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Patients with schizophrenia experience accelerated aging, accompanied by abnormalities in biomarkers such as shorter telomere length. Brain age prediction using neuroimaging data has gained attention in schizophrenia research, with consistently reported increases in brain-predicted age difference (brain-PAD). However, its associations with clinical symptoms and illness duration remain unclear.
Methods
We developed brain age prediction models using structural magnetic resonance imaging (MRI) data from 10,938 healthy individuals. The models were validated on an independent test dataset comprising 79 healthy controls, 57 patients with recent-onset schizophrenia, and 71 patients with chronic schizophrenia. Group comparisons and the clinical associations of brain-PAD were analyzed using multiple linear regression. SHapley Additive exPlanations (SHAP) values estimated feature contributions to the model, and between-group differences in SHAP values and group-by-SHAP value interactions were also examined.
Results
Patients with recent-onset schizophrenia and chronic schizophrenia exhibited increased brain-PAD values of 1.2 and 0.9 years, respectively. Between-group differences in SHAP values were identified in the right lateral prefrontal area (false discovery rate [FDR] p = 0.022), with group-by-SHAP value interactions observed in the left prefrontal area (FDR p = 0.049). A negative association between brain-PAD and Full-scale Intelligence Quotient scores in chronic schizophrenia was noted, which did not remain significant after correction for multiple comparisons.
Conclusions
Brain-PAD increases were pronounced in the early phase of schizophrenia. Regional brain abnormalities contributing to brain-PAD likely vary with illness duration. Future longitudinal studies are required to overcome limitations related to sample size, heterogeneity, and the cross-sectional design of this study.
As a method to ascertain person and item effects in psycholinguistics, a generalized linear mixed effect model (GLMM) with crossed random effects has met limitations in handing serial dependence across persons and items. This paper presents an autoregressive GLMM with crossed random effects that accounts for variability in lag effects across persons and items. The model is shown to be applicable to intensive binary time series eye-tracking data when researchers are interested in detecting experimental condition effects while controlling for previous responses. In addition, a simulation study shows that ignoring lag effects can lead to biased estimates and underestimated standard errors for the experimental condition effects.
Fungal metabolites are known to have potent and diverse properties such as antiviral, antidiabetic, antitumour, antioxidant, free radical scavenging, and antibacterial effects which can be utilized to treat diseases. In this study, we investigated the functional activity of stereumamide A (StA) derived from a culture broth of Trichaptum fuscoviolaceum during the in vitro fertilization (IVF) of pig oocytes, to determine its effects on sperm penetration. Oocytes matured in vitro were fertilized in the absence or presence of varying concentrations of StA (0-50 μg/ml StA). When StA was directly added into the IVF medium, significantly lower fertilization rates were seen with the 20 or 50 μg/ml StA (2.0–17.5%) treatments compared with those of 10 μg/ml StA or the controls (60.9–62.3%), whereas StA had no influence on the survival of oocytes and spermatozoa throughout the IVF process. For evaluating the control of sperm entry, mature oocytes were pre-incubated in a medium containing 20 μg/ml StA for 1 h, and then IVF was subsequently performed. The incidence of polyspermy was significantly reduced when oocytes were pre-incubated with StA (15.0% vs. 50.4–57.5% in controls). In conclusion, sperm penetration was inhibited in the medium in the presence of StA during IVF, while StA did not affect sperm motility and fertility competence. Fertilization was controlled when mature oocytes were incubated with StA prior to IVF, suggesting the possible use of the fungal metabolite in assisted reproductive technology for humans and animals.
Climate change poses a major threat to marine ecosystems, with its effects felt worldwide. A major effect of climate change on marine ecosystems is the rise in water temperature, leading to a northward expansion of habitats for marine organisms. Herdmania momus, a species of ascidians (sea squirts), originally found in tropical and subtropical regions, was introduced to the Korean Peninsula. In this study, we examined the habitat of H. momus along the southeastern coast of the Korean Peninsula between 2016 and 2022. We found that H. momus settlements were observed across the entire survey area, with confirmed habitation in Busan in 2016, Ulsan in 2021, and Gyeongju (the northernmost location) in 2022. The observed habitation trend indicates a rapid geographical expansion, occurring approximately 79 years earlier than previously predicted. These observations demonstrate that marine organisms are undergoing a more rapid geographical expansion than previously projected. These unexpected findings should inform government policies related to proactive measures and strategies for managing the impact of climate change on marine ecosystems.
