reported RP and SSc-related symptoms.Early SSc is often characterized by at least two of the following signs: the presence of RP, puffy fingers, typical capillaroscopic changes, and SSc-specific antibodies. These signs form the bases of the internationally recognized criteria for “very early diagnosis of SSc” (VEDOSS) ,39. AlthAlthough it has been reported that the presence of RP, puffy fingers, and positive ANA should be considered important predictive signs of an underlying SSc, the predictive value of the different SSc-related symptoms examined in our study (in combination with RP), in the general population remains unknown . The curAlthough information on the predictive value of finger-tip lesions remains unknown, the current study found that finger-tip lesions were the least reported SSc-related symptom. The low prevalence of finger-tip lesions, as compared to the other SSc-related symptoms, may reflect the relatively good state of the microcirculation of these subjects . MoreoveIn our exploratory sub-study, we aimed to determine the prevalence of pulmonary symptoms in subjects with RP and SSc-related symptoms. The current study showed that pulmonary symptoms, as well as lower FVC volumes, were more prevalent in subjects with RP and SSc-related symptoms. It is important to mention that pulmonary complaints can have multiple etiologies in the general population. However, we have demonstrated that dyspnea at rest and dyspnea on exertion were associated with an increased risk of SSc-related symptoms in subjects with RP, independent of known confounders . Although studies reporting on the prevalence of preclinical organ involvement in subjects with pre-SSc or VEDOSS are very limited, Valentini et al. (2012) reported that preclinical lung abnormalities are common in patients with early SSc . In addi2α) levels (a urinary oxidative stress marker) and pulmonary involvement. The level of 8-iso-PGF2α is higher in SSc patients with lung involvement [Previous research has shown that there is a correlation between oxidative stress  and on the total lung capacity (TLC). The latter could give us a correct estimation of restriction due to ILD, and, therefore, may help us to disentangle common pulmonary complaints from SSc-related pulmonary involvement  [The current study has some limitations. First, the self-reported nature of the questions used could lead to an overestimation of the prevalence of SSc-related symptoms. Although this could indeed be the case, the questionnaire used in this study was previously validated to screen for CTDs in large population studies. Furthermore, the self-reported RP is not confirmed by a clinician, and it cannot be concluded whether participants all comply with the criteria of having RP. However, by the question regarding biphasic and triphasic discoloration, we think that most people comply with the criteria for having RP. Second, information on nailfold capillaroscopy and ANA test are not part of the general clinical examination of the Lifelines cohort. Therefore, the exact prevalence of VEDOSS remains unknown. Future studies need to confirm whether this first line of screening will yield a substantial number of potential SSc patients as indicated by our data. Third, we do not have information on the diffusing capacity for carbon monoxide (DLfailure) . FurtherThe current study demonstrated an increased prevalence of SSc-related symptoms in subjects with RP compared to those without RP, and an increased prevalence of pulmonary symptoms in those with both RP and SSc-related symptoms. Our results suggest that the prevalence of clinical features of SSc in the general population is higher than what could be expected based on the current literature. By demonstrating an increased prevalence of pulmonary symptoms (which could indicate lung involvement in patients with RP in combination with SSc-related symptoms), our study underscores the need to take these potential SSc-related symptoms seriously. SSc-related symptoms in patients with RP should always alert the patient and physician to proceed with serological, nailfold capillaroscopy investigations and lung functions tests including DLco, therefore allowing for prompt diagnosis, monitoring, and treatment of a life-threatening disease.


