Drug-drug interaction and acute kidney injury development: A correlation-based network analysis.

BACKGROUND: Drug-induced nephrotoxicity is a relatively common preventable cause of acute kidney injury (AKI), providing early recognition and management. The pharmacokinetics or pharmacodynamics of drug-drug interactions may lead to additive or synergistic toxicity. The influx of new medications or off-label use of medications in the critical care setting can lead to additional nephrotoxicities, often challenging to predict or detect. This study evaluates the patterns of medication utilization, their combinations, and the related associations with AKI. METHODS: We utilized correlation-based network analysis (CNA) to investigate the relationship between medications or their combinations with AKI in a large cohort of critically ill patients in a tertiary medical center between 2007 and 2018. Pairwise medication-AKI correlation analysis was performed to evaluate drug synergistic or additive effects. To investigate the inherent nephrotoxicity of medications, we further analyzed medications that were not paired with any other medications within 24 hours before or after their administration time (isolated medication analysis). RESULTS: Among 147,289 ICU admissions, we identified 244 associations among 1,555 unique medication types. In pairwise analysis, 233 significant correlations were found among 13,150,198 medication pair instances. In isolated medication analysis, ten significant AKI associations were noted. When stratified by eGFR level, substantial differences between eGFR<90 vs. eGFR≥90 patients were observed. This highlights a need to determine eGFR as a risk factor for nephrotoxicity assessment when drug interactions are considered. CONCLUSIONS: This large-scale cohort study identified an artificial intelligence model to identify patient-agnostic relationships between medication or their pairs with AKI incidence among critically ill patients. It could be used as a continuous quality assurance tool to monitor drug-associated risk nephrotoxicity.

Randomized multicenter phase II trial of prophylactic irradiation of para-aortic lymph nodes in advanced cervical cancer according to tumor hypoxia: Korean Radiation Oncology Group (KROG 07-01) study.

We conducted a prospective phase II study on whether extended-field irradiation (EFI) confers survival benefits depending on hypoxic markers in locally advanced uterine cervical cancer (LAUCC). RNA-seq was performed to identify immune and hypoxic gene signatures. A total of 288 patients were randomized to either EFI or pelvic radiotherapy (PRT). All patients completed chemoradiotherapy. Overall, significantly higher 5-year para-aortic recurrence free survival (PARFS) rate occurred in EFI (97.6%) than in PRT group (87.2%), with marginal tendency to improve disease-free survival (DFS; 78% vs 70%, P = .066). Subgroup analyses were performed based on carbonic anhydrase 9 (CA9)-only positive, CA9/hypoxia-inducible factor (HIF) double positive and CA9 negative. In the CA9-only positive, EFI successfully increased 5-year PARFS (100% vs 76.4%, P = .010), resulting in significantly improved long-term DFS (85.7% vs 54.7%, P = .023) compared to the PRT, while there was no such benefit of EFI in the CA9/HIFs double positive. RNA-seq analysis identified distinct immunehigh subgroup with negative correlation with hypoxia gene signatures (R = -.37, P < .01), which showed a higher 5-year DFS than the immunelow (P = .032). Hypoxia-related genes were upregulated in the CA9/HIFs double positive compared to CA9 negative (P < .05). Only 17.4% of patients in CA9-negative group showed immunelow signatures, while 40.0% of patients in the double-positive group exhibited immunelow signatures. In conclusion, EFI improved PARFS significantly in all patients, but therapeutic efficacy of EFI in terms of improved DFS was solely observed in CA9-only positive LAUCC, and not in CA9/HIFs double-positive subgroup. RNA-seq analysis suggested that hypoxia-induced immunosuppression may be related to treatment resistance in LAUCC.

Assessing the global burden of hemorrhage: The global blood supply, deficits, and potential solutions.

