The IMPDH cytoophidium couples metabolism and fetal development in mice.

The cytoophidium is an evolutionarily conserved subcellular structure formed by filamentous polymers of metabolic enzymes. In vertebrates, inosine monophosphate dehydrogenase (IMPDH), which catalyses the rate-limiting step in guanosine triphosphate (GTP) biosynthesis, is one of the best-known cytoophidium-forming enzymes. Formation of the cytoophidium has been proposed to alleviate the inhibition of IMPDH, thereby facilitating GTP production to support the rapid proliferation of certain cell types such as lymphocytes, cancer cells and pluripotent stem cells (PSCs). However, past studies lacked appropriate models to elucidate the significance of IMPDH cytoophidium under normal physiological conditions. In this study, we demonstrate that the presence of IMPDH cytoophidium in mouse PSCs correlates with their metabolic status rather than pluripotency. By introducing IMPDH2 Y12C point mutation through genome editing, we established mouse embryonic stem cell (ESC) lines incapable of forming IMPDH polymers and the cytoophidium. Our data indicate an important role of IMPDH cytoophidium in sustaining a positive feedback loop that couples nucleotide biosynthesis with upstream metabolic pathways. Additionally, we find that IMPDH2 Y12C mutation leads to decreased cell proliferation and increased DNA damage in teratomas, as well as impaired embryo development following blastocoel injection. Further analysis shows that IMPDH cytoophidium assembly in mouse embryonic development begins after implantation and gradually increases throughout fetal development. These findings provide insights into the regulation of IMPDH polymerisation in embryogenesis and its significance in coordinating cell metabolism and development.

Allopregnanolone: Regenerative therapeutic to restore neurological health.

Chronic stress has been proposed as a driver of altered brain structure and function, including the pathogenesis of neurodegenerative diseases and a driver of disease progression. A key outcome of stress in the brain is structural remodeling of neural architecture, which may be a sign of successful adaptation, whereas persistence of these changes when stress ends indicate failed resilience. Neuroendocrine homeostasis and stress response are mainly dependent upon the functioning of the hypothalamic-pituitary-adrenal axis. Neurosteroids will fluctuate depending on whether the stress is acute or chronic. Advancements in neurosteroid research have led to the identification of multiple targets for drug development, but the most promising innovative target may be neurogenesis, given its potential impact in neurodegenerative disorders like Alzheimer's disease. Allopregnanolone is an endogenous pregnane neurosteroid and a reduced metabolite of progesterone, which acts as a potent allosteric modulator and direct activator of the GABA-chloride channel complex. Perhaps the most intriguing finding related to the potential therapeutic effects of allopregnanolone is its potential to promote neuroregeneration.

Effects of docosahexaenoic acid and eicosapentaoic acid supplementation on white matter integrity after repetitive sub-concussive head impacts during American football: Exploratory neuroimaging findings from a pilot RCT.

