Recruitment and positioning determine the specific role of the XPF-ERCC1 endonuclease in interstrand crosslink repair.

XPF-ERCC1 is a structure-specific endonuclease pivotal for several DNA repair pathways and, when mutated, can cause multiple diseases. Although the disease-specific mutations are thought to affect different DNA repair pathways, the molecular basis for this is unknown. Here we examine the function of XPF-ERCC1 in DNA interstrand crosslink (ICL) repair. We used Xenopus egg extracts to measure both ICL and nucleotide excision repair, and we identified mutations that are specifically defective in ICL repair. One of these separation-of-function mutations resides in the helicase-like domain of XPF and disrupts binding to SLX4 and recruitment to the ICL A small deletion in the same domain supports recruitment of XPF to the ICL, but inhibited the unhooking incisions most likely by disrupting a second, transient interaction with SLX4. Finally, mutation of residues in the nuclease domain did not affect localization of XPF-ERCC1 to the ICL but did prevent incisions on the ICL substrate. Our data support a model in which the ICL repair-specific function of XPF-ERCC1 is dependent on recruitment, positioning and substrate recognition.

The role of SLX4 and its associated nucleases in DNA interstrand crosslink repair.

A key step in the Fanconi anemia pathway of DNA interstrand crosslink (ICL) repair is the ICL unhooking by dual endonucleolytic incisions. SLX4/FANCP is a large scaffold protein that plays a central role in ICL unhooking. It contains multiple domains that interact with many proteins including three different endonucleases and also acts in several other DNA repair pathways. While it is known that its interaction with the endonuclease XPF-ERCC1 is required for its function in ICL repair, which other domains act in this process is unclear. Here, we used Xenopus egg extracts to determine ICL repair specific features of SLX4. We show that the SLX4-interacting endonuclease SLX1 is not required for ICL repair and demonstrate that all essential SLX4 domains are located at the N-terminal half of the protein. The MLR domain is crucial for the recruitment of XPF-ERCC1 but also has an unanticipated function in recruiting SLX4 to the site of damage. Although we find the BTB is not essential for ICL repair in our system, dimerization of SLX4 could be important. Our data provide new insights into the mechanism by which SLX4 acts in ICL repair.

Xenopus egg extract: A powerful tool to study genome maintenance mechanisms.

DNA repair pathways are crucial to maintain the integrity of our genome and prevent genetic diseases such as cancer. There are many different types of DNA damage and specific DNA repair mechanisms have evolved to deal with these lesions. In addition to these repair pathways there is an extensive signaling network that regulates processes important for repair, such as cell cycle control and transcription. Despite extensive research, DNA damage repair and signaling are not fully understood. In vitro systems such as the Xenopus egg extract system, have played, and still play, an important role in deciphering the molecular details of these processes. Xenopus laevis egg extracts contain all factors required to efficiently perform DNA repair outside a cell, using mechanisms conserved in humans. These extracts have been used to study several genome maintenance pathways, including mismatch repair, non-homologous end joining, ICL repair, DNA damage checkpoint activation, and replication fork stability. Here we describe how the Xenopus egg extract system, in combination with specifically designed DNA templates, contributed to our detailed understanding of these pathways.

Evolving brain and behaviour changes in rats following repetitive subconcussive head impacts.