There is a critical shortage of blood available for transfusion in many low- and middle-income countries. The consequences of this scarcity are dire, resulting in uncounted morbidity and mortality from trauma, obstetric hemorrhage, and pediatric anemias, among numerous other conditions. The process of collecting blood from a donor to administering it to a patient involves many facets from donor availability to blood processing to blood delivery. Each step faces particular challenges in low- and middle-income countries. Optimizing existing strategies and introducing new approaches will be imperative to ensure a safe and sufficient blood supply worldwide.

A prediction and interpretation framework of acute kidney injury in critical care.

Acute kidney injury (AKI) is a common clinical condition with high mortality and resource consumption. Early identification of high-risk patients to achieve an appropriate allocation of limited clinical resources and timely interventions is of significant importance, which has attracted substantial research to develop prediction models for AKI risk stratification. However, most available AKI prediction models have moderate performance and lack of interpretability, which limits their applicability in supporting care intervention. In this paper, a machine learning-based framework for AKI prediction and interpretation in critical care is presented. First, an ensemble model is developed to predict a patient's risk of AKI within 72 h of admission to the intensive care units. Next, the model is interpreted both globally and locally. For the global interpretation, the important predictors are pinpointed and the detailed relationships between AKI risk and these predictors are illustrated. For the local interpretation, patient-specific analysis is presented to provide a visualized explanation for each individual prediction. Experimental results show that such a prediction and interpretation framework can lead to good prediction and interpretation performance, which has the potential to provide effective clinical decision support.

Epidemiological Association Between Systemic Diseases and Keratoconus in a Korean Population: A 10-Year Nationwide Cohort Study.

PURPOSE: To investigate the association of systemic diseases with keratoconus in the general Korean population. METHODS: This is a nationwide population-based retrospective cohort study using the Korean National Health Insurance Service-National Sample Cohort database from 2002 to 2015, involving 1,108,369 individuals. Patients with keratoconus were identified using the Korean standard classification of diseases code H18.6. The prevalence and annual incidence rates were estimated. To examine the risk factors, 5 controls were matched per patient with keratoconus by propensity score matching using age and household income. Univariate and multivariate regression analyses were performed to assess the association between relevant factors and keratoconus. RESULTS: A total of 613 subjects were identified as patients with keratoconus from the cohort database. The prevalence rate was 55.31 cases per 100,000 people [95% confidence interval (CI): 51.01-59.86]. The annual incidence rate, calculated using a predate 1-year washout period, was 4.47 cases per 100,000 person-years (95% CI: 4.11-4.85). People with allergic conjunctivitis had a 37% increased odds of being diagnosed with keratoconus [odds ratio: 1.37 (95% CI: 1.12-1.67), P = 0.002] compared with those without allergic conjunctivitis. By contrast, people with allergic rhinitis had a 52% reduced odds of being diagnosed with keratoconus [odds ratio: 0.48 (95% CI: 0.38-0.59), P < 0.001]. Atopy and eczema, asthma, connective tissue disorders, diabetes mellitus, sleep apnea, and inflammatory bowel disease had no significant association with a positive keratoconus diagnosis. CONCLUSIONS: Allergic conjunctivitis may increase the risk of developing keratoconus in Koreans.

Visual Performance after a Unilateral or Bilateral Implantation of Enlarged Depth-of-Focus Intraocular Lens in Patients with Cataract: A Prospective Clinical Trial.