Accumulating evidence suggests that circRNAs play crucial roles in human diseases. CircRNA-disease association prediction is extremely helpful in understanding pathogenesis, diagnosis, and prevention, as well as identifying relevant biomarkers. During the past few years, a large number of deep learning (DL) based methods have been proposed for predicting circRNA-disease association and achieved impressive prediction performance. However, there are two main drawbacks to these methods. The first is these methods underutilize biometric information in the data. Second, the features extracted by these methods are not outstanding to represent association characteristics between circRNAs and diseases. In this study, we developed a novel deep learning model, named iCircDA-NEAE, to predict circRNA-disease associations. In particular, we use disease semantic similarity, Gaussian interaction profile kernel, circRNA expression profile similarity, and Jaccard similarity simultaneously for the first time, and extract hidden features based on accelerated attribute network embedding (AANE) and dynamic convolutional autoencoder (DCAE). Experimental results on the circR2Disease dataset show that iCircDA-NEAE outperforms other competing methods significantly. Besides, 16 of the top 20 circRNA-disease pairs with the highest prediction scores were validated by relevant literature. Furthermore, we observe that iCircDA-NEAE can effectively predict new potential circRNA-disease associations. CircRNA-disease association prediction is extremely helpful in understanding pathogenesis, diagnosis, and prevention, as well as identifying relevant biomarkers. In this paper, we proposed a novel deep learning-based method called iCircDA-NEAE to discover new potential circRNA-disease associations. Experimental results demonstrated that iCircDA-NEAE outperforms other state-of-the-art prediction methods, and can accurately predict potential circRNA-disease associations. Furthermore, according to the relevant literature, we observed that novel circRNA-disease associations predicted by iCircDA-NEAE are potential associations. The performance of iCircDA-NEAE mainly depends on three factors: (i) iCircDA-NEAE incorporates multi-source biometric information to measure complex associations between circRNAs and diseases. (ii) iCircDA-NEAE uses disease semantic similarity, Gaussian interaction kernel (GIP), circRNA expression profile similarity, and Jaccard similarity to make the most of biometric information in the data. (iii) iCircDA-NEAE incorporates the advantages of ANNE and DCAE, which not only effectively integrates multi-source information, but also effectively captures hidden high-level information of data. Circular RNAs (circRNAs) are a class of non-coding RNA characterized by a covalently closed-loop structure generated through a special type of alternative splicing termed back-splicing. Given that circRNAs lack free ends and are thus relatively stable, they are abundant in the eukaryotic transcriptomes. It has been shown that circRNAs are involved in various life activities of organisms, including functioning as microRNA (miRNA) sponges , regulatAt present, identifying circRNA-disease associations is appealing to find potential biomarkers and understand the diagnosis and treatment of diseases. However, the circRNA-disease associations are very complicated and remain still obscure. With the development of sequencing and analysis technology, various biological experiments have emerged to identify circRNA-disease associations –9. HowevRecently, researchers have proposed many deep learning-based methods to predict circRNA-disease associations. For example, GCNCDA , one of In this study, we developed a novel deep learning model for identifying Circrna-Disease Associations based on accelerated attribute Network Embedding and dynamic convolutional AutoEncoder (iCircDA-NEAE). The proposed model iCircDA-NEAE can (i) make the most of the bio-metric information in the data (ii) enhance the feature extraction capability of the model by using multiple feature extraction methods, and (iii) predict circRNA-disease associations accurately. Specifically, (i) circRNA-disease association data were collected from the circR2Disease database; (ii) disease semantic similarity, Gaussian interaction kernel (GIP), circRNA expression profile similarity, and Jaccard similarity were used to measure the biometric information in the data, then multisource information fusion descriptor was constructed; (iii) accelerated attribute network embedding (AANE) extracts features from the descriptor data; (IV) dynamic convolutional autoencoder (DCAE) extracts hidden features from data; (V) random forest classifier used hidden features to predict circRNA-disease association. The schematic overview of iCircDA-NEAE framework is shown in In a random forest classifier, max_feature determines the number of features in each decision tree. Too small max_feature may contain incomplete feature information, while too large max_feature led to overfitting problems. In this section, the important hyperparameter max_feature was investigated experimentally, whereas other hyperparameters were set to default values.The value of max_feature ranges