Journal of Investigative Medicine

The ability of translated cellular proteins to perform their functions requires their proper folding after synthesis. The endoplasmic reticulum (ER) is responsible for coordinating protein folding and maturation. Infections, genetic mutations, environmental factors and many other conditions can lead to challenges to the ER known as ER stress. Altering ER homeostasis results in accumulation of misfolded or unfolded proteins. To eliminate this problem, a response is initiated by the cell called the unfolded protein response (UPR), which involves multiple signaling pathways. Prolonged ER stress or a dysregulated UPR can lead to premature apoptosis and an exaggerated inflammatory response. Following these discoveries, ER stress was shown to be related to several chronic diseases, such as diabetes mellitus, neurodegenerative disorders, fatty liver disease and inflammatory bowel disease that have not yet been clearly demonstrated pathophysiologically. Here, we review the field and present up-to-date information on the relationship between biological processing, ER stress, UPR, and several chronic diseases.

Coccidioidomycosis is a fungal infection of the Western hemisphere that is endemic to the soil in areas with limited rainfall. Human and animal infections result with inhalation of arthroconidia. Most often, this is an asymptomatic event. When illness occurs, it is primarily a pneumonic presentation. A small minority of infections eventuate in disseminated disease. Predominately, this presents as meningitis or osteoarticular or integumentary disease. Treatment may not be required for the mildest illness. Azoles are commonly prescribed. Severe infections may require amphotericin B.

Quality gaps exist in the hepatitis C virus (HCV) care process from diagnosis to cure. To better understand current gaps and to identify targets for quality improvement, we constructed an HCV care cascade in a patient-centered medical home (PCMH) with an emphasis on the specialty referral process. We performed a retrospective study of HCV-infected patients in a PCMH using electronic health record (EPIC) data. Patients with a first positive HCV RNA between 2012 and 2019 were included. With an adaptation to analyze linkage to specialty care, we created an HCV care cascade that included the following: (1) a positive HCV RNA, (2) referral to a specialty provider, (3) a scheduled specialty appointment, (4) attendance at a specialty visit, (5) prescription for HCV therapy, and (6) evidence of sustained virological response (SVR). Patient and referring clinician characteristics were analyzed at each step of the care pathway, and the proportion of patients completing each step was calculated. Of the 256 HCV RNA-positive patients, 229 (89.5%) received a specialty referral; 215 (84.0%) had an appointment scheduled; 178 (69.5%) attended the specialty appointment; 116 (45.3%) were prescribed antiviral therapy; and 87 (34.1%) had documented SVR during the study period. Of the 178 patients attending a specialty visit, 62 (34.8%) did not receive a prescription, and the barrier most often noted was the desire for further workup (40.3%). Gaps occur at all stages of the HCV care continuum, with drop-offs in care occurring both before and after linkage to specialty care.

This study aimed to investigate the prognostic role of circulating miR-146a in the prediction of early response to imatinib treatment in patients with chronic myeloid leukemia (CML). Sixty patients with CML and 20 healthy controls were recruited in this study. BCR-ABL was assessed by quantitative rt-PCR at days 0 and 90 of imatinib therapy. Circulating miR-146a levels were assessed by quantitative rt-PCR at days 0, 14 and 90 of imatinib therapy for patients and once for controls. At day 90 of treatment, treatment response was achieved in 48 patients (80.0%). Responders had significantly lower baseline Sokal score when compared with non-responders. They also had significantly lower BCR-ABL expression at day 90 of treatment. The circulating miR-146a level was significantly lower in patients with CML than in healthy subjects and showed a significant rise after 14 days of imatinib treatment and an inverse correlation with BCR-ABL expression levels at 90 days. Using multivariate logistic regression analysis, baseline BCR-ABL (%) (OR (95% CI) 1.09 (1.03 to 1.016), p=0.006) and miR-146a at 14 days (OR (95% CI) 0.002 (0.0 to 0.09), p=0.001) were significant predictors of treatment response. Using ROC curve analysis, it was found that miR-146a expression at 14 and 90 days could distinguish responders from non-responders (AUC (95% CI) 0.849 (0.733 to 0.928) and 0.867 (0.755 to 0.941), respectively). This study reported for the first time that measurement of the circulating miR-146a expression at 14 days can predict the early response to imatinib treatment in patients with CML. Thus, this work indicates that miR-146a should be investigated in the setting of treatment response to other tyrosine kinase inhibitors.