It has been suggested that schizophrenia involves dysconnectivity between functional brain regions and also the white matter structural disorganisation. Thus, diffusion tensor imaging (DTI) has widely been used for studying schizophrenia. However, most previous studies have used the region of interest (ROI) based approach. We, therefore, performed the probabilistic tractography method in this study to reveal the alterations of white matter tracts in the schizophrenia brain.
Methods:
A total of four different datasets consisted of 189 patients with schizophrenia and 213 healthy controls were investigated. We performed retrospective harmonisation of raw diffusion MRI data by dMRIharmonisation and used the FMRIB Software Library (FSL) for probabilistic tractography. The connectivities between different ROIs were then compared between patients and controls. Furthermore, we evaluated the relationship between the connection probabilities and the symptoms and cognitive measures in patients with schizophrenia.
Results:
After applying Bonferroni correction for multiple comparisons, 11 different tracts showed significant differences between patients with schizophrenia and healthy controls. Many of these tracts were associated with the basal ganglia or cortico-striatal structures, which aligns with the current literature highlighting striatal dysfunction. Moreover, we found that these tracts demonstrated statistically significant relationships with few cognitive measures related to language, executive function, or processing speed.
Conclusion:
We performed probabilistic tractography using a large, harmonised dataset of diffusion MRI data, which enhanced the statistical power of our study. It is important to note that most of the tracts identified in this study, particularly callosal and cortico-striatal streamlines, have been previously implicated in schizophrenia within the current literature. Further research with harmonised data focusing specifically on these brain regions could be recommended.
The occurrence of various forms of disasters has increased worldwide. In South Korea, community resilience is particularly emphasized, especially in response to large-scale disasters in regional and group units. This study investigated the association between community resilience and the quality of life of disaster-affected people, and identified the moderating effects of perception of government relief services.
Methods:
Data from the third long-term survey on the change of life of disaster-affected people conducted in 2018 by the National Disaster Management Research Institute were used. The study selected 1046 participants ages ≥ 19 years from among the disaster-affected people. Statistical analyses were performed using Model 1 of the PROCESS Macro 4.0 in the SPSS program.
Results:
Community resilience positively affected disaster-affected people’s quality of life. The perception of government relief services significantly strengthened the association between community resilience and quality of life.
Conclusions:
The study highlights the importance of enhancing community resilience to improve disaster-affected people’s quality of life and emphasizes the role of perception of government relief services in reinforcing this relationship. Several practical and political measures that focus on improving community resilience and perception of government relief services are suggested to enhance disaster-affected people’s quality of life.
The aim of this study was to evaluate the impact of coronavirus disease 2019 (COVID-19) on treatment outcomes in critically ill patients with carbapenem-resistant Acinetobacter baumannii (CRAB) bloodstream infection (BSI). This single-centre, retrospective cohort study was conducted in a 1,048-bed university-affiliated tertiary hospital in the Republic of Korea from January 2021 to March 2022. The study participants included consecutive hospitalised adult patients (aged ≥18 years) in the intensive care unit with CRAB monomicrobial BSI. During the study period, a total of 70 patients were included in our study, and 24 (34.3%) were diagnosed with COVID-19. The 28-day mortality rate was 64.3%. In the multivariate Cox proportional hazard regression analysis, diagnosis of COVID-19 (hazard ratio (HR), 2.91; 95% confidence interval (CI): 1.45–5.87), neutropenia (HR, 2.76; 95% CI: 1.04–7.29), Pitt bacteraemia score (per point; HR, 1.30; 95% CI: 1.19–1.41), and appropriate definite antibiotic therapy (HR, 0.31; 95% CI: 0.15–0.62) were independent predictors of 28-day mortality in patients with CRAB BSI. In conclusion, our findings suggested that COVID-19 has a negative prognostic impact on patients with CRAB BSI. Further study is needed to investigate the specific mechanisms of how COVID-19 worsens the prognosis of CRAB infection.
Although disconnectivity among brain regions has been one of the main hypotheses for schizophrenia, the superficial white matter (SWM) has received less attention in schizophrenia research than the deep white matter (DWM) owing to the challenge of consistent reconstruction across subjects.