from 0.1 to 0.5 . As showIn this section, the effects of AANE and DCAE were evaluated by ablation experiments with five different models. Specifically, (i) iCircDA-NEAE without AANE; (ii) iCircDA-NEAE without DCAE; (iii) iCircDA-NEAE without AANE and DCAE; (IV) DCAE replaced by CAE in iCircDA-NEAE; (V) AANE replaced by NE in iCircDA-NEAE.As shown in We compared the run time of iCircDA-NEAE with iCircDA-NEAE’ (DCAE replaced by CAE) on the NVIDIA RTX 3080 GPU with 10GB of VRAM. Experimental results show that the computation time (63 min 27 s) of iCircDA-NEAE is less than that (80 min 23 s) of iCircDA-NEAE’. CAE model are computationally more expensive than DCAE model. The detailed results were recorded in In this section, we compared iCircDA-NEAE with traditional machine learning algorithms as well as common deep learning algorithms, including SVM (Support Vector Machine) , RF (RotWe compared the performance of iCircDA-NEAE with the five classifiers by using benchmark dataset and two independent datasets (circR-NAdisease and circ2Disease datasets). The ROC curves on the three datasets were shown in In this section, the model performance was evaluated by using two independent datasets (circRNAdisease dataset and circ2Disease dataset) with 5-fold and 10-fold cross-validation. As shown in In this section, we used 5-fold cross-validation to compare the performance of iCircDA-NEAE with five state-of-the-art circRNA-disease association prediction models, including iCDA-CGR , GCNCDA In terms of features, although these state-of-the-art methods have used a variety of feature information, they can consider more biometric information. Our proposed iCircDA-NEAE considers both circRNA expression profile similarity and Jaccard similarity. To the best of our knowledge, we are the first to use both circRNA expression profile similarity and Jaccard similarity to predict circRNA-disease associations. Furthermore, our method performs multi-source feature fusion, which can measure the correlation of multiple feature information and fuse this information into a unified information identifier. At the same time, features without redundant information can effectively improve model performance.In terms of models, these state-of-the-art methods used traditional deep learning or machine learning algorithms. iCDA-CGR used chaos game representation (CGR) technology to quantify the nonlinear relationship of circRNA sequences. However, the model did not deal with redundant information resulting in poor predictive performance. IMS-CDA and ASAECDA are two deep learning methods based on stacked autoencoder (SAE), which use SAE to extract features from multi-source information. Compared with SAE, our proposed DCAE can capture high-level representations of the data. GCNCDA is a GCN -based prediction method, and GATCDA is a GTN (Graph Attention Network)-based prediction method. Compared with these two methods, iCircDA-NEAE incorporates the advantages of ANNE and DCAE, which not only effectively integrates multi-source information, but also effectively capture hidden high-level information of data.In this section, we applied iCircDA-NEAE to the benchmark dataset circR2Disease for predicting novel potential circRNA-disease associations. We sorted all unconfirmed circRNA-disease associations in descending order based on their prediction scores. The higher the score, the greater the likelihood of a circRNA-disease association. We selected the top 20 circRNA-disease associations  iCircDA-NEAE incorporates multi-source biometric information to measure complex associations between circRNAs and diseases. (ii) iCircDA-NEAE uses disease semantic similarity, Gaussian interaction kernel (GIP), circRNA expression profile similarity, and Jaccard similarity to make the most of biometric information in the data. (iii) iCircDA-NEAE incorporates the advantages of ANNE and DCAE, which not only effectively integrates multi-source information, but also effectively captures hidden high-level information of data.Two possible issues in this paper should be discussed: (i) since negative samples are difficult to obtain, we can only randomly select samples from unconfirmed samples as negative samples. The number of positive samples and negative samples is the same, thus avoiding the sample imbalance problem. But doing this will inevitably lead to negative samples containing very few true positive samples. (ii) since iCircDA-NEAE utilizes the strongly-supervised label information (true association labels) to predict circRNA-disease associations, so iCircDA-NEAE is overwhelmingly dependent on the quality of the ground truth association labels. Therefore, some more comprehensive methods should be proposed to solve the two issues in future works.http://bioinfo.snnu.edu.cn/) is the most comprehensive and commonly used database, this study used circR2Disease as the benchmark database. The circRNA expression profiles and disease information were collected from the exoRBase database (http://www.exoRBase.org) [http://www.nlm.nih.gov/mesh) [Since circR2Disease (ase.org)  and the ov/mesh) , respectWe constructed a sample-balanced circRNA-disease association dataset using the circR2Disease dataset. The association dataset contains 661 circRNAs, 100 diseases, 739 circRNA-disease positive associations, and 739 circRNA-disease negative associations. 