Characteristics of Comorbid Physical Disease in Patients With Severe Mental Illness in South Korea: A Nationwide Population-Based Study (2014-2019).

OBJECTIVE: The purpose of this study was to identify the associations of chronic physical disease between patients with severe mental illness (SMI) and the general population of South Korea. METHODS: This study was conducted with National Health Insurance Corporation data from 2014 to 2019. A total of 848,058 people were diagnosed with SMI in this period, and the same number of controls were established by matching by sex and age. A descriptive analysis was conducted on the sociodemographic characteristics of patients with SMI. Conditional logistic regression analysis was performed to identify the associations between comorbid physical disease in patients with SMI and those of the general population. SAS Enterprise Guide 7.1 (SAS Inc, Cary, NC, USA) were used to perform all statistical tests. RESULTS: The analysis revealed significant differences in medical insurance, income level, and Charlson Comorbidity Index weighted by chronic physical disease, between patients with SMI and the general population. Conditional logistic regression analysis between the two groups also revealed significant differences in eight chronic physical diseases except hypertensive disease. CONCLUSION: This study confirmed the vulnerability of patients with SMI to chronic physical diseases and we were able to identify chronic physical disease that were highly related to patients with SMI.

How Can We Deal with Psychosocial Issues in an Emerging Infectious Disease Outbreak? Lessons from a Qualitative Study for the MERS Outbreak in Korea.

BACKGROUND: The 2015 Middle East respiratory syndrome (MERS) coronavirus outbreak in Korea led to profound emotional and social burdens, especially in patients and health care professionals. MATERIALS AND METHODS: Focus group interviews were conducted with 2 patients, 1 family member and 6 health care professionals about psychological distress related to MERS in 2017 and analyzed the interview data using the consensual qualitative research method. RESULTS: Four domains and 17 core ideas were identified within three interview groups, including psychological distress during the outbreak, problems regarding the response to the outbreak, positive experiences, and future directions for enhancing intervention to improve mental health and prevent psychosocial problems during the outbreak. Psychological consequences were affected by the characteristics of the emerging infectious disease and the structure and process of institutional or governmental response to the MERS outbreak. Mental health services and psychosocial support reduced the negative impact on psychological distress. CONCLUSION: The MERS outbreak in 2015 gave rise to emotional and social injuries to patients and health care professionals, some of which can be long-lasting constraints in their lives. Preparedness in a society's response to a pandemic considering mental health in related parties can minimize negative psychological consequences and enhance resilience at the individual and society levels.

Standardized Suicide Prevention Program for Gatekeeper Intervention of North Korean Defectors in South Korea.

OBJECTIVE: North Korean defectors (NKDs) have experienced substantial difficulties during the migration and settlement in South Korea. They have a high prevalence of depression, post-traumatic stress disorder, and suicidal behaviors. The high prevalence of mental disorders among NKDs can lead to a high suicide rate. However, there are no suicide prevention programs for NKDs. This study aims to customize a suicide prevention program with content suitable for NKDs' particular circumstances. METHODS: A multidisciplinary research team developed this program based on domestic and international gatekeeper training programs for suicide prevention and articles related to suicide prevention. RESULTS: We developed a multi-part gatekeeper training program, "Suicide CARE for NKDs." In the "Introduction," trainees learn about the need for the program and its importance. In "Careful observation," trainees learn to recognize linguistic, behavioral, and situational signals of suicide risk. In "Active listening," trainees learn how to ask about suicidal thoughts and to listen empathetically. In "Risk evaluation and expert referral," trainees learn to evaluate suicide risk and to connect NKDs with institutes or services. CONCLUSION: We expect this program to become useful for training gatekeepers to prevent suicide among NKD. A future follow-up study is needed to confirm the efficacy of the program.

Associations of health-related quality of life with depression and stigma in MERS-CoV survivors during the recovery period.

