Traumatic stress load and stressor reactivity score associated with accelerated gray matter maturation in youths indexed by normative models.

Understanding how traumatic stress affects typical brain development during adolescence is critical to elucidate underlying mechanisms related to both maladaptive functioning and resilience after traumatic exposures. The current study aimed to map deviations from normative ranges of brain gray matter for youths with traumatic exposures. For each cortical and subcortical gray matter region, normative percentiles of variations were established using structural MRI from typically developing youths without any traumatic exposure (n = 245; age range = 8-23) from the Philadelphia Neurodevelopmental Cohort (PNC). The remaining PNC participants with neuroimaging data (n = 1129) were classified as either within the normative range (5-95%), delayed (>95%) or accelerated (<5%) maturational ranges for each region using the normative model. An averaged quantile regression index was calculated across all regions. Mediation models revealed that high traumatic stress load was positively associated with poorer cognitive functioning and greater psychopathology, and these associations were mediated by accelerated gray matter maturation. Furthermore, higher stressor reactivity scores, which represent a less resilient response under traumatic stress, were positively correlated with greater acceleration of gray matter maturation (r = 0.224, 95% CI = [0.17, 0.28], p < 0.001), suggesting that more accelerated maturation was linked to greater stressor response regardless of traumatic stress load. We conclude that traumatic stress is a source of deviation from normative brain development associated with poorer cognitive functioning and more psychopathology in the long run.

Individual and Interactive Effects of Housing and Neighborhood Quality on Mental Health in Hong Kong: A Retrospective Cohort Study.

Existing literature has widely explored the individual roles of housing and neighborhood quality, and there is limited research examining their interactive effects on mental health. This 3-year cohort study utilized a longitudinal design to investigate the individual and interactive effects of housing and neighborhood quality on mental health among 962 community-dwelling adults in Hong Kong. Participants were asked to rate their residential qualities over the 3-year period. Mental health outcomes, including levels of psychological distress and common mental disorders (CMD), were assessed using the Revised Clinical Interview Schedule (CIS-R). Logistic regression and generalized linear models were used to examine the association between housing and neighborhood quality and CMD/psychological distress, adjusting for sociodemographic and residential characteristics and baseline mental disorders. Housing quality was associated with the 3-year CMD (adjusted OR 0.95; 95% CI 0.91 to 0.98). Likewise, neighborhood quality was associated with CMD over 3 years (adjusted OR 0.92; 95% CI 0.87 to 0.96). In a separate model including both quality measures, the effect of housing quality on CMD was attenuated, whereas the neighborhood impact remained significant (adjusted OR 0.92; 95% CI 0.87 to 0.98). Generalized linear models indicated that for participants residing in substandard housing, those with high neighborhood quality had lower CIS-R scores at follow-up compared to those with low neighborhood quality (p = 0.041). Better neighborhood quality alleviated the detrimental effects of poor housing quality on mental health. Planning for an enhanced neighborhood would improve population mental health in an urban environment.

Wastewater-based reproduction numbers and projections of COVID-19 cases in three areas in Japan, November 2021 to December 2022.

BackgroundWastewater surveillance has expanded globally as a means to monitor spread of infectious diseases. An inherent challenge is substantial noise and bias in wastewater data because of the sampling and quantification process, limiting the applicability of wastewater surveillance as a monitoring tool.AimTo present an analytical framework for capturing the growth trend of circulating infections from wastewater data and conducting scenario analyses to guide policy decisions.MethodsWe developed a mathematical model for translating the observed SARS-CoV-2 viral load in wastewater into effective reproduction numbers. We used an extended Kalman filter to infer underlying transmissions by smoothing out observational noise. We also illustrated the impact of different countermeasures such as expanded vaccinations and non-pharmaceutical interventions on the projected number of cases using three study areas in Japan during 2021-22 as an example.ResultsObserved notified cases were matched with the range of cases estimated by our approach with wastewater data only, across different study areas and virus quantification methods, especially when the disease prevalence was high. Estimated reproduction numbers derived from wastewater data were consistent with notification-based reproduction numbers. Our projections showed that a 10-20% increase in vaccination coverage or a 10% reduction in contact rate may suffice to initiate a declining trend in study areas.ConclusionOur study demonstrates how wastewater data can be used to track reproduction numbers and perform scenario modelling to inform policy decisions. The proposed framework complements conventional clinical surveillance, especially when reliable and timely epidemiological data are not available.