Methods:
We obtained the diffusion magnetic resonance imaging (dMRI) data of 223 healthy controls and 143 patients with schizophrenia. After harmonising the raw dMRIs from three different studies, we performed whole-brain two-tensor tractography and fibre clustering on the tractography data. We compared the fractional anisotropy (FA) of white matter tracts between healthy controls and patients with schizophrenia. Spearman’s rho was adopted for the associations with clinical symptoms measured by the Positive and Negative Syndrome Scale (PANSS). The Bonferroni correction was used to adjust multiple testing.
Results:
Among the 33 DWM and 8 SWM tracts, patients with schizophrenia had a lower FA in 14 DWM and 4 SWM tracts than healthy controls, with small effect sizes. In the patient group, the FA deviations of the corticospinal and superficial–occipital tracts were negatively correlated with the PANSS negative score; however, this correlation was not evident after adjusting for multiple testing.
Conclusion:
We observed the structural impairments of both the DWM and SWM tracts in patients with schizophrenia. The SWM could be a potential target of interest in future research on neural biomarkers for schizophrenia.
Substantial evidence indicates structural abnormalities in the cerebral cortex of patients with schizophrenia (SCZ), although their clinical implications remain unclear. Previous case-control studies have investigated group-level differences in structural abnormalities, although the study design cannot account for interindividual differences. Recent research has focused on the association between the heterogeneity of the cerebral cortex morphometric features and clinical heterogeneity.
Methods
We used neuroimaging data from 420 healthy controls and 695 patients with SCZ from seven studies. Four cerebral cortex measures were obtained: surface area, gray matter volume, thickness, and local gyrification index. We calculated the coefficient of variation (CV) and person-based similarity index (PBSI) scores and performed group comparisons. Associations between the PBSI scores and cognitive functions were evaluated using Spearman's rho test and normative modeling.
Results
Patients with SCZ had a greater CV of surface area and cortical thickness than those of healthy controls. All PBSI scores across cortical measures were lower in patients with SCZ than in HCs. In the patient group, the PBSI scores for gray matter volume and all cortical measures taken together positively correlated with the full-scale IQ scores. Patients with deviant PBSI scores for gray matter volume and all cortical measures taken together had lower full-scale IQ scores than those of other patients.
Conclusions
The cerebral cortex in patients with SCZ showed greater regional and global structural variability than that in healthy controls. Patients with deviant similarity of cortical structural profiles exhibited a lower general intelligence than those exhibited by the other patients.
Identification of geographical areas with high burden of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission in schools using spatial analyses has become an important tool to guide targeted interventions in educational setting. In this study, we aimed to explore the spatial distribution and determinants of coronavirus disease 2019 (COVID-19) among students aged 3–18 years in South Korea. We analysed the nationwide epidemiological data on laboratory-confirmed COVID-19 cases in schools and in the communities between January 2020 and October 2021 in South Korea. To explore the spatial distribution, the global Moran's I and Getis-Ord's G using incidence rates among the districts of aged 3–18 years and 30–59 years. Spatial regression analysis was performed to find sociodemographic predictors of the COVID-19 attack rate in schools and in the communities. The global spatial correlation estimated by Moran's I was 0.647 for the community population and 0.350 for the student population, suggesting that the students were spatially less correlated than the community-level outbreak of SARS-CoV-2. In schools, attack rate of adults aged 30–59 years in the community was associated with increased risk of transmission (P < 0.0001). Number of students per class (in kindergartens, primary schools, middle schools and high schools) did not show significant association with the school transmission of SARS-CoV-2. In South Korea, COVID-19 in students had spatial variations across the country. Statistically significant high hotspots of SARS-CoV-2 transmission among students were found in the capital area, with dense population level and high COVID-19 burden among adults aged 30–59 years. Our finding suggests that controlling community-level burden of COVID-19 can help in preventing SARS-CoV-2 infection in school-aged children.
The current research examined whether children’s expectations about labeling conventions can be influenced by limited exposure to a foreign language. Three- to four-year-old Korean children were presented with two speakers who each assigned a novel label either in Korean or Spanish to a novel object. Children were asked whether both labels were acceptable for the object. Children who had more exposure to a foreign language through live social interaction, but not through media, were more likely to accept both Korean and Spanish labels. These findings indicate the influence of social interaction in foreign language exposure on children’s understanding of different labeling conventions.