PURPOSE: To investigate visual performances after a unilateral or bilateral implantation of enlarged depth-of-focus intraocular lens in patients with cataract. METHODS: In this prospective study, uneventful phacoemulsification and TECNIS® Symfony intraocular lens implantation were performed in 20 eyes of 17 patients. At postoperative 1, 4, and 12 weeks, the logarithm of the minimal angle of resolution visual acuity at far, intermediate, and near distances and the spherical equivalent in manifest refraction and automated refraction were measured. A questionnaire was used to investigate glare, spectacle dependency, and satisfaction at 12 weeks. The mean numerical error and mean absolute error were compared between intraocular lens formulas to assess the best-fit formula. RESULTS: The logarithm of the minimal angle of resolution visual acuity significantly improved to 0.02 at far, 0.02 at intermediate, and 0.27 at near distances at 12 weeks (p < 0.05). Spherical equivalent was -0.79 D on automated refraction and was significantly lower than -0.26 D measured on manifest refraction. Patients' satisfaction score was 9.06, 8.94, and 6.65 for far, intermediate, and near distances, respectively. Near glasses were required in 5 patients and 2 patients complained of photic phenomenon. Visual performances were not significantly different between bilateral and unilateral implanted patients. No patients reported bilateral imbalance due to unilateral surgery. The mean numerical error was closest to 0 D using the Barrett Universal II formula. The mean absolute error was not significantly different between these formulas. CONCLUSION: Unilateral or bilateral implantation of the enlarged depth-of-focus intraocular lens seems to be equally effective in improving visual performances in patients with cataract.

Bilateral Effect of the Unilateral Corneal Nerve Cut on Both Ocular Surface and Lacrimal Gland.

Purpose: This study investigated the effect of a unilateral cut of the corneal nerve on the bilateral ocular surface and tear secretory function. Methods: Seven-week-old female BALB/c mice were divided into control and nerve-cutting (NC) groups (n = 60). The left cornea was partially incised with a 2-mm circular trephine through the upper half of the stromal layer. Lissamine green corneal staining and tear volume measurements were conducted, and corneal whole-mount staining using class III ß-tubulin antibody was performed to assess corneal nerves. Flow cytometric analyses for dendritic cells (DCs), CD4+/CD8+ and regulatory T cells and ELISA for neuropeptides were performed. Results: The grading of corneal staining increased in the NC group, while the tear volume decreased over the 4 weeks. The nerve density decreased in bilateral corneas over 2 weeks. At day 14, CD11b+ or CD11c+ DCs and the mature DCs expressing CD86 or MHCII increased in bilateral cornea/conjunctiva. At day 28, CD11c+CD86hi, CD11c+MHCIIhi, Th17 and IFN-γ-secreting CD8+ T cells highly increased in bilateral draining lymph nodes. CD4+CD25hiFoxp3hi and CD8+CD25hiFoxp3hi regulatory T cells notably increased in the spleen. In ELISA, neuropeptide Y, calcitonin gene-related peptide, and vasoactive intestinal peptide were generally suppressed in the extraorbital lacrimal glands at day14. Conclusions: The unilateral corneal nerve severing resulted in activation of the immune cells on the ocular surface and dysregulated lacrimal secretion bilaterally through the bidirectional neuronal signals. It suggests that the unilateral corneal nerve damage may alter immune homeostasis and mechanistically participate in the development of bilateral inflammatory disorders such as dry eye.

Reducing COPD readmissions through predictive modeling and incentive-based interventions.

This paper introduces a case study at a community hospital to develop a predictive model to quantify readmission risks for patients with chronic obstructive pulmonary disease (COPD), and use it to support decision making for appropriate incentive-based interventions. Data collected from the community hospital's database are analyzed to identify risk factors and a logistic regression model is developed to predict the readmission risk within 30 days post-discharge of an individual COPD patient. By targeting on the high-risk patients, we investigate the implementability of the incentive policy which encourages patients to take interventions and helps them to overcome the compliance barrier. Specifically, the conditions and scenarios are identified for either achieving the desired readmission rate while minimizing the total cost, or reaching the lowest readmission rate under incentive budget constraint. Currently, such models are under consideration for a pilot study at the community hospital.

An Analytical Framework for TJR Readmission Prediction and Cost-Effective Intervention.

This paper introduces an analytical framework for assessing the cost-effectiveness of intervention strategies to reduce total joint replacement (TJR) readmissions. In such a framework, a machine learning-based readmission risk prediction model is developed to predict an individual TJR patient's risk of hospital readmission within 90 days post-discharge. Specifically, through data sampling and boosting techniques, we overcome the class imbalance problem by iteratively building an ensemble of models. Then, utilizing the results of the predictive model, and by taking into account the imbalanced misclassification costs between readmitted and nonreadmitted patients, a cost analysis framework is introduced to support decision making in selecting cost-effective intervention policies. Finally, using this framework, a case study at a community hospital is presented to demonstrate the applicability of the analysis.