Assessing congestion is challenging but important to patients with chronic heart failure (CHF). However, there are limited data regarding the association between estimated plasma volume status (ePVS) determined using hemoglobin/hematocrit data and outcomes in patients with stable CHF. We prospectively analyzed 231 patients; the median follow-up period was 35.6 months. We calculated ePVS at admission using the Duarte and Strauss formula, derived from hemoglobin and hematocrit ratios and divided patients into three groups. The primary outcome was a composite of all-cause mortality or heart failure rehospitalization. Among 274 patients (61.98 years of age, 2.3% male), the mean ePVS was 3.98±0.90 dL/g. The third ePVS tertile had a higher proportion of primary outcome (71.4%) than the first or second tertile (48.1% and 59.7%, respectively; p=0.013). On multivariable Cox analysis, after adjusting for potential confounders, higher ePVS remained significantly associated with increased rate of primary outcome (adjusted HR 1.567, 95% CI 1.267 to 1.936; p<0.001). Kaplan-Meier survival analyses showed that the occurrence of primary outcome, all-cause mortality and rehospitalization increased progressively from first to third tertiles (p=0.006, 0.014 and 0.001; respectively). In receiver operating characteristic analysis, the area under the curve of ePVS for primary outcome was 0.645. ePVS determined using hemoglobin and hematocrit was independently associated with clinical outcomes for patients with stable CHF. Our study thus further strengthens the evidence that ePVS has important prognostic value in patients with stable CHF.

Trial registration number ChiCTR-ONC-14004463.

A recent study reported that coronary artery calcification (CAC) and serum homocysteine were well associated; however, no report is available for the cut-off value of serum homocysteine according to increase of coronary-artery calcification volume score (CVS). The data of 469 out of 777 subjects in 1 health promotion center located in Seoul were selected after exclusion of the missing data of serum homocysteine and CVS. CVS was categorized into 2 groups: CVS=0 and CVS>0. Serum homocysteine according to the CVS groups was compared, and the cut-off value of serum homocysteine according to the increase of CVS (>0) was calculated using the receiver operating characteristic curve. Mean age was 54.5 years and the proportion of females was 22.2%. Mean serum homocysteine concentration and CVS were 11.2 μmol/L and 50.4, respectively. After adjustments for age and sex, serum homocysteine was associated with CVS (r=0.167, p=0.001), and Log(Homocysteine) also showed a significant difference according to the CVS groups. The cut-off value of serum homocysteine according to the increase of CVS (>0) was 9.45 μmol/L (area under the curve=0.569 (95% CI 0.512 to 0.625), p=0.015). The cut-off value of serum homocysteine was 9.45 μmol/L according to the increase of coronary-artery CVS.

Acromegaly is a rare disease associated with comorbidities that are common in the general population. Most patients undergo screening for classic phenotypical (CP) or mass effect manifestations. By retrospective review of pituitary tumor surgeries performed between 1994 and 2016 (1836), we identified patients with acromegaly (112). Main presentations were: CP (43%), mass effect (26%), incidentally detected (ID) tumors (17%), and other (14%). We compared the ID and CP groups regarding prevalence, clinical, biochemical, radiological and histopathological characteristics, and postoperative outcomes. The prevalence of ID among all surgeries increased after 2011 from 0.6% to 1.9% (p=0.01), while prevalence of CP remained stable (2.8% and 2.33%, p=0.65). Almost half of ID (47.4%) presented with otolaryngological manifestations. The ID and CP groups were similar regarding age, gender, comorbidities (hypertension, diabetes, hypopituitarism), tumor diameter and cavernous sinus invasion. Median insulin-like growth factor (IGF-1) and growth hormone (GH) levels were lower in the ID than CP (p<0.05 and p=0.07). Patients younger than 40 had smaller tumors in the ID than CP, while the opposite was true for older patients. The 3-month biochemical remission rates were similar (68% ID and 58% CP). A similar number of patients had normal IGF-1 at last follow-up (89.5% ID and 81.25% CP) after surgery alone and multimodality treatment. In conclusion, an increased number of patients with GH-secreting adenomas were ID in recent years. Education of physicians other than endocrinologists regarding presentation and comorbidity clustering may lead to an earlier diagnosis of acromegaly and improved outcomes.