This article examines three Japan–South Korea postwar compensation cases: the comfort women issue, the Sakhalin Island forced labor issue, and Korean atomic bomb survivor issue. These compensation movements produced vastly different results, even though the basic policy directions for compensation provision in all three cases were similar. Japan's approach toward the comfort women problem has been a complete failure, while its treatment of the Sakhalin forced labor issue and the atomic bomb issues has been more successful. This article's explanation of the different outcomes focuses on the character and geographical base of the civic groups leading these compensation movements. In South Korea, women's rights activists spearheaded the comfort women compensation movement and related victim-relief activities. The Korean non-governmental organizations (NGOs) that assisted the comfort women treated this problem not only as a women's rights issue, but also as a nationalist issue. In contrast, the Red Cross, a politically neutral international organization, promoted the Sakhalin forced labor and atomic bomb issues. In short, the different receptions accorded to those championing the comfort women issue and those promoting the Sakhalin forced labor and atomic bomb issues depended on the principal agent of each compensation process. This article aims to provide some implications for successfully implementing postwar compensation policies. It suggests that, if successful postwar compensation policy depends on successful perpetrator–victim reconciliation, establishing solidarity between perpetrator and victim countries’ civic groups is important. This can only be facilitated through the depoliticized and transparent operation of leading NGOs both inside and outside the redressal-seeking nation.
Mood disorders require consistent management of symptoms to prevent recurrences of mood episodes. Circadian rhythm (CR) disruption is a key symptom of mood disorders to be proactively managed to prevent mood episode recurrences. This study aims to predict impending mood episodes recurrences using digital phenotypes related to CR obtained from wearable devices and smartphones.
Methods
The study is a multicenter, nationwide, prospective, observational study with major depressive disorder, bipolar disorder I, and bipolar II disorder. A total of 495 patients were recruited from eight hospitals in South Korea. Patients were followed up for an average of 279.7 days (a total sample of 75 506 days) with wearable devices and smartphones and with clinical interviews conducted every 3 months. Algorithms predicting impending mood episodes were developed with machine learning. Algorithm-predicted mood episodes were then compared to those identified through face-to-face clinical interviews incorporating ecological momentary assessments of daily mood and energy.
Results
Two hundred seventy mood episodes recurred in 135 subjects during the follow-up period. The prediction accuracies for impending major depressive episodes, manic episodes, and hypomanic episodes for the next 3 days were 90.1, 92.6, and 93.0%, with the area under the curve values of 0.937, 0.957, and 0.963, respectively.
Conclusions
We predicted the onset of mood episode recurrences exclusively using digital phenotypes. Specifically, phenotypes indicating CR misalignment contributed the most to the prediction of episodes recurrences. Our findings suggest that monitoring of CR using digital devices can be useful in preventing and treating mood disorders.
The adolescent brain may be susceptible to the influences of illicit drug use. While compensatory network reorganization is a unique developmental characteristic that may restore several brain disorders, its association with methamphetamine (MA) use-induced damage during adolescence is unclear.
Methods
Using independent component (IC) analysis on structural magnetic resonance imaging data, spatially ICs described as morphometric networks were extracted to examine the effects of MA use on gray matter (GM) volumes and network module connectivity in adolescents (51 MA users v. 60 controls) and adults (54 MA users v. 60 controls).
Results
MA use was related to significant GM volume reductions in the default mode, cognitive control, salience, limbic, sensory and visual network modules in adolescents. GM volumes were also reduced in the limbic and visual network modules of the adult MA group as compared to the adult control group. Differential patterns of structural connectivity between the basal ganglia (BG) and network modules were found between the adolescent and adult MA groups. Specifically, adult MA users exhibited significantly reduced connectivity of the BG with the default network modules compared to control adults, while adolescent MA users, despite the greater extent of network GM volume reductions, did not show alterations in network connectivity relative to control adolescents.
Conclusions
Our findings suggest the potential of compensatory network reorganization in adolescent brains in response to MA use. The developmental characteristic to compensate for MA-induced brain damage can be considered as an age-specific therapeutic target for adolescent MA users.