Corneal dysplastic melanosis associated with recurrent corneal erosions: A case report.

RATIONALE: Pigmented lesions of conjunctiva and cornea can be observed in various conditions, from the benign nevus to malignant melanoma. Pigmented acquired melanosis (PAM) is one of them, which is a neoplastic proliferation with malignant transformation potential of melanocytes. However, to our knowledge, there has been no report as to a disturbance of corneal barrier function caused by PAM. Here we report a case of corneal PAM which led to recurrent corneal erosions. PATIENT CONCERNS: A 60-year-old woman was referred with a 4-month history of intractable recurrent epithelial erosions in the left eye. She denied any history of ocular trauma or surgery. Slit-lamp examination showed small epithelial defects and loose epithelium of overlying pigmented corneal lesions. The pigmentations were scattered in the corneal epithelial layer, from limbus to the central cornea. DIAGNOSIS: Conservative treatment with therapeutic contact lens and oral doxycycline did not completely cure the corneal erosion. En bloc resection of the pigmented epithelium with cryotherapy and temporary amniotic membrane transplantation were performed. Histopathologic examination demonstrated pigmented melanocytes with mild atypia, scattered mainly in the corneal basal epithelium. Immunohistochemically, the cells were positive for Melan A/MART-1 and negative for CD68 and S100. The Ki-67 proliferation index was low. Therefore, it was diagnosed as primary acquired dysplastic melanosis causing epithelial barrier dysfunction. INTERVENTIONS: We performed en bloc resection of the pigmented epithelium with cryotherapy and temporary amniotic membrane transplantation. OUTCOMES: After the resection, recurrent corneal erosions and epithelial loosening were completely resolved. Although some pigmented lesions were recurred in the limbal epithelium at 8 o'clock, corneal erosion did not recur during the follow-up for 9 months. LESSONS: Our report suggests that primary acquired dysplastic corneal melanosis may cause epithelial dysfunction resulting in recurrent corneal epithelial erosions.

Comparison of a new swept-source optical biometer with a partial coherence interferometry.

BACKGROUND: The purpose of this study is to compare the biometric parameters and intraocular lens (IOL) power calculation by a new swept-source optical coherence tomography (SS-OCT) biometer with those by a partial coherence interferometry (PCI) biometer. METHODS: Medical records of 175 eyes from 175 patients were retrospectively reviewed. One of two monofocal IOLs (Tecnis ZCB00 or Acrysof SA60AT) were implanted in the eyes. Axial length (AL), mean keratometry (Km), J0, J45 and anterior chamber depth (ACD) were compared between PCI and SS-OCT biometers. The refractive mean error (ME) and refractive mean absolute error (MAE) were also compared. Examination failure rates were calculated in each device. RESULTS: Out of 175 eyes, 150 eyes were successfully examined by both devices. AL was measured slightly shorter when using SS-OCT than PCI biometer, while Km was measured higher (P < .0001, P = .03, respectively, paired t-test). J0, J45 and ACD were not significantly different between two devices. ME and MAE calculated using SRK-T, Hoffer Q, and Haigis formula were not significantly different except MAE calculated with Haigis formula for Tecnis ZCB00 IOLs (P = .03, paired t-test). The examination failure rates were 14.29 and 1.14% when using the PCI and SS-OCT biometers, respectively. CONCLUSIONS: AL and Km don't seem to be comparable between two devices, while J0, J45, and ACD do. IOL power calculation using SRK-T and Hoffer Q was correlated between the devices. The penetration ability of a SS-OCT biometer is superior.

Protection of Corneal Limbus from Riboflavin Prevents Epithelial Stem Cell Loss after Collagen Cross-Linking.