Infective endocarditis (IE) complicated by heart block can have adverse outcomes and usually requires immediate surgical and cardiac interventions. Data on outcomes and trends in patients with IE with concurrent heart block are lacking. Patients with a primary diagnosis of IE with or without heart block were identified by querying the Healthcare Cost and Utilization Project database, specifically the National Inpatient Sample for the years 2013 and 2014, based on International Classification of Diseases Clinical Modification Ninth Revision codes. During 2013 and 2014, a total of 18,733 patients were admitted with a primary diagnosis of IE, including 867 with concurrent heart blocks. Increased in-hospital mortality (13% vs 10.3%), length of stay (19 vs 14 days), and cost of care ($282,573 vs $223,559) were found for patients with IE complicated by heart block. Additionally, these patients were more likely to develop cardiogenic shock (8.9% vs 3.2%), acute kidney injury (40.1% vs 32.6%), and hematologic complications (19.3% vs 15.2%), and require placement of a pacemaker (30.6% vs 0.9%). IE and concurrent heart block resulted in increased requirement for aortic (25.7% vs 6.1%) and mitral (17.3% vs 4.2%) valvular replacements. Conclusion was made that IE with concurrent heart block worsens in-hospital mortality, length of stay, and cost for patients. Our analysis demonstrates an increase in cardiac procedures, specifically aortic and/or mitral valve replacements, and Implantable Cardiovascular Defibrillator/Cardiac Resynchronization Therapy/ Permanent Pacemaker (ICD/CRT/PPM) placement in IE with concurrent heart block. A close telemonitoring system and prompt interventions may represent a significant mitigation strategy to avoid the adverse outcomes observed in this study.

Patients diagnosed with heart failure with reduced ejection fraction (HFrEF) are at increased risk of monomorphic ventricular tachycardia (VT) and ventricular fibrillation. The presence of myocardial fibrosis provides both anatomical and functional barriers that promote arrhythmias in these patients. Propagation of VT in a reentrant circuit depends on the presence of excitable myocardium and the refractoriness of the circuit. We hypothesize that myocardial refractoriness can be modulated surgically in a model of HFrEF, leading to decreased susceptibility to VT.

Male Sprague-Dawley rats were infarcted via permanent left coronary artery ligation. At 3 weeks post-infarction, engineered grafts composed of human dermal fibroblasts cultured into a polyglactin-910 biomaterial were implanted onto the epicardium to cover the area of infarction. Three weeks post-graft treatment, all rats underwent a terminal electrophysiologic study to compare monophasic action potential electroanatomic maps and susceptibility to inducible monomorphic VT.

HFrEF rats (n=29) demonstrated a longer (p=0.0191) ventricular effective refractory period (ERP) and a greater (p=0.0394) VT inducibility compared with sham (n=7). HFrEF rats treated with the graft (n=12) exhibited no change in capture threshold (p=0.3220), but had a longer ventricular ERP (p=0.0029) compared with HFrEF. No statistically significant change in VT incidence was found between HFrEF rats treated with the graft and untreated HFrEF rats (p=0.0834).

Surgical deployment of a fibroblast-containing biomaterial in a rodent ischemic cardiomyopathy model prolonged ventricular ERP as measured by programmed electrical stimulation. This hypothesis-generating study warrants additional studies to further characterize the antiarrhythmic or proarrhythmic effects of this novel surgical therapy.

Pseudomonas aeruginosa is a nosocomial pathogen containing various resistance mechanisms. Among them, metallo-β-lactamase (MBL)-producing Pseudomonas are difficult to treat. Fosfomycin is an older antibiotic that has recently seen increased usage due to its activity against a broad spectrum of multidrug-resistant organisms. Our aim was to evaluate the combination of fosfomycin and meropenem against 20 MBL-producing P. aeruginosa (100% meropenem-resistant and 20% fosfomycin-resistant) using both an Etest minimal inhibitory concentration (MIC): MIC method and time-kill assay. MICs for fosfomycin and meropenem were determined by Etest and by broth microdilution method for the latter. The combination demonstrated synergy by Etest in 3/20 (15%) isolates and 5/20 (25%) isolates by time-kill assay. Results from the Etest method and time-kill assay were in agreement for 14/20 (70%) of isolates. No antagonism was found. Comparing both methods, Etest MIC: MIC method may be useful to rapidly evaluate other antimicrobial combinations.