ABSTRACT: We explored factors related to health-related quality of life (HRQOL), including psychiatric symptoms and stigma related to Middle East respiratory syndrome coronavirus (MERS-CoV) infection, among MERS-CoV survivors during the recovery period.Sixty-three MERS-COV survivors were recruited from five hospitals for a cohort study, one year after their infection in 2015. The subjects' demographic information and medical conditions associated with MERS-CoV were recorded. HRQOL was evaluated using the Short Form-8 Health Survey (SF-8). Depression, post-traumatic stress symptoms, chronic fatigue, and perceived stigma were assessed using several questionnairesThe mean physical component summary (PCS) and mean mental component summary (MCS) of the SF-8 score were below 50 T (43.47 ±â€Š9.60, 45.74 ±â€Š10.18). Depression, chronic fatigue, posttraumatic stress symptoms and stigma were negatively correlated with the SF-8 PCS and MCS. Multivariate logistic regression analysis showed that the PCS was associated with stigma (OR 8.66, 95% CI 1.96-38.23), whereas MCS was associated with depression (OR 26.62, 95% CI 3.56-198.85).The estimated HRQOL of MERS-CoV survivors during recovery was poor and appeared to be associated with depression and MERS-related stigma.

Hospital-Based Case Management for Suicide High-Risk Group Using Delphi Survey.

OBJECTIVE: As of 2019, suicide is serious problem in Korea, with the highest suicide rate among OECD countries. To reduce suicide rates Emergency Department Based Post-Suicide Attempt Case Management carried out with government funding in South Korea, but it is insufficient to address the issue. Aim of this study is to prevent suicide attempts through continuous provision of mental health services even after discharge from acute care. METHODS: We selected 15 mental health specialists who are multidisciplinary experts in Suicide Prevention. Two-round Delphi survey was conducted on them to reach an agreement for hospital-based case management. RESULTS: The first Delphi survey consisted of 8 areas and 39 questions. Among them, 30 questions draw agreement above the reference value. The second Delphi survey, consisted of 37 questions, resulted in 32 above-standard questions. CONCLUSION: Consensus was reached in most category of the Hospital Based Case Management for Suicide High-Risk Group. Core of the developed plan was to provide services to patients who visited the hospital, pursue the stability and universalization of services through a medical insurance fee system. In the future, hospital-based case management service will be implemented as a new model contributing to the reduction of suicide rates in Korea.

The Effects of Inhumane Treatment in North Korean Detention Facilities on the Posttraumatic-Stress Disorder Symptoms of North Korean Refugees.

OBJECTIVE: The study investigated the effects of severe human rights abuses in North Korean on Posttraumatic-stress disorder (PTSD) in North Korean Refugees (NKRs). METHODS: The study included 300 NKRs (245 females and 55 males) who completed self-report questionnaires that assessed PTSD, experiences of imprisonment, and exposure to inhumane treatment, by authorities in North Korea. A moderation analysis was conducted using a hierarchical multiple regression model to determine whether a moderation effect existed. In the next step, a post-hoc probing procedure of the moderation effect was performed using multiple regression models that included conditional moderator variables. RESULTS: The influence of the frequency of being imprisoned on PTSD varied as a function of recurrent exposure to inhumane treatment or punishment by authorities. Experiences of imprisonment were associated with PTSD only among those who were exposed to recurrent violence, such as beating or torture, by North Korean authorities. CONCLUSION: The present findings highlight the significant effects of human rights violations, such as the inhumane treatment of prisoners in North Korea, on the PTSD of NKRs.

Association between chronic fatigue syndrome and suicidality among survivors of Middle East respiratory syndrome over a 2-year follow-up period.

Suicide is an important public health issue during the current pandemic of emerging infectious diseases (EIDs). In EIDs, various symptoms persist even after recovery, and chronic fatigue is among those that are commonly reported. The aim of this study was to examine the effects of chronic fatigue syndrome on suicidality during the recovery phase among survivors of Middle East respiratory syndrome (MERS). MERS survivors were recruited from five centers and prospectively followed up for 2 years. In total, 63 participants were registered at 12 months (T1), of whom 53 and 50 completed the assessments at 18 months (T2) and 24 months (T3), respectively. Suicidality and chronic fatigue were evaluated using the suicidality module of the Mini-International Neuropsychiatric Interview (MINI) and the Fatigue Severity Scale (FSS), respectively. We analyzed the relationship between chronic fatigue and suicidality during the follow-up period using the generalized estimating equation (GEE). The suicidality rates were 22.2% (n = 14), 15.1% (n = 8), and 10.0% (n = 5) at T1-T3, respectively. Of the 63 participants, 29 had chronic fatigue syndrome at T1. The group that reported chronic fatigue syndrome at T1 was more likely to experience suicidality during the 2-year follow-up than the group that reported otherwise (RR: 7.5, 95% CI: 2.4-23.1). This association was present even after adjusting for potential confounders (RR: 7.6, 95% CI: 2.2-26.0). Chronic fatigue syndrome and suicide risk among emerging infectious disease (EID) survivors should be acknowledged, and effective interventions must be developed.