PURPOSE: To investigate whether the protection of corneal limbus from riboflavin exposure during collagen cross-linking (CXL) prevents limbal epithelial stem cell (LESC) loss. METHODS: Ten New Zealand white rabbits received an epithelium-off CXL using an accelerated protocol. Seven days before procedure, 5-bromo-2-deoxyuridine (BrdU) was intraperitoneally injected. During procedure, riboflavin was applied to the corneal surface within a 9 mm diameter retention ring in 5 rabbits, thereby preventing the limbus from riboflavin exposure. In other 5 rabbits, riboflavin was instilled every 2 min, allowing the spillover to the limbus. One day after UVA irradiation, corneas were subjected to histological and molecular assays. RESULTS: There were no differences in corneal thickness and epithelial healing between the groups. The numbers of BrdU-labelled and p63+ limbal epithelial cells were markedly reduced in the group without a ring, but significantly increased when a ring was used. Robust expression of CK3/12 was observed in the limbal epithelium in the group with a ring. The mRNA levels of ABCG2, FGF2, IL-1ß, and IL-6 were significantly increased in the corneas with a ring. CONCLUSIONS: Protection of limbus from riboflavin during CXL was effective in preserving LESCs. However, inflammation was increased in the cornea treated with riboflavin using a ring.

Corneal Abnormalities in Congenital Aniridia: Congenital Central Corneal Opacity Versus Aniridia-associated Keratopathy.

PURPOSE: To clinically characterize and compare 2 types of corneal abnormalities in patients with congenital aniridia: (1) congenital central corneal opacity from birth (CCO) and (2) aniridia-associated keratopathy (AAK) that develops progressively with age. DESIGN: Retrospective cohort study. METHODS: Medical records of Korean patients who were diagnosed with congenital aniridia at Seoul National University Hospital between 1991 and 2016 were reviewed. Prevalence of corneal abnormalities (CCO and AAK), other ocular and systemic comorbidities, severity of AAK depending on the age, logarithm of the minimum angle of resolution (logMAR) visual acuities, and types and results of surgical intervention were collected. RESULTS: Among a total of 275 eyes (138 patients), 13% (35 eyes, 20 patients) had CCO and 25% (68 eyes, 35 patients) developed AAK. The AAK became prominent at a mean of 21.6 years of age, and the severity progressed with age. Glaucoma was more prevalent in aniridia patients with CCO (74%), compared to those with AAK (37%) (P = .0003). Cataract frequently occurred in patients with AAK (78%), who required cataract surgeries at mean 26.6 years. The logMAR visual acuity was worse in patients with CCO (2.04 ± 0.71) than in those with AAK (1.29 ± 0.62) (P < .0001). Penetrating keratoplasty was performed in 6 eyes with CCO, and the graft survival was 33.3% during mean 45 months of follow-up (range 14-79 months). CONCLUSIONS: In total, 13% of aniridia patients had CCO at birth, while 25% progressively developed clinically significant AAK with age. The visual outcome was worse in patients with CCO than in those with AAK.

Reducing Bottlenecks to Improve the Efficiency of the Lung Cancer Care Delivery Process: A Process Engineering Modeling Approach to Patient-Centered Care.

The process of lung cancer care from initial lesion detection to treatment is complex, involving multiple steps, each introducing the potential for substantial delays. Identifying the steps with the greatest delays enables a focused effort to improve the timeliness of care-delivery, without sacrificing quality. We retrospectively reviewed clinical events from initial detection, through histologic diagnosis, radiologic and invasive staging, and medical clearance, to surgery for all patients who had an attempted resection of a suspected lung cancer in a community healthcare system. We used a computer process modeling approach to evaluate delays in care delivery, in order to identify potential 'bottlenecks' in waiting time, the reduction of which could produce greater care efficiency. We also conducted 'what-if' analyses to predict the relative impact of simulated changes in the care delivery process to determine the most efficient pathways to surgery. The waiting time between radiologic lesion detection and diagnostic biopsy, and the waiting time from radiologic staging to surgery were the two most critical bottlenecks impeding efficient care delivery (more than 3 times larger compared to reducing other waiting times). Additionally, instituting surgical consultation prior to cardiac consultation for medical clearance and decreasing the waiting time between CT scans and diagnostic biopsies, were potentially the most impactful measures to reduce care delays before surgery. Rigorous computer simulation modeling, using clinical data, can provide useful information to identify areas for improving the efficiency of care delivery by process engineering, for patients who receive surgery for lung cancer.