There is growing concern that repetitive subconcussive head impacts, independent of concussion, alter brain structure and function, and may disproportionately affect the developing brain. Animal studies of repetitive subconcussive head impacts are needed to begin to characterize the pathological basis and mechanisms underlying imaging and functional effects of repetitive subconcussive head impacts seen in humans. Since repetitive subconcussive head impacts have been largely unexplored in animals, we aimed to characterize the evolution of imaging, behavioural and pathological effects of repetitive subconcussive head impacts in awake adolescent rodents. Awake male and female Sprague Dawley rats (postnatal Day 35) received 140 closed-head impacts over the course of a week. Impacted and sham-impacted animals were restrained in a plastic cone, and unrestrained control animals were included to account for effects of restraint and normal development. Animals (n = 43) underwent repeated diffusion tensor imaging prior to and over 1 month following the final impact. A separate cohort (n = 53) was assessed behaviourally for fine motor control, emotional-affective behaviour and memory at acute and chronic time points. Histological and immunohistochemical analyses, which were exploratory in nature due to smaller sample sizes, were completed at 1 month following the final impact. All animals tolerated the protocol with no overt changes in behaviour or stigmata of traumatic brain injury, such as alteration of consciousness, intracranial haemorrhage or skull fracture. We detected longitudinal, sex-dependent diffusion tensor imaging changes (fractional anisotropy and axial diffusivity decline) in corpus callosum and external capsule of repetitive subconcussive head impact animals, which diverged from both sham and control. Compared to sham animals, repetitive subconcussive head impact animals exhibited acute but transient mild motor deficits. Repetitive subconcussive head impact animals also exhibited chronic anxiety and spatial memory impairment that differed from the control animals, but these effects were not different from those seen in the sham condition. We observed trends in the data for thinning of the corpus callosum as well as regions with elevated Iba-1 in the corpus callosum and cerebral white matter among repetitive subconcussive head impact animals. While replication with larger study samples is needed, our findings suggest that subconcussive head impacts cause microstructural tissue changes in the developing rat brain, which are detectable with diffusion tensor imaging, with suggestion of correlates in tissue pathology and behaviour. The results point to potential mechanisms underpinning consequences of subconcussive head impacts that have been described in humans. The congruence of our imaging findings with human subconcussive head impacts suggests that neuroimaging could serve as a translational bridge to advance study of injury mechanisms and development of interventions.

Characteristics of COVID-19 patients with multiorgan injury across the pandemic in a large academic health system in the Bronx, New York.

Purpose: To investigate the evolution of COVID-19 patient characteristics and multiorgan injury across the pandemic. Methods: This retrospective cohort study consisted of 40,387 individuals tested positive for SARS-CoV-2 in the Montefiore Health System in Bronx, NY, between March 2020 and February 2022, of which 11,306 were hospitalized. Creatinine, troponin, and alanine aminotransferase were used to define acute kidney injury (AKI), acute cardiac injury (ACI) and acute liver injury, respectively. Demographics, comorbidities, emergency department visits, hospitalization, intensive care utilization, and mortality were analyzed across the pandemic. Results: COVID-19 positive cases, emergency department visits, hospitalization and mortality rate showed four distinct waves with a large first wave in April 2020, two small (Alpha and Delta) waves, and a large Omicron wave in December 2021. Omicron was more infectious but less lethal (p = 0.05). Among hospitalized COVID-19 patients, age decreased (p = 0.014), female percentage increased (p = 0.023), Hispanic (p = 0.028) and non-Hispanic Black (p = 0.05) percentages decreased, and patients with pre-existing diabetes (p = 0.002) and hypertension (p = 0.04) decreased across the pandemic. More than half (53.1%) of hospitalized patients had major organ injury. Patients with AKI, ACI and its combinations were older, more likely males, had more comorbidities, and consisted more of non-Hispanic Black and Hispanic patients (p = 0.005). Patients with AKI and its combinations had 4-9 times higher adjusted risk of mortality than those without. Conclusions: There were shifts in demographics toward younger age and proportionally more females with COVID-19 across the pandemic. While the overall trend showed improved clinical outcomes, a substantial number of COVID-19 patients developed multi-organ injuries over time. These findings could bring awareness to at-risk patients for long-term organ injuries and help to better inform public policy and outreach initiatives.

New-onset and persistent neurological and psychiatric sequelae of COVID-19 compared to influenza: A retrospective cohort study in a large New York City healthcare network.