Previous studies have reported that as the main extract of areca nut, arecoline (ARE) causes DNA damage and in turn contributes to the carcinogenesis of oral epithelial cells. It has been reported that ARE can inhibit the expression of miR-886-3p. In the current study, we aimed to explore the expression and biological functions of miR-886-3p in oral squamous cell carcinoma (OSCC). Herein, we demonstrated that in OSCC cells treated with ARE, the expression level of miR-886-3p was negatively correlated with the concentration of ARE. Compared with adjacent tissue, the expression level of miR-886-3p in OSCC tissue was remarkably downregulated. Transfection of miR-886-3p mimics markedly decreased viability, migration and invasion of OSCC cells. These experimental data implied that miR-886-3p suppression mediated by ARE took part in the proliferation and metastasis of OSCC. This study can help elucidate the mechanism by which areca nut chewing contributes to the malignant transformation of oral epithelial cells.

African Americans (AAs) are disproportionately affected by kidney disease and also report higher psychosocial stressors than other racial groups. Goal-striving stress (GSS) is an understudied psychosocial stressor related to attempting to accomplish one's life goals. Given the numerous social determinants that contribute to health inequities among AAs, stress from goal striving may also disproportionately affect the health of AAs and in particular kidney disease outcomes. The objective of this study was to explore the association between GSS and rapid kidney function decline (RKFD) in an AA cohort. Using examination 1 (2000-2004) and examination 3 (2009-2013) data from the Jackson Heart Study (n=2630), we examined associations of baseline levels of GSS with RKFD among AAs using multivariable Poisson regression models, adjusting for sociodemographics, health behaviors, chronic disease and discrimination. We also explored baseline cortisol as a mediator. The incidence of RKFD in this sample was 7.34% (mean years of follow-up: 8.06±0.84 years). The mean GSS score was 3.80 (±4.88) and total GSS score ranged from 0 to 36. Those who reported high (vs low) GSS were 1.60 times more likely to experience RKFD after full adjustment (incidence rate ratio (IRR) 1.60; 95% CI 1.11 to 2.14, p=0.01). After confirming cortisol as a mediator and adding it to the model, those who reported high (vs low) GSS had 1.58 times the rate of RKFD (IRR 1.58; 95% CI 1.09 to 2.30, p=0.0153). Stress related to not achieving goals was associated with a greater risk of RKFD in this sample of AAs.

Acute suppurative parotitis (ASP) is an acute infection of the parotid gland that necessitates hospitalization in some patients. The aim of this study was to evaluate clinical laboratory values including hydration, nutritional status, inflammatory markers and age, and to compare them with duration of hospitalization of patients with ASP. This is a retrospective chart review in a tertiary academic center. We investigated the factors affecting length of hospitalization in patients admitted to Galilee Medical Center with a diagnosis of ASP between 2010 and 2018. Of the 60 patients with ASP included in the study, 24 were male. The average age of patients was 60, ranging from 18 to 99. We found statistically significant correlations between length of hospitalization and patient age (r=0.3), C reactive protein (r=0.3), white cell count (WCC) at presentation (r=0.3), blood urea nitrogen to creatinine ratio (BUN:Cr) (r=0.2), and platelet levels at discharge (r=0.4). Examination of these factors on multivariate analysis found hospitalization duration was exclusively affected by patients’ level of dehydration as represented by BUN:Cr. Patient age, WCC levels at presentation, and platelet levels were not found to be statistically significant. Treatment and interventions should be planned accordingly.

Vitiligo, an autoimmune disease, is a depigmentation skin disorder characterized by hypopigmentation spots and patches that are difficult to treat. The purpose of this study is to analyze the clinical efficacy of simvastatin in the treatment of vitiligo. From December 2016 to October 2019, five vitiligo patients from Peking Union Medical College Hospital were treated with simvastatin and tacrolimus. For simvastatin, the first three patients (patient 1, patient 2, and patient 3) began to take 40 mg/day, and the latter two patients began to take 20 mg/day. From week 5, patients 1 and 2 received 20 mg simvastatin once a day. And the 0.1% tacrolimus ointment was used topically. The response was measured using the Vitiligo European Task Force (VETF) scoring system at baseline and at the fourth and eighth weeks of treatment. The results of the VETF score showed that three of the patients achieved significant clinical efficacy. There was no significant improvement in the other two cases. No serious acute or chronic side effects were observed. In conclusion, our results suggest that conventional oral simvastatin is safe, although it may not be effective in the treatment of vitiligo.