Evidence suggests a link between smaller hippocampal volume (HV) and post-traumatic stress disorder (PTSD). However, there has been little prospective research testing this question directly and it remains unclear whether smaller HV confers risk or is a consequence of traumatization and PTSD.
Methods
U.S. soldiers (N = 107) completed a battery of clinical assessments, including structural magnetic resonance imaging pre-deployment. Once deployed they completed monthly assessments of traumatic-stressors and symptoms. We hypothesized that smaller HV would potentiate the effects of traumatic stressors on PTSD symptoms in theater. Analyses evaluated whether total HV, lateral (right v. left) HV, or HV asymmetry (right – left) moderated the effects of stressor-exposure during deployment on PTSD symptoms.
Results
Findings revealed no interaction between total HV and average monthly traumatic-stressors on PTSD symptoms b = −0.028, p = 0.681 [95% confidence interval (CI) −0.167 to 0.100]. However, in the context of greater exposure to average monthly traumatic stressors, greater right HV was associated with fewer PTSD symptoms b = −0.467, p = 0.023 (95% CI −0.786 to −0.013), whereas greater left HV was unexpectedly associated with greater PTSD symptoms b = 0.435, p = 0.024 (95% CI 0.028–0.715).
Conclusions
Our findings highlight the importance of considering the complex role of HV, in particular HV asymmetry, in predicting the emergence of PTSD symptoms in response to war-zone trauma.
Economic inequalities matter to human rights. There are two main reasons for concern about economic inequalities from human rights perspectives. First, economic inequalities matter to human rights because of their consequences. As Philip Alston, Special Rapporteur on extreme poverty and human rights (2014–20), stressed, “economic inequalities severely affect a range of civil, political, economic, social and cultural rights” (Alston 2015, 10). Research indicates that higher income inequality correlates to higher rates of homicides and robbery (Elhar and Aitken 2011, 241–6; Melamed and Samman 2013, 7). Economic inequality is often closely linked with “rising levels of crime and social unrest” (UNRISD 2010, 62).
Clozapine is generally considered as the treatment of choice for patients with treatment-resistant schizophrenia (TRS). However, its superiority has recently been questioned because olanzapine has been suggested as non-inferior to clozapine in its effectiveness.
Aims
We aimed to investigate the current status of clozapine prescriptions to identify any disparity between clinical guidelines and real-world practices.
Method
In this study, we utilised the Health Insurance Review Agency database in the Republic of Korea to investigate the real-world effectiveness of clozapine for patients with TRS. We compared differences in patient variables before and after clozapine administration, and we also performed survival analyses for both psychiatric admissions and emergency room visits among patients who used clozapine or olanzapine.
Results
This study investigated an incident cohort of 64 442 patients, and 2338 patients have been prescribed clozapine. Of these, 998 patients had TRS. In survival analysis, clozapine showed a worse survival rate for psychiatric admissions than olanzapine (hazard ratio 0.615). We also identified that clinicians tended to try a number of antipsychotics, as recommended, before starting patients on clozapine.
Conclusions
In conclusion, we found that olanzapine led to higher survival rates for psychiatric admissions than clozapine. Thus, considering the risk of serious adverse effects, clozapine may be used conservatively. Considering several studies advocating superior efficacy of clozapine, further studies with extensive data are recommended.
Current evidence on antipsychotic treatment and risk of psychiatric hospitalization in first-episode schizophrenia (FES) is largely based on the findings from randomized clinical trials (RCTs). However, the generalization of the findings to real-world patients is limited due to inherent caveats of the RCT. We aimed to investigate the treatment discontinuation and risk of psychiatric hospitalization using a nationwide population database.
Methods
The Health Insurance Review Agency database in South Korea was obtained, and the observation period started from 1 January 2009 to 31 December 2016. We defined the maintenance period as the period from 6-month after the diagnosis of schizophrenia, which is utilized for the main results. For a total of 44 396 patients with FES, a within-individual Cox regression model was used to compare the risk of the treatment discontinuation and psychiatric hospitalization.
Results
In group comparison, a long-acting injectable (LAI) antipsychotic group was associated with the lowest risk of the treatment discontinuation (0.64, 0.55–0.75) and psychiatric hospitalization (0.29, 0.22–0.38) in comparison with a typical antipsychotic group and no use, respectively. Among individual antipsychotics, the lowest risk of the treatment discontinuation was observed in LAI paliperidone (0.46, 0.37–0.66) compared to olanzapine. Clozapine was found to be the most effective antipsychotic in lowering the risk of psychiatric hospitalization as monotherapy compared to no use (0.23, 0.18–0.31).