OBJECTIVES: Neurological and neuropsychiatric manifestations of post-acute SARS-CoV-2 infection (neuro-PASC) are common among COVID-19 survivors, but it is unknown how neuro-PASC differs from influenza-related neuro-sequelae. This study investigated the clinical characteristics of COVID-19 patients with and without new-onset neuro-PASC, and of flu patients with similar symptoms. METHODS: We retrospectively screened 18,811 COVID-19 patients and 5772 flu patients between January 2020 and June 2021 for the presence of new-onset neuro-sequelae that persisted at least 2 weeks past the date of COVID-19 or flu diagnosis. RESULTS: We observed 388 COVID-19 patients with neuro-PASC versus 149 flu patients with neuro-sequelae. Common neuro-PASC symptoms were anxiety (30%), depression (27%), dizziness (22%), altered mental status (17%), chronic headaches (17%), and nausea (11%). The average time to neuro-PASC onset was 138 days, with hospitalized patients reporting earlier onset than non-hospitalized patients. Neuro-PASC was associated with female sex and older age (p < 0.05), but not race, ethnicity, most comorbidities, or COVID-19 disease severity (p > 0.05). Compared to flu patients, COVID-19 patients were older, exhibited higher incidence of altered mental status, developed symptoms more quickly, and were prescribed psychiatric drugs more often (p < 0.05). CONCLUSIONS: This study provides additional insights into neuro-PASC risk factors and differentiates between post-COVID-19 and post-flu neuro-sequelae.

Prophylactic versus therapeutic dose anticoagulation effects on survival among critically ill patients with COVID-19.

INTRODUCTION: Although patients with severe COVID-19 are known to be at high risk of developing thrombotic events, the effects of anticoagulation (AC) dose and duration on in-hospital mortality in critically ill patients remain poorly understood and controversial. The goal of this study was to investigate survival of critically ill COVID-19 patients who received prophylactic or therapeutic dose AC and analyze the mortality rate with respect to detailed demographic and clinical characteristics. MATERIALS AND METHODS: We conducted a retrospective, observational study of critically ill COVID-19 patients admitted to the ICU at Stony Brook University Hospital in New York who received either prophylactic (n = 158) or therapeutic dose AC (n = 153). Primary outcome was in-hospital death assessed by survival analysis and covariate-adjusted Cox proportional hazard model. RESULTS: For the first 3 weeks of ICU stay, we observed similar survival curves for prophylactic and therapeutic AC groups. However, after 3 or more weeks of ICU stay, the therapeutic AC group, characterized by high incidence of acute kidney injury (AKI), had markedly higher death incidence rates with 8.6 deaths (95% CI = 6.2-11.9 deaths) per 1,000 person-days and about 5 times higher risk of death (adj. HR = 4.89, 95% CI = 1.71-14.0, p = 0.003) than the prophylactic group (2.4 deaths [95% CI = 0.9-6.3 deaths] per 1,000 person-days). Among therapeutic AC users with prolonged ICU admission, non-survivors were characterized by older males with depressed lymphocyte counts and cardiovascular disease. CONCLUSIONS: Our findings raise the possibility that prolonged use of high dose AC, independent of thrombotic events or clinical background, might be associated with higher risk of in-hospital mortality. Moreover, AKI, age, lymphocyte count, and cardiovascular disease may represent important risk factors that could help identify at-risk patients who require long-term hospitalization with therapeutic dose AC treatment.

Clinical outcomes of COVID-19 in patients with sickle cell disease and sickle cell trait: A critical appraisal of the literature.