Orlando has the second highest HIV incidence in the USA. Tenofovir disoproxil fumarate/emtricitabine is approved as pre-exposure prophylaxis (PrEP) to minimize HIV transmission. Our study describes the PrEP care continuum and factors impacting PrEP persistence during the first year of PrEP care at a sexual health clinic in Orlando. Patients initiating PrEP between 2014 and 2017 with at least 1 year of follow-up were eligible for inclusion. Demographic and clinical factors were extracted from medical records. At the end of the first year of PrEP care, patients seen within the last 6 months were defined as ‘persistent’ whereas patients lost to follow-up for ≥6 months were defined as ‘not persistent’. We evaluated factors associated with PrEP persistence with Firth's multivariable logistic regression. Of 300 patients meeting inclusion criteria, 96% were male, 59% were ≥30 years old, 59% identified as men who have sex with men and 57% endorsed recent condomless anal intercourse. Of PrEP initiators, 133 (44.3%) were persistent in the first year, whereas 167 (55.7%) were not persistent. PrEP persistence was positively associated with age ≥30 years (OR 1.04, 95% CI 1.0 to 1.08) and negatively associated with non-white race (OR 0.33, 95% CI 0.12 to 0.83). There were no HIV seroconversions among persistent patients. In our study, younger and minority patients were less likely to persist in PrEP care and persistence was poor despite many being insured and ‘high-risk’. Further research is needed to identify and address barriers that hinder PrEP persistence, specifically among younger, minority patients.

We investigated the association between variants rs12997 in activin A receptor type I (ACVR1) and rs1043784 in BMP6 located in the 3’ untranslated region, and primary open-angle glaucoma (POAG). The retrospective case-control study used TaqMan real-time PCR assay to genotype 400 subjects, including 150 patients with POAG and 250 controls. The minor ‘G’ allele of rs12997 in ACVR1 showed significant association with POAG (p=0.027, OR=1.39, 95% CI=1.03 to 1.87). Likewise, rs12997 genotypes showed moderate association with POAG in recessive (p=0.048, OR=1.80, 95% CI=1.01 to 3.20) and log-additive models (p=0.030, OR=1.39, 95% CI=1.03 to 1.87), but did not survive Bonferroni correction. Rs1043784 in BMP6 showed no associations. Furthermore, rs12997 G/G genotype significantly (p=0.033) increased the risk of POAG (twofolds) independent of age, sex and rs1043784 genotypes in regression analysis. However, clinical variables such as intraocular pressure and cup/disc ratio showed no association with both the polymorphisms. To conclude, the study shows a modest association between rs12997 in the ACVR1 gene, a member of the bone morphogenic protein signaling pathway and POAG. However, the results need further replication in large population-based cohorts and different ethnicities to validate its role as an important genetic biomarker.

The Pediatric Emergency Care Applied Research Network (PECARN) Head Injury/Trauma Algorithm is a well-validated decision rule used to identify patients at low risk of clinically important traumatic brain injuries who may not need head CT. In adult patients with mild head trauma, elevated serum glucose and white cell count (WCC) have been associated with abnormal head CT findings. Currently, glucose or WCC is not considered in pediatric patients. The objective of this study was to determine if elevations in glucose or WCC could be used as additional tools to risk-stratify pediatric trauma patients for intracranial injury (ICI). Data were abstracted from the Maryland Trauma Registry and from electronic medical records for patients at the Johns Hopkins Children's Center from 2017 to 2020. We evaluated 145 encounters that met the inclusion criteria. There were 33 cases of ICI on CT. In addition to higher median glucose and WCC, we found that patients with ICI had a younger median age and were less likely to have other clinically significant injuries than patients without ICI. Following multiple logistic regression analysis, WCC (OR 1.113, 95% CI 1.02 to 1.21), younger age (OR 0.89, 95% CI 0.8 to 0.98), and absence of other injuries (OR 0.41, 95% CI 0.23 to 0.73) were found to be associated with risk of ICI. The area under the curve for our model was 0.79. When used with the PECARN algorithm, our model could help determine which patients may avoid head CT or undergo a shorter observation period.