A novel role for PGE2-EP4 in the developmental programming of the mouse ductus arteriosus: consequences for vessel maturation and function.

The ductus arteriosus (DA) is a vascular shunt that allows oxygenated blood to bypass the developing lungs in utero. Fetal DA patency requires vasodilatory signaling via the prostaglandin E2 (PGE2) receptor EP4. However, in humans and mice, disrupted PGE2-EP4 signaling in utero causes unexpected patency of the DA (PDA) after birth, suggesting another role for EP4 during development. We used EP4-knockout (KO) mice and acute versus chronic pharmacological approaches to investigate EP4 signaling in DA development and function. Expression analyses identified EP4 as the primary EP receptor in the DA from midgestation to term; inhibitor studies verified EP4 as the primary dilator during this period. Chronic antagonism recapitulated the EP4 KO phenotype and revealed a narrow developmental window when EP4 stimulation is required for postnatal DA closure. Myography studies indicate that despite reduced contractile properties, the EP4 KO DA maintains an intact oxygen response. In newborns, hyperoxia constricted the EP4 KO DA but survival was not improved, and permanent remodeling was disrupted. Vasomotion and increased nitric oxide (NO) sensitivity in the EP4 KO DA suggest incomplete DA development. Analysis of DA maturity markers confirmed a partially immature EP4 KO DA phenotype. Together, our data suggest that EP4 signaling in late gestation plays a key developmental role in establishing a functional term DA. When disrupted in EP4 KO mice, the postnatal DA exhibits signaling and contractile properties characteristic of an immature DA, including impairments in the first, muscular phase of DA closure, in addition to known abnormalities in the second permanent remodeling phase.NEW & NOTEWORTHY EP4 is the primary EP receptor in the ductus arteriosus (DA) and is critical during late gestation for its development and eventual closure. The "paradoxical" patent DA (PDA) phenotype of EP4-knockout mice arises from a combination of impaired contractile potential, altered signaling properties, and a failure to remodel associated with an underdeveloped immature vessel. These findings provide new mechanistic insights into women who receive NSAIDs to treat preterm labor, whose infants have unexplained PDA.

Evaluating Antibody Mediated Protection against Alpha, Beta, and Delta SARS-CoV-2 Variants of Concern in K18-hACE2 Transgenic Mice.

SARS-CoV-2 variants of concern (VoC) are impacting responses to the COVID-19 pandemic. Here, we utilized passive immunization using human convalescent plasma (HCP) obtained from a critically ill COVID-19 patient in the early pandemic to study the efficacy of polyclonal antibodies generated to ancestral SARS-CoV-2 against the Alpha, Beta, and Delta VoC in the K18 human angiotensin converting enzyme 2 (hACE2) transgenic mouse model. HCP protected mice from challenge with the original WA-1 SARS-CoV-2 strain; however, only partially protected mice challenged with the Alpha VoC (60% survival) and failed to save Beta challenged mice from succumbing to disease. HCP treatment groups had elevated receptor binding domain (RBD) and nucleocapsid IgG titers in the serum; however, Beta VoC viral RNA burden in the lung and brain was not decreased due to HCP treatment. While mice could be protected from WA-1 or Alpha challenge with a single dose of HCP, six doses of HCP could not decrease mortality of Delta challenged mice. Overall, these data demonstrate that VoC have enhanced immune evasion and this work underscores the need for in vivo models to evaluate future emerging strains. IMPORTANCE Emerging SARS-CoV-2 VoC are posing new problems regarding vaccine and monoclonal antibody efficacy. To better understand immune evasion tactics of the VoC, we utilized passive immunization to study the effect of early-pandemic SARS-CoV-2 HCP against, Alpha, Beta, and Delta VoC. We observed that HCP from a human infected with the original SARS-CoV-2 was unable to control lethality of Alpha, Beta, or Delta VoC in the K18-hACE2 transgenic mouse model of SARS-CoV-2 infection. Our findings demonstrate that passive immunization can be used as a model to evaluate immune evasion of emerging VoC strains.