Individuals with sickle cell disease (SCD) and sickle cell trait (SCT) have many risk factors that could make them more susceptible to COVID-19 critical illness and death compared to the general population. With a growing body of literature in this field, a comprehensive review is needed. We reviewed 71 COVID-19-related studies conducted in 15 countries and published between January 1, 2020, and October 15, 2021, including a combined total of over 2000 patients with SCD and nearly 2000 patients with SCT. Adults with SCD typically have a mild to moderate COVID-19 disease course, but also a 2- to 7-fold increased risk of COVID-19-related hospitalization and a 1.2-fold increased risk of COVID-19-related death as compared to adults without SCD, but not compared to controls with similar comorbidities and end-organ damage. There is some evidence that persons with SCT have increased risk of COVID-19-related hospitalization and death although more studies with risk-stratification and properly matched controls are needed to confirm these findings. While the literature suggests that most children with SCD and COVID-19 have mild disease and low risk of death, some children with SCD, especially those with SCD-related comorbidities, are more likely to be hospitalized and require escalated care than children without SCD. However, children with SCD are less likely to experience COVID-19-related severe illness and death compared to adults with or without SCD. SCD-directed therapies such as transfusion and hydroxyurea may be associated with better COVID-19 outcomes, but prospective studies are needed for confirmation. While some studies have reported favorable short-term outcomes for COVID-19 patients with SCD and SCT, the long-term effects of SARS-CoV-2 infection are unknown and may affect individuals with SCD and SCT differently from the general population. Important focus areas for future research should include multi-center studies with larger sample sizes, assessment of hemoglobin genotype and SCD-modifying therapies on COVID-19 outcomes, inclusion of case-matched controls that account for the unique sample characteristics of SCD and SCT populations, and longitudinal assessment of post-COVID-19 symptoms.

Clinical predictors of acute cardiac injury and normalization of troponin after hospital discharge from COVID-19.

BACKGROUND: Although acute cardiac injury (ACI) is a known COVID-19 complication, whether ACI acquired during COVID-19 recovers is unknown. This study investigated the incidence of persistent ACI and identified clinical predictors of ACI recovery in hospitalized patients with COVID-19 2.5 months post-discharge. METHODS: This retrospective study consisted of 10,696 hospitalized COVID-19 patients from March 11, 2020 to June 3, 2021. Demographics, comorbidities, and laboratory tests were collected at ACI onset, hospital discharge, and 2.5 months post-discharge. ACI was defined as serum troponin-T (TNT) level >99th-percentile upper reference limit (0.014ng/mL) during hospitalization, and recovery was defined as TNT below this threshold 2.5 months post-discharge. Four models were used to predict ACI recovery status. RESULTS: There were 4,248 (39.7%) COVID-19 patients with ACI, with most (93%) developed ACI on or within a day after admission. In-hospital mortality odds ratio of ACI patients was 4.45 [95%CI: 3.92, 5.05, p<0.001] compared to non-ACI patients. Of the 2,880 ACI survivors, 1,114 (38.7%) returned to our hospitals 2.5 months on average post-discharge, of which only 302 (44.9%) out of 673 patients recovered from ACI. There were no significant differences in demographics, race, ethnicity, major commodities, and length of hospital stay between groups. Prediction of ACI recovery post-discharge using the top predictors (troponin, creatinine, lymphocyte, sodium, lactate dehydrogenase, lymphocytes and hematocrit) at discharge yielded 63.73%-75.73% accuracy. INTERPRETATION: Persistent cardiac injury is common among COVID-19 survivors. Readily available patient data accurately predict ACI recovery post-discharge. Early identification of at-risk patients could help prevent long-term cardiovascular complications. FUNDING: None.

Outcomes of Hospitalized Patients With COVID-19 With Acute Kidney Injury and Acute Cardiac Injury.