739 circRNA-disease positive associations are experimentally validated associations, and 739 circRNA-disease negative associations are randomly selected from 66100 unknown associations of the circR2Disease dataset. The circRNAdisese database contains 330 circRNAs, 48 diseases and 354 circRNA-disease associations. The circ2Disease database contains 249 circRNAs, 61 diseases and 273 circRNA-disease associations.https://github.com/nathanyl/iCircDA-NEAE.First, iCircDA-NEAE uses disease semantic similarity, Gaussian interaction kernel (GIP), circRNA expression profile similarity and Jaccard similarity to measure the biometric information in the data, and constructs multisource information fusion descriptor. Second, AANE extracts feature from the descriptor data. Third, DCAE extracts hidden features from data. Finally, the random forest classifier uses hidden features to predict circRNA-disease association. The flow chart of iCircDA-NEAE is shown in A or a; lower case boldface indicates a vector quantity, as in a; upper case boldface indicates a matrix quantity, as in A.Before introducing the method, we summarize the notation used in this paper as follows: italic indicates a scalar quantity, as in Similarity measurement can convert the relationship between biological factors into feature information that can be used by the model, so it is a crucial step in building a prediction model. We constructed similarity matrices from four aspects: disease semantic similarity, Gaussian interaction profile kernel, circRNA expression profile similarity, and Jaccard similarity.d is used to represent information about disease d, Nd represents the set of disease nodes that are related to d and contain d itself, and Ed represents the set of edges between these diseases. For disease e, if Nd contains e and e = d, the disease contribution value of e to d is defined as 1(Dd(e) = 1). If e≠d, the disease contribution value is calculated as follows:μ is the semantic contribution factor between diseases, we set μ to 0.5 according to the study [Disease semantic similarity measures the relationship between diseases –40. The he study .DV(d) of disease d is defined as follows:Then, the semantic value DSS1(d(i), d(j)) between disease d(i) and d(j) is defined as follows:DSS1 is the disease semantic similarity matrix.In DAG, the more nodes are shared between two diseases, the more similar the two diseases are. The semantic similarity DSS1, the impact of disease number on disease contribution should also be considered. Inspired by Wang’s method [e under the influence of the disease number can be defined as follows:num(DAGd(e)) is the number of diseases associated with disease d and num(diseases) is the number of all diseases.While considering the disease semantic similarity s method , the conDSS2(d(i), d(j)) of disease d(i) and d(j) can be defined as follows:Then, the disease semantic similarity c1 is associated with disease d1, if disease d2 is highly similar to disease d1, then disease d2-associated circRNAs tend to have similar functions to circRNA c1 [di and dj, the formula is defined as follows:d(i) represents the row vector of the i-th disease and μ is the bandwidth parameter of the GIP, which can be calculated by the following formula:n is the number of rows of the circRNA-disease association matrix.To obtain comprehensive disease similarity information, we used Gaussian interaction profile (GIP) –45 kernercRNA c1 . Therefoc(i) represents the column vector of the i-th circRNA and μ is the bandwidth parameter of the GIP, which can be calculated by the following formula:m is the number of columns of the circRNA-disease association matrix.Similarly, the GIP kernel similarity between circRNAs is defined as follows:dp is the feature vector difference between circRNA i and circRNA j, li represents the 32-dimensional vector of i-th circRNA after sorting, and k is the number of circRNAs. Let SE be an k×k circRNA adjacency matrix consisting of ρ.The circRNA expression profile (EP) similarity from exoRBase data-base is another important information for constructing circRNA-disease association prediction models. We used 32-dimensional feature vectors to represent circRNAs, and sorted the circRNAs in descending order according to the feature vectors ,47,48. SJ is the ratio of the intersection of sets A and B to the union of A and B. The larger the Jaccard value, the higher the similarity between sets A and B. We used Jaccard to calculate the similarities between diseases and circRNAs. We calculated the Jaccard similarity of disease d(i) and disease d(j) with the following formula:JD is the Jaccard similarity matrix between diseases. ca(d(i)) represents the circRNAs associated with disease d(i).Jaccard similarity is used to represent the similarity between sets –52. J) represents the diseases associated with circRNA c(i).The Jaccard similarity calculation formula of circRNAs is defined as follows:The multisource feature fusion method can fuse a variety of biological feature information, eliminate redundant information, and improve the accuracy of feature extraction. Feature fusion was