Local shape volume alterations in subcortical structures of suicide attempters with major depressive disorder.

Suicide is among the most important global health concerns; accordingly, an increasing number of studies have shown the risks for suicide attempt(s) in terms of brain morphometric features and their clinical correlates. However, brain studies addressing suicidal vulnerability have been more focused on demonstrating impairments in cortical structures than in the subcortical structures. Using local shape volumes (LSV) analysis, we investigated subcortical structures with their clinical correlates in depressed patients who attempted suicide. Then we compared them with depressed patients without a suicidal history and age- and sex-matched healthy controls (HCs; i.e., 47 suicide attempters with depression, 47 non-suicide attempters with depression, and 109 HCs). Significant volumetric differences were found between suicidal and nonsuicidal depressed patients in several vertices: 16 in the left amygdala; 201 in the left hippocampus; 1,057 in the left putamen; and 140 in the left pallidum; 1 in the right pallidum; and 6 in the bilateral thalamus. These findings indicated subcortical alterations in LSV in components of the limbic-cortical-striatal-pallidal-thalamic circuits. Moreover, our results demonstrated that the basal ganglia was correlated with perceived stress levels, and the thalamus was correlated with suicidal ideation. We suggest that suicidality in major depressive disorder may involve subcortical volume alterations.

Development and validation study of Game Overuse Screening Questionnaire.

The aim of this study was to develop a screening questionnaire to distinguish high-risk individuals associated with game overuse from casual internet users. Reliability, validity, and diagnostic ability were evaluated for the newly developed Game Overuse Screening Questionnaire (GOS-Q). Preliminary items were assessed by 50 addiction experts online and 30 questions were selected. A total of 158 subjects recruited from six community centers for internet addiction participated in this study. Finally, 150 people were used in the analysis after excluding eight non-respondents. GOS-Q, Young's internet addiction scale, and Korean scale for internet addiction were used to assess concurrent validity. Internal consistency and item-total correlations were favorable (α= 0.96, r= 0.47-0.82). Test-retest reliability was moderate in size (r= 0.74). GOS-Q showed superior concurrent validity, and the highest correlation with Y-Scale (r= 0.77). The construct validity was marginally supported by a six-factor model using exploratory factor analysis. The area under the Receiver Operating Characteristic curve was 0.945. The high-risk addiction group was effectively characterized by a cut-off point of 38.5, with a sensitivity of 0.87 and a specificity of 0.88. Overall, the current study supports the use of GOS-Q as a reliable screening tool in a variety of settings.

Posttraumatic stress disorder and depression of survivors 12 months after the outbreak of Middle East respiratory syndrome in South Korea.

BACKGROUND: The 2015 outbreak of Middle East Respiratory Syndrome (MERS) in the Republic of Korea is a recent and representative occurrence of nationwide outbreaks of Emerging Infectious Diseases (EIDs). In addition to physical symptoms, posttraumatic stress disorder (PTSD) and depression are common following outbreaks of EID. METHODS: The present study investigated the long-term mental health outcomes and related risk factors in survivors of MERS. A prospective nationwide cohort study was conducted 12 months after the MERS outbreak at multi-centers throughout Korea. PTSD and depression as the main mental health outcomes were assessed with the Impact of Event Scale-Revised Korean version (IES-R-K) and the Patient Health Questionnaire-9 (PHQ-9) respectively. RESULTS: 42.9% of survivors reported PTSD (IES-R-K ≥ 25) and 27.0% reported depression (PHQ-9 ≥ 10) at 12 months post-MERS. A multivariate analysis revealed that anxiety (adjusted odds ratio [aOR], 5.76; 95%CI, 1.29-25.58; P = 0.021), and a greater recognition of stigma (aOR, 11.09, 95%CI, 2.28-53.90; P = 0.003) during the MERS-affected period were independent predictors of PTSD at 12 months after the MERS outbreak. Having a family member who died from MERS predicted the development of depression (aOR, 12.08, 95%CI, 1.47-99.19; P = 0.020). CONCLUSION: This finding implies that psychosocial factors, particularly during the outbreak phase, influenced the mental health of patients over a long-term period. Mental health support among the infected subjects and efforts to reduce stigma may improve recovery from psychological distress in an EID outbreak.