PURPOSE: This study investigated the incidence, disease course, risk factors, and mortality in COVID-19 patients who developed both acute kidney injury (AKI) and acute cardiac injury (ACI), and compared to those with AKI only, ACI only, and no injury (NI). METHODS: This retrospective study consisted of hospitalized COVID-19 patients at Montefiore Health System in Bronx, New York between March 11, 2020 and January 29, 2021. Demographics, comorbidities, vitals, and laboratory tests were collected during hospitalization. Predictive models were used to predict AKI, ACI, and AKI-ACI onset. Longitudinal laboratory tests were analyzed with time-lock to discharge alive or death. RESULTS: Of the 5,896 hospitalized COVID-19 patients, 44, 19, 9, and 28% had NI, AKI, ACI, and AKI-ACI, respectively. Most ACI presented very early (within a day or two) during hospitalization in contrast to AKI (p < 0.05). Patients with combined AKI-ACI were significantly older, more often men and had more comorbidities, and higher levels of cardiac, kidney, liver, inflammatory, and immunological markers compared to those of the AKI, ACI, and NI groups. The adjusted hospital-mortality odds ratios were 17.1 [95% CI = 13.6-21.7, p < 0.001], 7.2 [95% CI = 5.4-9.6, p < 0.001], and 4.7 [95% CI = 3.7-6.1, p < 0.001] for AKI-ACI, ACI, and AKI, respectively, relative to NI. A predictive model of AKI-ACI onset using top predictors yielded 97% accuracy. Longitudinal laboratory data predicted mortality of AKI-ACI patients up to 5 days prior to outcome, with an area-under-the-curve, ranging from 0.68 to 0.89. CONCLUSIONS: COVID-19 patients with AKI-ACI had markedly worse outcomes compared to those only AKI, ACI and NI. Common laboratory variables accurately predicted AKI-ACI. The ability to identify patients at risk for AKI-ACI could lead to earlier intervention and improvement in clinical outcomes.

Clinical characteristics of the first and second COVID-19 waves in the Bronx, New York: A retrospective cohort study.

BACKGROUND: There is limited clinical patient data comparing the first and second waves of the coronavirus disease 2019 (COVID-19) in the United States and the effects of a COVID-19 resurgence on different age, racial and ethnic groups. We compared the first and second COVID-19 waves in the Bronx, New York, among a racially and ethnically diverse population. METHODS: Patients in this retrospective cohort study were included if they had a laboratory-confirmed SARS-CoV-2 infection by a real-time PCR test of a nasopharyngeal swab specimen detected between March 11, 2020, and January 21, 2021. Main outcome measures were critical care, in-hospital acquired disease and death. Patient demographics, comorbidities, vitals, and laboratory values were also collected. FINDINGS: A total of 122,983 individuals were tested for SARS-CoV-2 infection, of which 12,659 tested positive. The second wave was characterized by a younger demographic, fewer comorbidities, less extreme laboratory values at presentation, and lower risk of adverse outcomes, including in-hospital mortality (adj. OR = 0·23, 99·5% CI = 0·17 to 0·30), hospitalization (adj. OR = 0·65, 99·5% CI = 0·58 to 0·74), invasive mechanical ventilation (adj. OR = 0·70, 99·5% CI = 0·56 to 0·89), acute kidney injury (adj. OR = 0·62, 99·5% CI = 0·54 to 0·71), and length of stay (adj. OR = 0·71, 99·5% CI = 0·60 to 0·85), with Black and Hispanic patients demonstrating most improvement in clinical outcomes. INTERPRETATION: The second COVID-19 wave in the Bronx exhibits improved clinical outcomes compared to the first wave across all age, racial, and ethnic groups, with minority groups showing more improvement, which is encouraging news in the battle against health disparities.

Animal models of closed-skull, repetitive mild traumatic brain injury.

The underlying mechanisms that result in neurophysiological changes and cognitive sequelae in the context of repetitive mild traumatic brain injury (rmTBI) remain poorly understood. Animal models provide a unique opportunity to examine cellular and molecular responses using histological assessment, which can give important insights on the neurophysiological changes associated with the evolution of brain injury. To better understand the potential cumulative effects of multiple concussions, the focus of animal models is shifting from single to repetitive head impacts. With a growing body of literature on this subject, a review and discussion of current findings is valuable to better understand the neuropathology associated with rmTBI, to evaluate the current state of the field, and to guide future research efforts. Despite variability in experimental settings, existing animal models of rmTBI have contributed to our understanding of the underlying mechanisms following repeat concussion. However, how to reconcile the various impact methods remains one of the major challenges in the field today.

Diffusion Tensor Imaging of the Evolving Response to Mild Traumatic Brain Injury in Rats.