used to integrate multiple similarity information into a unified identifier, which contains a large number of circRNA and disease feature information, and contains multiple association information. The fusion of disease similarity multisource in-formation can be defined as follows:The fusion of circRNA similarity multisource information can be defined as follows:CM and DM, and obtain CM and DM. The fusion information of circRNA and disease is obtained according to the following formula:CM(c(i)) represents the i-th row vector of CM, and DM(d(j)) represents the j-th column vector of DM.Finally, we used principal component analysis (PCA)  to reducAM be an m×n adjacency matrix corresponding to the circRNA-disease association dataset from circR2Disease database, where m (m = 661) is the number of circRNAs and n (n = 100) is the number of diseases. If AM = 1, it means that circRNA c(i) is associated with disease d(j), otherwise AM = 0.Let Compared with widely used feature extraction methods PCA, LINE  , node2veV, E, W), V is the node set, W is the edge set, and the edge eij in W represents the edge connecting node i and node j. The value of eij is closely related to the similarity between nodes. The larger the value of eij, the more similar node i is to node j. According to the theory that a real symmetric matrix can be diagonalized by an orthogonal matrix, the formula is defined as follows:A is a semi-definite symmetric matrix, which can be represented by an orthogonal matrix H and a diagonal matrix Λ. B is a matrix consisting of the square root of the elements in the Λ.For a network N =  is used to solve the objective function:Node vectors have high similarity in two situations, one is that the nodes have high similarity in topological structure, and the other is that the weight value between nodes is large. The objective function is defined as follows:x passes through the dynamic convolution layer, the pooling layer and hidden layer to obtain an output vector y. This process is called encoding. The encoding formula is as follows:Πk denotes the attention weight of the K-th linear function, ⨂ de-notes the convolution operation, W and b are the weight matrix and bias vector, g is the sigmoid activation function, Convolutional autoencoder (CAE) can efficiently extract hidden features from data ,58. Inspy passes through the deconvolution layer and the out-put layer to obtain the reconstructed vector x’. This process is called decoding. The formula for decoding is as follows:Then, the input x’ and the input vector x, and optimized the value of the loss function to a threshold. An optimization process was performed at each layer.During the training of each layer, we computed the loss function between the reconstruction vector x to obtain the optimal aggregation model. Therefore, the dynamic convolutional autoencoder can achieve better higher level representations than the ordinary autoencoder. The dynamic convolution consists of three parts, including attention weights, H×W×Cin is much smaller than that of ordinary convolution. The computational cost is as follows:O(•) denotes computational cost, Dk denotes kernel size, Cout denotes the number of output channels. The computational cost of attention weights is much lower than directly calculating the optimal parameters. DCAE has better flexibility and lower computational cost than ordinary autoencoders.The attention weights will vary according to In the experiment, we set the DCAE as a two-layer network with a learning rate of 0.001, using minimum mean squared error (MSE) as the loss function and gradient descent algorithm as the optimization method.In the experiment, a random forest classifier used the extracted features to complete a classification task to discover potential circRNA-disease associations. The execution steps of the random forest classifier can be summarized as follows:N samples using Bootstrap method. The selected N samples are used to train a decision tree.The classifier selects M features of the sample (m << M), and selects one feature from the m features as the split feature of the node using the information gain ratio. In the process of forming a decision tree, each node is split until it can no longer be split.The classifier randomly selects m features from the According to steps 1~2, a large number of decision trees are constructed to form a random forest.The random forest classifier predicts scores for circRNA-disease associations. An association is considered a potential association if the prediction score is greater than a set threshold. The grid search algorithm was used to determine parameters in the classifier, and the number of decision trees was set to 100.k-fold cross-validation and independent dataset testing) were used to evaluate the model performance. In the experiments, we recorded the true positive (TP), false negative (FN), true negative (TN) and false positive (FP) values. Five evaluation metrics were used to assess the model, namely area under curve (AUC), accuracy (ACC), sensitivity (Sen), F1-Score and Matthew correlation coefficient (MCC). These evaluation metrics are defined as follows:The two commonly used methods (S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.