Alterations in functional brain networks in depressed patients with a suicide attempt history.

Suicide is a major challenge in public health and is strongly associated with major depressive disorder (MDD). Despite recent neuroimaging developments, the neural correlates of suicide behavior in patients with MDD remain unclear. Independent component analysis (ICA) for neuroimaging data allows the identification of functional brain networks without prior regions of interest and may help to identify neurobiological markers of specific disorders. Using ICA, we investigated the differences in resting-state brain networks in patients with MDD who had or did not have a history of suicide attempts and in healthy controls (HCs). Suicidal depressed (SD) patients, non-suicidal depressed (NSD) patients, and HCs significantly differed from each other in the pattern of connectivity of multiple functional networks, network synchronization, and functional network connectivity (FNC). The patient groups had a decreased network synchronization in the insular, cerebellum, basal ganglia, thalamus, operculum, frontoparietal cortices, and sensory cortices relative to the HCs. The decreased FNC between these networks (insular-default mode network and insular-cerebellum) was found in the SD group compared to the NSD and HC groups. These differences were not related to illness duration and medication status differences between SD and NSD. Furthermore, the degree of FNC in these networks was associated with the suicide ideation and stress level. Our results demonstrated that widespread but discrete network changes in brain networks and their interconnectivity was associated with suicide attempts in patients with MDD. Our results suggest that the neural basis underlying the psychopathology of attempted suicide in patients with MDD involves multiple brain networks and their interaction.

Depression and suicide risk prediction models using blood-derived multi-omics data.

More than 300 million people worldwide experience depression; annually, ~800,000 people die by suicide. Unfortunately, conventional interview-based diagnosis is insufficient to accurately predict a psychiatric status. We developed machine learning models to predict depression and suicide risk using blood methylome and transcriptome data from 56 suicide attempters (SAs), 39 patients with major depressive disorder (MDD), and 87 healthy controls. Our random forest classifiers showed accuracies of 92.6% in distinguishing SAs from MDD patients, 87.3% in distinguishing MDD patients from controls, and 86.7% in distinguishing SAs from controls. We also developed regression models for predicting psychiatric scales with R2 values of 0.961 and 0.943 for Hamilton Rating Scale for Depression-17 and Scale for Suicide Ideation, respectively. Multi-omics data were used to construct psychiatric status prediction models for improved mental health treatment.

Development of Korean Disaster Mental Health Support Guidelines: Results of a Scoping Review and a Delphi Survey.

OBJECTIVE: It is necessary to develop new guidelines to delineate the best ways of providing psychosocial care to ensure mental health following a disaster. METHODS: This study applied the scoping review method as a means of establishing evidence-based guidelines for disaster mental health services. A total of 440 literatures were selected through a scoping review of 20,864 documents. Twenty-three recognized experts were invited to participate in the survey and a two-round online Delphi survey was conducted. RESULTS: The concordance rate in the Delphi Round 1 was 95.1%. Six items were excluded and new items were formulated with experts' suggestions. A total of 23 statements were slightly modified to clarify their meaning. In the Delphi Round 2, all items were met with consensus. The three items with the highest consensus among the experts were related to the protection of personal information and privacy. The item with the lowest consensus among experts was related to debriefing. Other items were related to establishing mental health support centers and suicide prevention activities. CONCLUSION: 140 items were developed through scoping reviews based on evidence-based methodology. These items were used to describe the disaster mental health support identified in Delphi. The guideline will provide a foundation for effective preparation and response in disaster situations.

Efficacy of Cilostazol Administration in Alzheimer's Disease Patients with White Matter Lesions: A Positron-Emission Tomography Study.