Context: Repetitive sub-concussive head impacts (RSHIs) are common in American football and result in changes to the microstructural integrity of white matter. Both docosahexaenoic acid (DHA) and eicosapentaoic acid (EPA) supplementation exerted neuroprotective effects against RSHIs in animal models and in a prior study in football players supplemented with DHA alone. Objective: Here, we present exploratory neuroimaging outcomes from a randomized controlled trial of DHA + EPA supplementation in American football players. We hypothesized that supplementation would result in less white matter integrity loss on diffusion weighted imaging over the season. Design setting participants: We conducted a double-blind placebo-controlled trial in 38 American football players between June 2019 and January 2020. Intervention: Participants were randomized to the treatment (2.442 g/day DHA and 1.020 g/day EPA) or placebo group for five times-per-week supplementation for 7 months. Of these, 27 participants were included in the neuroimaging data analysis (n = 16 placebo; n = 11 DHA + EPA). Exploratory outcome measures: Changes in white matter integrity were quantified using both voxelwise diffusion kurtosis scalars and deterministic tractography at baseline and end of season. Additional neuroimaging outcomes included changes in regional gray matter volume as well as intra-regional, edge-wise, and network level functional connectivity. Serum neurofilament light (NfL) provided a peripheral biomarker of axonal damage. Results: No voxel-wise between-group differences were identified on diffusion tensor metrics. Deterministic tractography using quantitative anisotropy (QA) revealed increased structural connectivity in ascending corticostriatal fibers and decreased connectivity in long association and commissural fibers in the DHA+EPA group compared to the placebo group. Serum NfL increases were correlated with increased mean (ρ = 0.47), axial (ρ = 0.44), and radial (ρ = 0.51) diffusivity and decreased QA (ρ = -0.52) in the corpus callosum and bilateral corona radiata irrespective of treatment group. DHA + EPA supplementation did preserve default mode/frontoparietal control network connectivity (g = 0.96, p = 0.024). Conclusions: These exploratory findings did not provide strong evidence that DHA + EPA prevented or protected against axonal damage as quantified via neuroimaging. Neuroprotective effects on functional connectivity were observed despite white matter damage. Further studies with larger samples are needed to fully establish the relationship between omega-3 supplementation, RSHIs, and neuroimaging biomarkers. Trial registration: ClinicalTrials.gov-NCT04796207.

Effects of Fish Oil on Biomarkers of Axonal Injury and Inflammation in American Football Players: A Placebo-Controlled Randomized Controlled Trial.

There are limited studies on neuroprotection from repeated subconcussive head impacts (RSHI) following docosahexaenoic acid (DHA) + eicosapentaenoic acid (EPA) supplementation in contact sports athletes. We performed a randomized, placebo-controlled, double-blinded, parallel-group design trial to determine the impact of 26 weeks of DHA+EPA supplementation (n = 12) vs. placebo (high-oleic safflower oil) (n = 17) on serum concentrations of neurofilament light (NfL), a biomarker of axonal injury, and inflammatory cytokines (interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-a)) in National Collegiate Athletic Association Division I American football athletes. DHA+EPA supplementation increased (p < 0.01) plasma DHA and EPA concentrations throughout the treatment period. NfL concentrations increased from baseline to week 26 in both groups (treatment (<0.001); placebo (p < 0.05)), with starting players (vs. non-starters) showing significant higher circulating concentrations at week 26 (p < 0.01). Fish oil (DHA+EPA) supplementation did not mitigate the adverse effects of RSHI, as measured by NfL levels; however, participants with the highest plasma DHA+EPA concentrations tended to have lower NfL levels. DHA+EPA supplementation had no effects on inflammatory cytokine levels at any of the timepoints tested. These findings emphasize the need for effective strategies to protect American football participants from the effects of RSHI.

Exploratory imaging outcomes of a phase 1b/2a clinical trial of allopregnanolone as a regenerative therapeutic for Alzheimer's disease: Structural effects and functional connectivity outcomes.