The Effect of Building-Level Socioeconomic Status on Bystander Cardiopulmonary Resuscitation: A Retrospective Cohort Study.

OBJECTIVE: Understanding the social determinants of bystander cardiopulmonary resuscitation (CPR) receipt can inform the design of public health interventions to increase bystander CPR. The association of socioeconomic status with bystander CPR is generally poorly understood. We evaluated the relationship between socioeconomic status and bystander CPR in cases of out-of-hospital cardiac arrest (OHCA). METHODS: This was a retrospective cohort study based on the Singapore cohort of the Pan-Asian Resuscitation Outcomes Study registry between 2010 and 2018. We categorized patients into low, medium, and high Singapore Housing Index (SHI) levels-a building-level index of socioeconomic status. The primary outcome was receipt of bystander CPR. The secondary outcomes were prehospital return of spontaneous circulation and survival to discharge. RESULTS: A total of 12,730 OHCA cases were included, the median age was 71 years, and 58.9% were male. The bystander CPR rate was 56.7%. Compared to patients in the low SHI category, those in the medium and high SHI categories were more likely to receive bystander CPR (medium SHI: adjusted odds ratio [aOR] 1.48, 95% CI 1.30-1.69; high SHI: aOR 1.93, 95% CI 1.67-2.24). High SHI patients had higher survival compared to low SHI patients on unadjusted analysis (OR 1.79, 95% CI 1.08-2.96), but not adjusted analysis (adjusted for age, sex, race, witness status, arrest time, past medical history of cancer, and first arrest rhythm). When comparing high with low SHI, females had larger increases in bystander CPR rates than males. CONCLUSIONS: Lower building-level socioeconomic status was independently associated with lower rate of bystander CPR, and females were more susceptible to the effect of low socioeconomic status on lower rate of bystander CPR.

Cyclic di-GMP Regulates the Type III Secretion System and Virulence in Bordetella bronchiseptica.

The second messenger cyclic di-GMP (c-di-GMP) is a ubiquitous molecule in bacteria that regulates diverse phenotypes. Among them, motility and biofilm formation are the most studied. Furthermore, c-di-GMP has been suggested to regulate virulence factors, making it important for pathogenesis. Previously, we reported that c-di-GMP regulates biofilm formation and swimming motility in Bordetella bronchiseptica. Here, we present a multi-omics approach for the study of B. bronchiseptica strains expressing different cytoplasmic c-di-GMP levels, including transcriptome sequencing (RNA-seq) and shotgun proteomics with label-free quantification. We detected 64 proteins significantly up- or downregulated in either low or high c-di-GMP levels and 358 genes differentially expressed between strains with high c-di-GMP levels and the wild-type strain. Among them, we found genes for stress-related proteins, genes for nitrogen metabolism enzymes, phage-related genes, and virulence factor genes. Interestingly, we observed that a virulence factor like the type III secretion system (TTSS) was regulated by c-di-GMP. B. bronchiseptica with high c-di-GMP levels showed significantly lower levels of TTSS components like Bsp22, BopN, and Bcr4. These findings were confirmed by independent methods, such as quantitative reverse transcription-PCR (q-RT-PCR) and Western blotting. Higher intracellular levels of c-di-GMP correlated with an impaired capacity to induce cytotoxicity in a eukaryotic cell in vitro and with attenuated virulence in a murine model. This work presents data that support the role that the second messenger c-di-GMP plays in the pathogenesis of Bordetella.

Maternal Adverse Childhood Experience and Depression in Relation with Brain Network Development and Behaviors in Children: A Longitudinal Study.