This study tested the efficacy of the phosphodiesterase type III inhibitor cilostazol in Alzheimer's disease patients with white matter lesions treated with donepezil in comparison with donepezil monotherapy using fluorodeoxyglucose (18F) positron-emission tomography (FDG PET). A 24-week, randomized, double-blind, placebo-controlled, parallel-group study was conducted. Thirty-six Alzheimer's disease patients with white matter lesions who received donepezil (n = 18 each in the cilostazol and placebo groups) were enrolled. Participants underwent pre and post FDG PET imaging scans and three rounds of clinical and neuropsychological tests. The cilostazol group did not show a significant decrease of regional glucose metabolism; however, regional glucose metabolism was significantly decreased in the parietal and frontal lobes of the placebo group. The repeated measures ANOVA measuring differences in uptake change revealed that regional glucose metabolism in the left inferior frontal gyrus was significantly more preserved in the cilostazol group than that in the placebo group (p < 0.005). Mean changes from baseline on the Mini-Mental State Exam, Alzheimer's Disease Assessment Scale-cognitive subscale, Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory, and the Clinical Dementia Rating Sum of Boxes did not differ between the two groups. In the cilostazol group, the increase of glucose metabolism correlated with the improvment of the Alzheimer's Disease Assessment Scale-cognitive score. We conclude that cilostazol treatment added to donepezil may delay the decline in regional cerebral metabolism in Alzheimer's disease with white matter lesions compared with donepezil monotherapy. In additon, our results verified the efficacy of cilostazol in improving or protecting cognitive function in Alzheimer's disease through increased glucose metabolism. However, the long-term effect of cilostazol on cognitive function and Alzheimer's disease modification must be tested in further studies with larger sample size and longer study period. Trial registration: http://clinicaltrials.gov : NCT01409564.

Depression as a Mediator of Chronic Fatigue and Post-Traumatic Stress Symptoms in Middle East Respiratory Syndrome Survivors.

OBJECTIVE: The relationship among chronic fatigue, depressive symptoms, and post-traumatic stress symptoms (PTSSs) among Middle East respiratory syndrome (MERS) survivors is poorly understood. METHODS: Of 148 survivors who consented to be registered and underwent assessments at 12 months (T1) and 18 months (T2) after the MERS outbreak, 72 (48.65%) were evaluated for chronic fatigue, depressive symptoms, and PTSSs based on the Impact of Event ScaleRevised (IES-R), the Patient Health Questionnaire-9 (PHQ-9), and the Fatigue Severity Scale (FSS). Data from 52 subjects, who completed both assessments, were analyzed using a regression-based serial multiple mediation model (PROCESS Model 6). RESULTS: Bootstrap analyses indicated no direct effects of T1 FSS on T2 IES-R but significant positive indirect effects of T1 FSS on T2 IESR through T1 PHQ-9 and T2 PHQ-9 (B=2.1601, SE=1.3268, 95% confidence interval=0.4250-6.1307). In other words, both T1 PHQ-9 and T2 PHQ-9 fully mediated the relationship between T1 FSS and T2 IES. CONCLUSION: Chronic fatigue 12 months after MERS had indirect effects on prolonged PTSSs 18 months after MERS via persisting depression in MERS survivors. This finding supports the need to promote interventional programs for emerging infectious disease survivors with chronic fatigue to reduce depression and prevent prolonged PTSSs.

Development and Validation Study of the Internet Overuse Screening Questionnaire.

OBJECTIVE: Concerns over behavioral and emotional problems caused by excessive internet usage have been developed. This study intended to develop and a standardize questionnaire that can efficiently identify at-risk internet users through their internet usage habits. METHODS: Participants (n=158) were recruited at six I-will-centers located in Seoul, South Korea. From the initial 36 questionnaire item pool, 28 preliminary items were selected through expert evaluation and panel discussions. The construct validity, internal consistency, and concurrent validity were examined. We also conducted Receiver Operating Curve (ROC) analysis to assess diagnostic ability of the Internet Overuse Screening-Questionnaire (IOS-Q). RESULTS: The exploratory factor analysis yielded a five factor structure. Four factors with 17 items remained after items that had unclear factor loading were removed. The Cronbach's alpha for the IOS-Q total score was 0.91, and test-retest reliability was 0.72. The correlation between Young's internet addiction scale and K-scale supported concurrent validity. ROC analysis showed that the IOS-Q has superior diagnostic ability with the Area Under the Curve of 0.87. At the cut-off point of 25.5, the sensitivity was 0.93 and specificity was 0.86. CONCLUSION: Overall, this study supports the use of IOS-Q for internet addiction research and for screening high-risk individuals.

Internet Game Addiction, Depression, and Escape From Negative Emotions in Adulthood: A Nationwide Community Sample of Korea.