Self-harm and suicidality are associated with substantial social and economic burden, especially among children, adolescents and young adults. The aim of this review was to systematically synthesize the literature on the association between health-related quality of life and self-harm/suicidality in children, adolescents and young adults.Searches were conducted via MEDLINE, PsycINFO, CINAHL, EconLit and EMBASE. Search terms were the combination of the following blocks: (1) self-harm/suicidality, (2) health-related quality of life/well-being/life satisfaction and (3) children/adolescents/young adults. The quality of studies was assessed using the Effective Public Health Practice Project tool.n = 8), 39% (n = 9) and 26% (n = 6) of studies were scored as ‘Strong’, ‘Moderate’ and ‘Weak’, respectively.We identified 23 relevant studies. Findings showed that participants who reported self-harm had lower well-being, life satisfaction or overall health-related quality of life compared to those without self-harm. There was also evidence supporting the association between health-related quality of life and suicidal attempt. However, the results for the association with suicidal ideation remained inconsistent. Additionally, mental health, emotional well-being, physical health, oral health, existential well-being and family quality of life were found to be significant domains associated with self-harm or suicidality. Regarding the quality of included studies, 35% . There was also no evidence to infer the direction of causality between health-related quality of life and self-harm/suicidality. The findings suggest a need for further research, in particular longitudinal studies to fill identified gaps in the literature. According to international statistics, 13.7% of children and adolescents reported self-harm in their lifetime  is a multi-dimensional concept that extends to the physical, mental and social aspects of well-being and functioning  and can truments . Genericsponsive . Among bsponsive .Exploring the association between HRQoL and self-harm/suicidality in young people is important from a descriptive, disease burden perspective as well as from an economic perspective. By investigating distinct QoL dimensions, insights into the decrements of a young person’s functioning and well-being may be gained. The research findings will correspondingly help inform understandings of self-harm and suicidal risk, contributing to the development of effective suicide prevention strategies among young populations. The importance of prevention programmes is undeniable in terms of the obvious benefits with regard to lives saved and emotional trauma avoided . From thThis review followed the guidelines in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses: the PRISMA statement . The revSupplemental Appendix 1). Finally, a secondary search was conducted before final analysis to retrieve additional articles for inclusion up to May 2022.Searches were conducted in the following databases: MEDLINE, PsycINFO, CINAHL, EconLit and EMBASE in July 2021. A supplementary search was also undertaken by hand to identify additional articles. The search terms included a broad range of terms and were combined in the following blocks: (1) self-harm or suicidality, (2) HRQoL or well-being or life satisfaction and (3) children or adolescents or young adults  with self-harm/suicidality. Moreover, studies on young people with self-harm/suicidality were eligible for inclusion regardless of whether they had other health conditions.There was no restriction on the types of study design .QoL, well-being and life satisfaction, these terms are often used interchangeably to refer to a person’s subjective perception of aspects of life  were included. It should be noted that reported outcomes could be HRQoL scores measured by any non-preference-based or preference-based instruments . Furthermore, although some researchers suggest that there are major differences among  of life , 2018b. Data from the searches were imported into an electronic software package (Endnote® version 20)  by the fUsing the Effective Public Health Practice Project  tool, thWe used narrative synthesis to report findings from the included studies. Due to the data’s heterogeneity , a meta-analysis could not be conducted. , followed by the United States (n = 5), Asia (n = 5), Australia (n = 2), Africa (n = 2) and South America (n = 1).In summary, among the 23 included studies, there were 20 studies based on self-report and 3 studies based on both self-report and parent proxy report . Sample n = 8), 39% (n = 9) and 26% (n = 6) of studies were scored as ‘Strong’, ‘Moderate’ and ‘Weak’, respectively. Almost all studies used reliable and valid data collection tools  and were therefore rated as ‘Strong’ for this component. For example, two studies used the Satisfaction with Life Scale (SWLS) with Cronbach’s alpha = 0.74 , the SWLS and the Warwick-Edinburgh Mental Wellbeing Scale (WEMWBS) were the most commonly used. Twelve studies used generic non-preference-based HRQoL instruments and only one study used a preference-based HRQoL instrument . Among non-preference-based instruments, the Inventory of Life Quality for Children and Adolescents (ILK) and the SF-36 survey were most frequently used.Among the group of 10 studies using well-being or life satisfaction scales, 3 studies reported results for self-harm and 7 studies reported results for suicidality. Findings generally showed that self-harm was inversely associated with overall well-being or life satisfaction . In seveFindings with respect to non-preference-based HRQoL instruments showed that self-harm was significantly