Maternal childhood maltreatment and depression increase risks for the psychopathology of the offspring. This study employed a longitudinal dataset of mother-child dyads to investigate the developmental trajectories of brain functional networks and behaviors of children in relation with maternal childhood adverse experience and depression. Maternal childhood trauma was retrospectively assessed via childhood trauma questionnaire, whereas maternal depressive symptoms were prospectively evaluated during pregnancy and after delivery (n = 518). Child brain scans were acquired at age of 4.5, 6, and 7.5 years (n = 163) and behavioral problems were measured at 7.5 years using the Child Behavior Checklist. We found the functional connectivity of the language network with the sensorimotor, frontal, and attentional networks as a function of maternal adverse experience that interacted with sex and age. Girls exposed to mothers with depressive symptoms or childhood abuse showed the increased development of the functional connectivity of the language network with the visual networks, which was associated with social problems. Girls exposed to mothers with depressive symptoms showed the slower growth of the functional connectivity of the language network with the sensorimotor networks. Our findings, in a community sample, suggest the language network organization as neuroendophenotypes for maternal childhood trauma and depression.

The modified frailty index-11 predicts medium-term outcomes after endovascular revascularisation for chronic limb threatening ischaemia in Asian patients.

OBJECTIVE: The aim was to evaluate the utility of frailty, as defined by the modified Frailty Index-1 1 (mFI-11) on predicting outcomes following endovascular revascularisation in Asian patients with chronic limb-threatening ischaemia (CLTI). METHODS: CLTI patients who underwent endovascular revascularisation between January 2015 and March 2017 were included. Patients were retrospectively scored using the mFI-11 to categorise frailty as low, medium or high risk. Observed outcomes included 30-day complication rate and unplanned readmissions, 1-, 6- and 12-month mortality, and ambulation status at 6- and 12 months post-intervention. RESULTS: A total of 233 patients (250 procedures) were included; 137 (58.8%) were males and the mean age was 69.0 (±10.7) years. 202/233 (86.7%) were diabetic and 196/233 (84.1%) had a prior diagnosis of peripheral arterial disease (PAD). The mean mFI-11 score was 4.2 (±1.5). 28/233 (12.0%), 155/233 (66.5%), and 50/233 (21.5%) patients were deemed low (mF-11 score 0-2), moderate (mFI-11 score 3-5) and high (mFI-11 score 5-7) frailty risk, respectively. High frailty was associated with an increased 12-month mortality (OR 8.54, 95% CI 1.05-69.5; p = 0.05), 30-day complication rate (OR 9.41, 95% CI 2.01-44.1; p < 0.01) and 30-day unplanned readmission (OR 5.06, 95% CI 1.06-24.2; p = 0.04). Furthermore, a high score was associated with a significantly worse 6- (OR 0.320, 95% CI 0.120-0.840; p = 0.02) and 12-month (OR 0.270, 95% CI 0.100-0.710; p < 0.01) ambulatory status. CONCLUSION: The mFI-11 is a useful, non-invasive tool that can be readily calculated using readily available patient data, for prediction of medium-term outcomes for Asian CLTI patients following endovascular revascularisation. Early recognition of short- and mid-term loss of ambulation status amongst high-frailty patients in this challenging cohort of patients could aid decision-making for whether a revascularisation or amputation-first policy is appropriate, and manage patient and caregiver expectations on potential improvement in functional outcome.

λ-Deformation: A Canonical Framework for Statistical Manifolds of Constant Curvature.

This paper systematically presents the λ-deformation as the canonical framework of deformation to the dually flat (Hessian) geometry, which has been well established in information geometry. We show that, based on deforming the Legendre duality, all objects in the Hessian case have their correspondence in the λ-deformed case: λ-convexity, λ-conjugation, λ-biorthogonality, λ-logarithmic divergence, λ-exponential and λ-mixture families, etc. In particular, λ-deformation unifies Tsallis and Rényi deformations by relating them to two manifestations of an identical λ-exponential family, under subtractive or divisive probability normalization, respectively. Unlike the different Hessian geometries of the exponential and mixture families, the λ-exponential family, in turn, coincides with the λ-mixture family after a change of random variables. The resulting statistical manifolds, while still carrying a dualistic structure, replace the Hessian metric and a pair of dually flat conjugate affine connections with a conformal Hessian metric and a pair of projectively flat connections carrying constant (nonzero) curvature. Thus, λ-deformation is a canonical framework in generalizing the well-known dually flat Hessian structure of information geometry.

Mucosal Immunization with DTaP Confers Protection against Bordetella pertussis Infection and Cough in Sprague-Dawley Rats.