Conclusions
In real-world patients with FES, LAI paliperidone and clozapine were associated with low treatment discontinuation and better effectiveness in lowering the risk of psychiatric hospitalization.
We report our experience with an emergency room (ER) shutdown related to an accidental exposure to a patient with coronavirus disease 2019 (COVID-19) who had not been isolated.
Setting:
A 635-bed, tertiary-care hospital in Daegu, South Korea.
Methods:
To prevent nosocomial transmission of the disease, we subsequently isolated patients with suspected symptoms, relevant radiographic findings, or epidemiology. Severe acute respiratory coronavirus 2 (SARS-CoV-2) reverse-transcriptase polymerase chain reaction assays (RT-PCR) were performed for most patients requiring hospitalization. A universal mask policy and comprehensive use of personal protective equipment (PPE) were implemented. We analyzed effects of these interventions.
Results:
From the pre-shutdown period (February 10–25, 2020) to the post-shutdown period (February 28 to March 16, 2020), the mean hourly turnaround time decreased from 23:31 ±6:43 hours to 9:27 ±3:41 hours (P < .001). As a result, the proportion of the patients tested increased from 5.8% (N=1,037) to 64.6% (N=690) (P < .001) and the average number of tests per day increased from 3.8±4.3 to 24.7±5.0 (P < .001). All 23 patients with COVID-19 in the post-shutdown period were isolated in the ER without any problematic accidental exposure or nosocomial transmission. After the shutdown, several metrics increased. The median duration of stay in the ER among hospitalized patients increased from 4:30 hours (interquartile range [IQR], 2:17–9:48) to 14:33 hours (IQR, 6:55–24:50) (P < .001). Rates of intensive care unit admissions increased from 1.4% to 2.9% (P = .023), and mortality increased from 0.9% to 3.0% (P = .001).
Conclusions:
Problematic accidental exposure and nosocomial transmission of COVID-19 can be successfully prevented through active isolation and surveillance policies and comprehensive PPE use despite longer ER stays and the presence of more severely ill patients during a severe COVID-19 outbreak.
Low rates of bystander cardiopulmonary resuscitation (CPR) were identified as a shortcoming in the “chain of survival” for out-of-hospital cardiac arrest (OHCA) care in the Korean city of Ansan. This study sought to evaluate the effect of an initiative to increase bystander CPR and quality of out-of-hospital resuscitation on outcome from OHCA. The post-intervention data were used to determine the next quality improvement (QI) target as part of the “Plan-Do-Study-Act” (PDSA) model for QI.
Hypothesis:
The study hypothesis was that bystander CPR, return of spontaneous circulation (ROSC), and survival to discharge after OHCA would increase in the post-intervention period.
Methods:
This was a retrospective pre/post study. The data from the pre-intervention period were abstracted from 2008–2011 and the post-intervention period from 2012–2013. The effect of the intervention on the odds of ROSC and survival to hospital discharge was determined using a generalized estimating equation to account for confounders and the effect of clustering within medical centers. The analysis was then used to identify other factors associated with outcomes to determine the next targets for intervention in the chain of survival for cardiac arrest in this community.
Results:
Rates of documented bystander CPR increased from 13% in the pre-intervention period to 37% in the post-intervention period. The overall rate of ROSC decreased from 18.4% to 14.3% (risk difference −4.1%; 95% CI, −7.1%–1.0%), whereas survival to hospital discharge increased from 3.9% to 5.0% (risk difference 1.1%; 95% CI, −1.8%–3.8%), and survival with good neurologic outcome increased from 0.8% to 1.6% (risk difference 0.8%; 95% CI, −0.8%–2.4%). In multivariable analyses, there was no association between the intervention and the rate of ROSC or survival to hospital discharge. The designated level of the treating hospital was a significant predictor of both survival and ROSC.
Conclusion:
In this case study, there were no observed improvements in outcomes from OHCA after the targeted intervention to improve out-of-hospital CPR. However, utilizing the PDSA model for QI, the designated level of the treating hospital was found to be a significant predictor of survival in the post-period, identifying the next target for intervention.