Mild traumatic brain injury (mTBI), also known as concussion, is a serious public health challenge. Although most patients recover, a substantial minority suffers chronic disability. The mechanisms underlying mTBI-related detrimental effects remain poorly understood. Although animal models contribute valuable preclinical information and improve our understanding of the underlying mechanisms following mTBI, only few studies have used diffusion tensor imaging (DTI) to study the evolution of axonal injury following mTBI in rodents. It is known that DTI shows changes after human concussion and the role of delineating imaging findings in animals is therefore to facilitate understanding of related mechanisms. In this work, we used a rodent model of mTBI to investigate longitudinal indices of axonal injury. We present the results of 45 animals that received magnetic resonance imaging (MRI) at multiple time points over a 2-week period following concussive or sham injury yielding 109 serial observations. Overall, the evolution of DTI metrics following concussive or sham injury differed by group. Diffusion tensor imaging changes within the white matter were most noticeable 1 week following injury and returned to baseline values after 2 weeks. More specifically, we observed increased fractional anisotropy in combination with decreased radial diffusivity and mean diffusivity, in the absence of changes in axial diffusivity, within the white matter of the genu corpus callosum at 1 week post-injury. Our study shows that DTI can detect microstructural white matter changes in the absence of gross abnormalities as indicated by visual screening of anatomical MRI and hematoxylin and eosin (H&E)-stained sections in a clinically relevant animal model of mTBI. Whereas additional histopathologic characterization is required to better understand the neurobiological correlates of DTI measures, our findings highlight the evolving nature of the brain's response to injury following concussion.

Limbic system white matter microstructure and long-term treatment outcome in major depressive disorder: a diffusion tensor imaging study using legacy data.

OBJECTIVES: Treatment-resistant depression is a common clinical occurrence among patients with major depressive disorder (MDD), but its neurobiology is poorly understood. We used data collected as part of routine clinical care to study white matter integrity of the brain's limbic system and its association to treatment response. METHODS: Electronic medical records of multiple large New England hospitals were screened for patients with an MDD billing diagnosis, and natural language processing was subsequently applied to find those with concurrent diffusion-weighted images, but without any diagnosed brain pathology. Treatment outcome was determined by review of clinical charts. MDD patients (n = 29 non-remitters, n = 26 partial-remitters, and n = 37 full-remitters), and healthy control subjects (n = 58) were analyzed for fractional anisotropy (FA) of the fornix and cingulum bundle. RESULTS: Failure to achieve remission was associated with lower FA among MDD patients, statistically significant for the medial body of the fornix. Moreover, global and regional-selective age-related FA decline was most pronounced in patients with treatment-refractory, non-remitted depression. CONCLUSIONS: These findings suggest that specific brain microstructural white matter abnormalities underlie persistent, treatment-resistant depression. They also demonstrate the feasibility of investigating white matter integrity in psychiatric populations using legacy data.

Task-induced brain activity patterns in type 2 diabetes: a potential biomarker for cognitive decline.

Patients with type 2 diabetes demonstrate reduced functional connectivity within the resting state default mode network (DMN), which may signal heightened risk for cognitive decline. In other populations at risk for cognitive decline, additional magnetic resonance imaging abnormalities are evident during task performance, including impaired deactivation of the DMN and reduced activation of task-relevant regions. We investigated whether middle-aged type 2 diabetic patients show these brain activity patterns during encoding and recognition tasks. Compared with control participants, we observed both reduced 1) activation of the dorsolateral prefrontal cortex during encoding and 2) deactivation of the DMN during recognition in type 2 diabetic patients, despite normal cognition. During recognition, activation in several task-relevant regions, including the dorsolateral prefrontal cortex and DMN regions, was positively correlated with HbA1c and insulin resistance, suggesting that these important markers of glucose metabolism impact the brain's response to a cognitive challenge. Plasma glucose ≥11 mmol/L was associated with impaired deactivation of the DMN, suggesting that acute hyperglycemia contributes to brain abnormalities. Since elderly type 2 diabetic patients often demonstrate cognitive impairments, it is possible that these task-induced brain activity patterns observed in middle age may signal impending cognitive decline.