Pertussis is a respiratory disease caused by the Gram-negative pathogen, Bordetella pertussis. The transition from a whole-cell pertussis vaccine (wP and DTP) to an acellular pertussis vaccine (aP, DTaP, and Tdap) correlates with an increase in pertussis cases, despite widespread vaccine implementation and coverage, and it is now appreciated that the protection provided by aP rapidly wanes. To recapitulate the localized immunity observed from natural infection, mucosal vaccination with aP was explored using the coughing rat model of pertussis. Overall, our goal was to evaluate the route of vaccination in the coughing rat model of pertussis. Immunity induced by both oral gavage and intranasal vaccination of aP in B. pertussis challenged rats over a 9-day infection was compared to intramuscular wP (IM-wP)- and IM-aP-immunized rats that were used as positive controls. Our data demonstrate that mucosal immunization of aP resulted in the production of anti-B. pertussis IgG antibody titers similar to IM-wP- and IM-aP-vaccinated controls postchallenge. IN-aP also induced anti-B. pertussis IgA antibodies in the nasal cavity. Immunization with IM-wP, IM-aP, IN-aP, and OG-aP immunization protected against B. pertussis-induced cough, whereas OG-aP immunization did not protect against respiratory distress. Mucosal immunization by both intranasal and oral gavage administration protected against acute inflammation and decreased bacterial burden in the lung compared to mock-vaccinated challenge rats. The data presented in this study suggest that mucosal vaccination with aP can induce a mucosal immune response and provide protection against B. pertussis challenge. This study highlights the potential benefits and uses of the coughing rat model of pertussis; however, further questions regarding waning immunity still require additional investigation.

Intranasal Immunization with Acellular Pertussis Vaccines Results in Long-Term Immunity to Bordetella pertussis in Mice.

Bordetella pertussis colonizes the respiratory mucosa of humans, inducing an immune response seeded in the respiratory tract. An individual, once convalescent, exhibits long-term immunity to the pathogen. Current acellular pertussis (aP) vaccines do not induce the long-term immune response observed after natural infection in humans. In this study, we evaluated the durability of protection from intranasal (i.n.) pertussis vaccines in mice. Mice that convalesced from B. pertussis infection served as a control group. Mice were immunized with a mock vaccine (phosphate-buffered saline [PBS]), aP only, or an aP base vaccine combined with one of the following adjuvants: alum, curdlan, or purified whole glucan particles (IRI-1501). We utilized two study designs: short term (challenged 35 days after priming vaccination) and long term (challenged 6 months after boost). The short-term study demonstrated that immunization with i.n. vaccine candidates decreased the bacterial burden in the respiratory tract, reduced markers of inflammation, and induced significant serum and lung antibody titers. In the long-term study, protection from bacterial challenge mirrored the results observed in the short-term challenge study. Immunization with pertussis antigens alone was surprisingly protective in both models; however, the alum and IRI-1501 adjuvants induced significant B. pertussis-specific IgG antibodies in both the serum and lung and increased numbers of anti-B. pertussis IgG-secreting plasma cells in the bone marrow. Our data indicate that humoral responses induced by the i.n. vaccines correlated with protection, suggesting that long-term antibody responses can be protective.

Reinvestigating the Coughing Rat Model of Pertussis To Understand Bordetella pertussis Pathogenesis.

Bordetella pertussis is a highly contagious bacterium that is the causative agent of whooping cough (pertussis). Currently, acellular pertussis vaccines (aP, DTaP, and Tdap) are used to prevent pertussis disease. However, it is clear that the aP vaccine efficacy quickly wanes, resulting in the reemergence of pertussis. Furthermore, recent work performed by the CDC suggest that current circulating strains are genetically distinct from strains of the past. The emergence of genetically diverging strains, combined with waning aP vaccine efficacy, calls for reevaluation of current animal models of pertussis. In this study, we used the rat model of pertussis to compare two genetically divergent strains Tohama 1 and D420. We intranasally challenged 7-week-old Sprague-Dawley rats with 108 viable Tohama 1 and D420 and measured the hallmark signs/symptoms of B. pertussis infection such as neutrophilia, pulmonary inflammation, and paroxysmal cough using whole-body plethysmography. Onset of cough occurred between 2 and 4 days after B. pertussis challenge, averaging five coughs per 15 min, with peak coughing occurring at day 8 postinfection, averaging upward of 13 coughs per 15 min. However, we observed an increase of coughs in rats infected with clinical isolate D420 through 12 days postchallenge. The rats exhibited increased bronchial restriction following B. pertussis infection. Histology of the lung and flow cytometry confirm both cellular infiltration and pulmonary inflammation. D420 infection induced higher production of anti-B. pertussis IgM antibodies compared to Tohama 1 infection. The coughing rat model provides a way of characterizing disease manifestation differences between B. pertussis strains.