associated with worse overall HRQoL . There wThe only study to find that participants who self-harmed and reported suicidal ideation had significantly lower utility scores than those who did not have such behaviours as measured by the CHU9D instrument was by It is noteworthy that there were three studies investigating the association between HRQoL and self-harm/suicidality in relation to a mediational relationship with other interested factors. Specifically, p-value = 0.074), Resch et al. found that parents rated their children/adolescents with higher HRQoL than the children/adolescents scored themselves   . Both thTo the best of our knowledge, this is the first systematic review on the association between self-harm/suicidality and HRQoL in young people. Not surprisingly, our synthesis showed that findings from included studies reported an inverse association between self-harm/suicidality and overall HRQoL. This outcome remained the same irrespective of the types of scales used. The outcome might support the notion that people with relatively poorer HRQoL might be more likely to self-harm or to be suicidal. Alternatively, it might suggest that people who reported self-harm or suicidal individuals might ultimately have poorer HRQoL. Moreover, findings on the association between specific HRQoL domains and self-harm/suicidality provided insights into which aspects of people HRQoL are associated with self-harm/suicidality. Mental health, emotional well-being, physical health, oral health, existential well-being and family QoL were all found to be significant domains associated with reductions in HRQoL in those who reported self-harm/suicidality.Furthermore, evidence of the association between self-harm/suicidality and family QoL suggests that family might play a significant role for young people who are under 18 years old and have these thoughts and behaviours. This result was in line with previous research that emphasized the impacts of various family-related factors on self-harm/suicidality in this population. For example, there was evidence from two studies that those who engaged in self-harm reported impairments in general family functioning and had lower quality interaction with their parents than those without these behaviours . AnotherAnother important issue related to HRQoL measurement in young people is the issue of informants. Although many instruments rely substantially on child/adolescent self-report, self-report questionnaires may be problematic, particularly for younger children who lack the necessary language skills, cognitive capacity and long-term view of events . ConsequFindings suggest that the association between HRQoL and self-harm/suicidality could be in either direction or reciprocal. All of the studies included in this review were cross-sectional and none were longitudinal. Thus, there were no findings about how the relationship between HRQoL and self-harm/suicidality plays out over time and the direction of causality could not be inferred. In addition, findings on the association between HRQoL and self-harm/suicidality in relation to a mediational relationship with other factors implied that there might be other mechanisms driving their association. On the one hand, there might be aetiological factors that impact both HRQoL and self-harm/suicidality. For example, more emotional and peer problems resulted in lower HRQoL that, in turn, increased suicidal risk . On the The current review has some limitations. First, although a comprehensive search was conducted across many databases, the review excluded studies that were not published in English. Therefore, this may limit the relevance of our findings in non-English cultures and mean that we retrieved fewer studies from low- and middle-income countries. Second, it is possible that we might have missed studies where HRQoL was one of many exposure variables for self-harm/suicidality and was not explicitly listed in the title and abstract of the given article. Third, the diversity and heterogeneity of populations and scales/instruments considered in the studies presented a challenge for the review team in synthesizing results and drawing relevant conclusions. Finally, despite the importance of HRQoL as an outcome measurement for humans’ well-being and functioning in health research, it is undeniable that the construct of HRQoL has its own limitations. There has been an argument that HRQoL instruments mostly focus on a person’s functioning ability rather than well-being or how the person values his or her own health status . The argThis review provided an overview of literature on the relationship between HRQoL and self-harm/suicidality in young people. Results from included studies showed there was an inverse association between self-harm/suicidal attempt and overall HRQoL irrespective of whether the included studies used well-being scales, life satisfaction scales, preference- or non-preference-based HRQoL instruments. Findings on specific QoL domains also suggested a number of QoL domains to be significantly associated with self-harm/suicidality in young people. We also identified different HRQoL according to the severity of suicidality (from ideation to attempt). Further research based on longitudinal study designs is required to fill these gaps in the literature.Click here for additional data file.Supplemental material, sj-docx-1-anp-10.1177_00048674231165477 for Health-related quality of life in children, adolescents and young adults with self-harm or suicidality: A systematic review by Ngoc Le, Yared Belete Belay, Long Khanh-Dao Le, Jane Pirkis and Cathrine Mihalopoulos in Australian & New Zealand Journal of Psychiatry