Corneal keloid: four case reports of clinicopathological features and surgical outcome.

BACKGROUND: Surgical outcome of corneal keloid is largely variable depending on reports, although surgical management is inevitable in visually significant cases. We here report clinical features, histopathological findings, and surgical outcome of four cases of corneal keloid. CASE PRESENTATION: Four Korean male patients without a history of corneal trauma or disease were clinically and histologically evaluated for a slowly-growing, white opacity in the cornea. On slit lamp examination, corneal lesions appeared as a solitary, pearly white, well-circumscribed nodule with a smooth and glistening surface. Because the lesions involved the visual axis deteriorating the visual acuity, the nodules were surgically removed by superficial keratectomy in all patients. Amniotic membrane transplantation was combined in three patients, and an intraoperative mitomycin C application in two patients. Hematoxylin-eosin staining of the excised nodules revealed epithelial hyperplasia, Bowman's layer disruption, thick and irregularly-arranged collagen fibers in the stroma, and accumulation of prominent fibroblasts, which are consistent with the diagnosis of corneal keloid. The corneal keloids recurred in all patients within 10 months of surgical excision and outgrew the boundary of the excised area. CONCLUSION: A diagnosis of corneal keloid should be suspected in patients presenting with an enlarging, white, glistening corneal nodule, even in the absence of a history of corneal trauma or disease. The recurrence is common after surgical excision, and the lesion can be exacerbated by surgery.

Computer modeling of lung cancer diagnosis-to-treatment process.

We introduce an example of a rigorous, quantitative method for quality improvement in lung cancer care-delivery. Computer process modeling methods are introduced for lung cancer diagnosis, staging and treatment selection process. Two types of process modeling techniques, discrete event simulation (DES) and analytical models, are briefly reviewed. Recent developments in DES are outlined and the necessary data and procedures to develop a DES model for lung cancer diagnosis, leading up to surgical treatment process are summarized. The analytical models include both Markov chain model and closed formulas. The Markov chain models with its application in healthcare are introduced and the approach to derive a lung cancer diagnosis process model is presented. Similarly, the procedure to derive closed formulas evaluating the diagnosis process performance is outlined. Finally, the pros and cons of these methods are discussed.

Comparison of choroidal thickness in patients with diabetes by spectral-domain optical coherence tomography.

PURPOSE: To evaluate choroidal thickness in diabetes patients using spectral-domain optical coherence tomography. METHODS: We examined 203 eyes of 203 diabetic participants and 48 eyes of 48 healthy controls. The choroidal thickness at the foveal lesion was measured by enhanced-depth imaging optical coherence tomography. The participants were grouped according to diabetic retinopathy grade: no diabetic change, mild-to-moderate or severe non-proliferative, or proliferative diabetic retinopathy. The study parameters included history, age, axial length, intraocular pressure, central retinal thickness, fasting glucose, and blood pressure. RESULTS: The subfoveal choroidal thickness was thinner in eyes with non-proliferative or proliferative diabetic retinopathy than in normal eyes (p < 0.01). However, there was no difference between eyes with non-proliferative and proliferative diabetic retinopathy or between eyes with no diabetic change and the controls. Eyes exhibiting macular edema showed no significant difference in choroidal thickness compared with eyes having normal macular contours. CONCLUSIONS: The central choroid is thinner when eyes show diabetic changes on the retina. However, the presence of diabetic macular edema or proliferative change is not associated with more pronounced choroidal thinning.