Common functional brain networks between attention deficit and disruptive behaviors in youth.

Attention deficits (AD) and disruptive behavior (DB) are highly comorbid youth externalizing behaviors. This study aimed to study reliable functional brain networks shared by AD and DB in youth aged from 8 to 21 years from the Philadelphia Neurodevelopmental Cohort (PNC). The PNC study assessed AD and DB behaviors via Kiddie-Schedule for Affective Disorders and Schizophrenia (K-SADS). This study employed sparse canonical correlation analysis (SCCA) to examine the correlation of AD and DB behaviors with resting-state functional connectivity maps of the brain regions identified via activation likelihood estimation (ALE) meta-analyses on attention deficit/hyperactivity disorder (ADHD) and DB disorder (DBD). Our meta-analyses identified that the middle cingulate cortex, pre-supplementary motor area (pre-SMA), and striatum had a great consensus in existing ADHD studies and the amygdala and inferior parietal lobule were consistently found in existing DBD studies. Our SCCA analysis revealed that the AD and DB behavioral items relevant to inattention and delinquency were correlated with the functional connectivity of the pre-SMA with the ventral attentional and frontoparietal networks (FPN), and the striatum with the default mode (DMN) and dorsal attentional networks. The AD and DB behavioral items relevant to inattention and irritability were associated with the functional connectivity between the amygdala and the DMN and FPN. Our findings suggest that the functional organization of the ADHD- and DBD-related brain regions provides insights on the shared neural basis in AD and DB.

Leveraging open data to reconstruct the Singapore Housing Index and other building-level markers of socioeconomic status for health services research.

BACKGROUND: Socioeconomic status (SES) is an important determinant of health, and SES data is an important confounder to control for in epidemiology and health services research. Individual level SES measures are cumbersome to collect and susceptible to biases, while area level SES measures may have insufficient granularity. The 'Singapore Housing Index' (SHI) is a validated, building level SES measure that bridges individual and area level measures. However, determination of the SHI has previously required periodic data purchase and manual parsing. In this study, we describe a means of SHI determination for public housing buildings with open government data, and validate this against the previous SHI determination method. METHODS: Government open data sources (e.g. DATA: gov.sg, Singapore Land Authority OneMAP API, Urban Redevelopment Authority API) were queried using custom Python scripts. Data on residential public housing block address and composition from the HDB Property Information dataset (data.gov.sg) was matched to postal code and geographical coordinates via OneMAP API calls. The SHI was calculated from open data, and compared to the original SHI dataset that was curated from non-open data sources in 2018. RESULTS: Ten thousand seventy-seven unique residential buildings were identified from open data. OneMAP API calls generated valid geographical coordinates for all (100%) buildings, and valid postal code for 10,012 (99.36%) buildings. There was an overlap of 10,011 buildings between the open dataset and the original SHI dataset. Intraclass correlation coefficient was 0.999 for the two sources of SHI, indicating almost perfect agreement. A Bland-Altman plot analysis identified a small number of outliers, and this revealed 5 properties that had an incorrect SHI assigned by the original dataset. Information on recently transacted property prices was also obtained for 8599 (85.3%) of buildings. CONCLUSION: SHI, a useful tool for health services research, can be accurately reconstructed using open datasets at no cost. This method is a convenient means for future researchers to obtain updated building-level markers of socioeconomic status for policy and research.

Utilizing Machine Learning Methods for Preoperative Prediction of Postsurgical Mortality and Intensive Care Unit Admission.