The aim of this study was to investigate the association between adult Internet game addiction (IGA) and mental disorders. A total of 1401 adults aged between 18 and 74 years participated in this study. The IGA group had significantly younger patients, and it showed a higher proportion of unmarried and unemployed adults, and higher rates of suicidal ideation, plan, and attempt than the non-IGA group. Multivariate logistic regression indicated that IGA was significantly associated with major depressive disorder, dysthymia, and depressive disorders adjusting for all variables. The Patient Health Questionnaire-9 score was significantly higher in the IGA group than in the non-IGA group for both young adults and middle groups. "Escape from negative emotions like nervousness, sadness, and anger" was the only significant item associated with depression among symptoms of IGA. This study suggests that adults with IGA and depression may use Internet games to escape from negative emotions.

Poor sleep quality and suicide attempt among adults with internet addiction: A nationwide community sample of Korea.

PURPOSE: Internet addiction (IA) is defined as a psychological dependence on the internet, regardless of the type of activities once logged on, and previous studies have focused on adolescents and young adults. The aim of this study was to investigate the association between suicide attempts and sleep among community-dwelling adults with IA. METHODS: The Young's Internet Addiction Test (IAT), the Korean version of the Composite International Diagnostic Interview (K-CIDI) and a suicide questionnaire were used in this cross-sectional multistage, cluster sampling population-based study. A total of 3212 adults aged 18-64 years were interviewed face-to-face, and they had been randomly selected through a one-person-per-household method. RESULTS: Of the 3212 adults, 204 were assessed as having IA (6.35%). Adults with IA were younger, and more frequently male, unmarried, and unemployed, and had poorer sleep quality than adults without IA (32.8% vs. 19.8%), whereas there was no significant difference in the absolute duration of sleep between the two groups. Adults with IA showed more frequent difficulty initiating and maintaining sleep, non-restorative sleep, daytime functional impairment, and duration of sleep more than 10 hours on weekdays than adults without IA. IA with poor sleep quality was significantly associated with lifetime suicide attempts (AOR = 3.34, 95% CI 1.38-8.05) after adjusting for demographic covariates. Adults with IA who had more sleep problems showed more severe IA, especially those who experienced a previous suicidal attempt. Among mental disorders, IA with poor sleep quality was significantly associated with anxiety disorder and overall psychiatric disorders. CONCLUSIONS: Among adults with IA, poor sleep quality was found to be associated with more severe IA and lifetime suicide attempt.

Characterization of mammalian cell culture raw materials by combining spectroscopy and chemometrics.

Two of the primary issues with characterizing the variability of raw materials used in mammalian cell culture, such as wheat hydrolysate, is that the analyses of these materials can be time consuming, and the results of the analyses are not straightforward to interpret. To solve these issues, spectroscopy can be combined with chemometrics to provide a quick, robust and easy to understand methodology for the characterization of raw materials; which will improve cell culture performance by providing an assessment of the impact that a given raw material will have on final product quality. In this study, four spectroscopic technologies: near infrared spectroscopy, middle infrared spectroscopy, Raman spectroscopy, and fluorescence spectroscopy were used in conjunction with principal component analysis to characterize the variability of wheat hydrolysates, and to provide evidence that the classification of good and bad lots of raw material is possible. Then, the same spectroscopic platforms are combined with partial least squares regressions to quantitatively predict two cell culture critical quality attributes (CQA): integrated viable cell density and IgG titer. The results showed that near infrared (NIR) spectroscopy and fluorescence spectroscopy are capable of characterizing the wheat hydrolysate's chemical structure, with NIR performing slightly better; and that they can be used to estimate the raw materials' impact on the CQAs. These results were justified by demonstrating that of all the components present in the wheat hydrolysates, six amino acids: arginine, glycine, phenylalanine, tyrosine, isoleucine and threonine; and five trace elements: copper, phosphorus, molybdenum, arsenic and aluminum, had a large, statistically significant effect on the CQAs, and that NIR and fluorescence spectroscopy performed the best for characterizing the important amino acids. It was also found that the trace elements of interest were not characterized well by any of the spectral technologies used; however, the trace elements were also shown to have a less significant effect on the CQAs than the amino acids. © 2017 The Authors Biotechnology Progress published by Wiley Periodicals, Inc. on behalf of American Institute of Chemical Engineers, 33:1127-1138, 2017.