Cerebral white matter integrity and resting-state functional connectivity in middle-aged patients with type 2 diabetes.

Early detection of brain abnormalities at the preclinical stage can be useful for developing preventive interventions to abate cognitive decline. We examined whether middle-aged type 2 diabetic patients show reduced white matter integrity in fiber tracts important for cognition and whether this abnormality is related to preestablished altered resting-state functional connectivity in the default mode network (DMN). Diabetic and nondiabetic participants underwent diffusion tensor imaging, functional magnetic resonance imaging, and cognitive assessment. Multiple diffusion measures were calculated using streamline tractography, and correlations with DMN functional connectivity were determined. Diabetic patients showed lower fractional anisotropy (FA) (a measure of white matter integrity) in the cingulum bundle and uncinate fasciculus. Control subjects showed stronger functional connectivity than patients between the posterior cingulate and both left fusiform and medial frontal gyri. FA of the cingulum bundle was correlated with functional connectivity between the posterior cingulate and medial frontal gyrus for combined groups. Thus, middle-aged patients with type 2 diabetes show white matter abnormalities that correlate with disrupted functional connectivity in the DMN, suggesting that common mechanisms may underlie structural and functional connectivity. Detecting brain abnormalities in middle age enables implementation of therapies to slow progression of neuropathology.

Feasibility of studying brain morphology in major depressive disorder with structural magnetic resonance imaging and clinical data from the electronic medical record: a pilot study.

For certain research questions related to long-term outcomes or to rare disorders, designing prospective studies is impractical or prohibitively expensive. Such studies could instead utilize clinical and magnetic resonance imaging data (MRI) collected as part of routine clinical care, stored in the electronic medical record (EMR). Using major depressive disorder (MDD) as a disease model, we examined the feasibility of studying brain morphology and associations with remission using clinical and MRI data exclusively drawn from the EMR. Advanced automated tools were used to select MDD patients and controls from the EMR who had brain MRI data, but no diagnosed brain pathology. MDD patients were further assessed for remission status by review of clinical charts. Twenty MDD patients (eight full-remitters, six partial-remitters, and six non-remitters), and 15 healthy control subjects met all study criteria for advanced morphometric analyses. Compared to controls, MDD patients had significantly smaller right rostral-anterior cingulate volume, and level of non-remission was associated with smaller left hippocampus and left rostral-middle frontal gyrus volume. The use of EMR data for psychiatric research may provide a timely and cost-effective approach with the potential to generate large study samples reflective of the real population with the illness studied.

Resting-state brain functional connectivity is altered in type 2 diabetes.

Type 2 diabetes mellitus (T2DM) is a risk factor for Alzheimer disease (AD). Populations at risk for AD show altered brain activity in the default mode network (DMN) before cognitive dysfunction. We evaluated this brain pattern in T2DM patients. We compared T2DM patients (n = 10, age = 56 ± 2.2 years, fasting plasma glucose [FPG] = 8.4 ± 1.3 mmol/L, HbA(1c) = 7.5 ± 0.54%) with nondiabetic age-matched control subjects (n = 11, age = 54 ± 1.8 years, FPG = 4.8 ± 0.2 mmol/L) using resting-state functional magnetic resonance imaging to evaluate functional connectivity strength among DMN regions. We also evaluated hippocampal volume, cognition, and insulin sensitivity by homeostasis model assessment of insulin resistance (HOMA-IR). Control subjects showed stronger correlations versus T2DM patients in the DMN between the seed (posterior cingulate) and bilateral middle temporal gyrus (ß = 0.67 vs. 0.43), the right inferior and left medial frontal gyri (ß = 0.75 vs. 0.54), and the left thalamus (ß = 0.59 vs. 0.37), respectively, with no group differences in cognition or hippocampal size. In T2DM patients, HOMA-IR was inversely correlated with functional connectivity in the right inferior frontal gyrus and precuneus. T2DM patients showed reduced functional connectivity in the DMN compared with control subjects, which was associated with insulin resistance in selected brain regions, but there were no group effects of brain structure or cognition.