OBJECTIVE: To compare the performance of machine learning models against the traditionally derived Combined Assessment of Risk Encountered in Surgery (CARES) model and the American Society of Anaesthesiologists-Physical Status (ASA-PS) in the prediction of 30-day postsurgical mortality and need for intensive care unit (ICU) stay >24 hours. BACKGROUND: Prediction of surgical risk preoperatively is important for clinical shared decision-making and planning of health resources such as ICU beds. The current growth of electronic medical records coupled with machine learning presents an opportunity to improve the performance of established risk models. METHODS: All patients aged 18 years and above who underwent noncardiac and nonneurological surgery at Singapore General Hospital (SGH) between 1 January 2012 and 31 October 2016 were included. Patient demographics, comorbidities, preoperative laboratory results, and surgery details were obtained from their electronic medical records. Seventy percent of the observations were randomly selected for training, leaving 30% for testing. Baseline models were CARES and ASA-PS. Candidate models were trained using random forest, adaptive boosting, gradient boosting, and support vector machine. Models were evaluated on area under the receiver operating characteristic curve (AUROC) and area under the precision-recall curve (AUPRC). RESULTS: A total of 90,785 patients were included, of whom 539 (0.6%) died within 30 days and 1264 (1.4%) required ICU admission >24 hours postoperatively. Baseline models achieved high AUROCs despite poor sensitivities by predicting all negative in a predominantly negative dataset. Gradient boosting was the best performing model with AUPRCs of 0.23 and 0.38 for mortality and ICU admission outcomes respectively. CONCLUSIONS: Machine learning can be used to improve surgical risk prediction compared to traditional risk calculators. AUPRC should be used to evaluate model predictive performance instead of AUROC when the dataset is imbalanced.

An overlapping pattern of cerebral cortical thinning is associated with both positive symptoms and aggression in schizophrenia via the ENIGMA consortium.

BACKGROUND: Positive symptoms are a useful predictor of aggression in schizophrenia. Although a similar pattern of abnormal brain structures related to both positive symptoms and aggression has been reported, this observation has not yet been confirmed in a single sample. METHOD: To study the association between positive symptoms and aggression in schizophrenia on a neurobiological level, a prospective meta-analytic approach was employed to analyze harmonized structural neuroimaging data from 10 research centers worldwide. We analyzed brain MRI scans from 902 individuals with a primary diagnosis of schizophrenia and 952 healthy controls. RESULTS: The result identified a widespread cortical thickness reduction in schizophrenia compared to their controls. Two separate meta-regression analyses revealed that a common pattern of reduced cortical gray matter thickness within the left lateral temporal lobe and right midcingulate cortex was significantly associated with both positive symptoms and aggression. CONCLUSION: These findings suggested that positive symptoms such as formal thought disorder and auditory misperception, combined with cognitive impairments reflecting difficulties in deploying an adaptive control toward perceived threats, could escalate the likelihood of aggression in schizophrenia.

The Modified Frailty Index Does Not Predict Mortality After Major Lower Extremity Amputation for Peripheral Arterial Disease in an Asian Population.

BACKGROUND: Patients with critical limb ischemia (CLI) who undergo major lower extremity amputation (LEA) have been associated with high one-year mortality rates. Previous western-based studies have identified risk factors that exponentiate these poor outcomes, including nonambulatory status and cardiovascular morbidity. We assessed the effect of frailty, using the modified frailty index (mFI) in a cohort undergoing major LEA for CLI to predict mortality, perioperative complications, and unplanned readmissions in a tertiary institution from Singapore. METHODS: Data on patients who had undergone major LEA from January 2016 to December 2017 were collected retrospectively. Inclusion criteria were below-knee amputations (BKAs) or above-knee amputations (AKAs) performed for peripheral arterial disease-related tissue loss or sepsis only. Patients were categorized into 3 risk groups based on the 11-variable mFI: low mFI, 0-0.27; moderate mFI, 0.36-0.54; and high mFI ≥0.63. Univariate and multivariate analysis was performed using logistic regression analysis. RESULTS: 211 patients underwent major LEA, of whom 133 (63.0%) had undergone BKA. The mean mFI was 0.41 (range 0-0.81). 84/211 (39.8%) died within 1 year after the procedure, with mortality rates of 25/65 (38.4%), 49/127 (38.6%), and 10/19 (52.6%) in the low-, moderate-, high-mFI categories, respectively. High and moderate mFI had failed to demonstrate an increased risk of mortality when compared with the low-mFI group (P > 0.05). 91/211 (43.1%) patients had perioperative complications, whereas 27/211 (12.8%) patients were readmitted within 30 days of discharge. Myocardial infarction, chronic kidney disease, and atrial fibrillation were found to be predictive of poor outcomes after major LEA. CONCLUSIONS: Frailty as measured with the mFI did not predict outcome after major LEA. This could be due to confounding effects such as high prevalence of renal dysfunction and the constancy of diabetes and peripheral vascular disease in this population that would reduce the differentiation of patients using the mFI.

Sentinel Lymph Node Biopsy in Early Breast Cancer: Magnetic Tracer as the Only Localizing Agent.

BACKGROUND: The combined use of radioisotope and blue dye is the gold standard in sentinel lymph node (SLN) localization in early breast cancer. Superparamagnetic iron oxide (SPIO) has recently emerged as a non-inferior new tracer in sentinel lymph node mapping with fewer disadvantages. This study represents the first and the largest cohort of superparamagnetic iron oxide application in Asian population. METHODS: Retrospective analysis of a prospectively maintained database was performed from August 2016 to December 2017. All patients with SLN localization by SPIO were included in this study. RESULTS: A total of 328 breast cancer patients with 333 SLNB procedures were included in this study. Median age was 54 years (range 32-86). Median tumor size was 1.9 cm (range 0.1-12 cm).There were 138 breast-conserving surgeries and 195 mastectomies. All patients received injection of SPIO 1 day prior to operation. A total of 329 successful sentinel lymph node biopsy (SLNB) procedures were undertaken with 1514 sentinel lymph nodes (SLNs) identified. One hundred and fifty-three (10.1%) of the SLNs were positive for malignancy. There were 54 patients with macrometastases, 26 with micrometastases and 24 with isolated tumor cells. Sixty-seven patients underwent subsequent axillary dissection. Four patients failed sentinel lymph node identification with SPIO. The success rate of SPIO in sentinel lymph node localization was 98.8%. CONCLUSION: SPIO represents a feasible alternative in sentinel lymph node mapping with comparably high nodal detection rate.

Post-stroke patients with moderate function have the greatest risk of falls: a National Cohort Study.

BACKGROUND: Stroke patients have increased risks of falls. We examined national registry data to evaluate the association between post-stroke functional level and the risk of low falls among post-stroke patients. METHODS: This retrospective cohort study analyzed data from national registries to examine the risk factors for post-stroke falls. Data for patients who suffered ischemic strokes and survived the index hospital admission was obtained from the Singapore National Stroke Registry and matched to the National Trauma Registry, from 2011 to 2015. The primary outcome measure was a low fall (fall height ≤ 0.5 m). Competing risk analysis was performed to examine the association between functional level (by modified Rankin score [mRS] at discharge) and the risk of subsequent low falls. RESULTS: In all, 2255 patients who suffered ischemic strokes had recorded mRS. The mean age was 66.6 years and 58.5% were men. By the end of 2015, 54 (2.39%) had a low fall while 93 (4.12%) died. After adjusting for potential confounders, mRS was associated with fall risk with an inverted U-shaped relationship. Compared to patients with a score of zero, the sub-distribution hazard ratio (SHR) increased to a maximum of 3.42 (95%CI:1.21-9.65, p = 0.020) for patients with a score of 2. The SHR then declined to 2.45 (95%CI:0.85-7.12, p = 0.098), 2.86 (95%CI:0.95-8.61, p = 0.062) and 1.93 (95%CI:0.44-8.52, p = 0.38) for patients with scores of 3, 4 and 5 respectively. CONCLUSIONS: An inverted U-shaped relationship between functional status and fall risk was observed. This is consistent with the complex interplay between decreasing mobility (hence decreased opportunity to fall) and increasing susceptibility to falls. Fall prevention intervention could be targeted accordingly. (263 words).