Introduction: Allopregnanolone (ALLO), an endogenous neurosteroid, promoted neurogenesis and oligogenesis and restored cognitive function in animal models of Alzheimer's disease (AD). Based on these discovery research findings, we conducted a randomized-controlled phase 1b/2a multiple ascending dose trial of ALLO in persons with early AD (NCT02221622) to assess safety, tolerability, and pharmacokinetics. Exploratory imaging outcomes to determine whether ALLO impacted hippocampal structure, white matter integrity, and functional connectivity are reported. Methods: Twenty-four individuals participated in the trial (n = 6 placebo; n = 18 ALLO) and underwent brain magnetic resonance imaging (MRI) before and after 12 weeks of treatment. Hippocampal atrophy rate was determined from volumetric MRI, computed as rate of change, and qualitatively assessed between ALLO and placebo sex, apolipoprotein E (APOE) ε4 allele, and ALLO dose subgroups. White matter microstructural integrity was compared between placebo and ALLO using fractional and quantitative anisotropy (QA). Changes in local, inter-regional, and network-level functional connectivity were also compared between groups using resting-state functional MRI. Results: Rate of decline in hippocampal volume was slowed, and in some cases reversed, in the ALLO group compared to placebo. Gain of hippocampal volume was evident in APOE ε4 carriers (range: 0.6% to 7.8% increased hippocampal volume). Multiple measures of white matter integrity indicated evidence of preserved or improved integrity. ALLO significantly increased fractional anisotropy (FA) in 690 of 690 and QA in 1416 of 1888 fiber tracts, located primarily in the corpus callosum, bilateral thalamic radiations, and bilateral corticospinal tracts. Consistent with structural changes, ALLO strengthened local, inter-regional, and network level functional connectivity in AD-vulnerable regions, including the precuneus and posterior cingulate, and network connections between the default mode network and limbic system. Discussion: Indicators of regeneration from previous preclinical studies and these exploratory MRI-based outcomes from this phase 1b/2a clinical cohort support advancement to a phase 2 proof-of-concept efficacy clinical trial of ALLO as a regenerative therapeutic for mild AD (REGEN-BRAIN study; NCT04838301).

Serum Myostatin and Follistatin Levels in Patients With Dermatomyositis and Polymyositis.

BACKGROUND: Myostatin is a protein in the TGF-ß family that negatively regulates muscle mass, and follistatin is a myostatin antagonist. OBJECTIVE: The aim of this study was to measure serum levels of myostatin and follistatin in idiopathic inflammatory myopathy patients and correlate these levels with muscle strength, fatigue, functional capacity, damage, and serum levels of muscle enzymes. METHODS: This was a multicenter cross-sectional study including 50 patients (34 dermatomyositis and 16 polymyositis [PM]) and 52 healthy individuals (control group [CG]). The disease status was evaluated according to the International Myositis Assessment & Clinical Studies. Fatigue was rated according to the Fatigue Severity Scale, and body composition was measured using dual-energy x-ray emission densitometry. Myostatin and follistatin were measured using enzyme-linked immunosorbent assays. RESULTS: Mean age was 50.9 ± 14.0 years, and mean disease duration was 89.2 ± 80.9 months. There were no differences in levels of myostatin (14.15 ± 9.65 vs. 10.97 ± 6.77 ng/mL; p = 0.131) or follistatin (0.53 ± 0.71 vs. 0.49 ± 0.60 ng/mL; p = 0.968) between patients and the CG. However, myostatin levels were higher in PM than CG (16.9 ± 12.1 vs. 11.0 ± 6.8 ng/mL; p = 0.036). There was no difference in serum myostatin among patients with and without low lean mass. Patients not treated with corticosteroids had higher serum levels of myostatin than the CG. There was a weak negative correlation between follistatin and Manual Muscle Testing and a Subset of Eight Muscles and a weak positive correlation between follistatin and Healthy Assessment Questionnaire. CONCLUSIONS: Serum levels of myostatin and follistatin did not differ between dermatomyositis and PM patients and control subjects. The assessment of serum levels of myostatin and follistatin in idiopathic inflammatory myopathy patients seems not to be helpful in clinical practice.

Nasal Administration of Anti-CD3 Monoclonal Antibody (Foralumab) Reduces Lung Inflammation and Blood Inflammatory Biomarkers in Mild to Moderate COVID-19 Patients: A Pilot Study.

BACKGROUND: Immune hyperactivity is an important contributing factor to the morbidity and mortality of COVID-19 infection. Nasal administration of anti-CD3 monoclonal antibody downregulates hyperactive immune responses in animal models of autoimmunity through its immunomodulatory properties. We performed a randomized pilot study of fully-human nasal anti-CD3 (Foralumab) in patients with mild to moderate COVID-19 to determine if its immunomodulatory properties had ameliorating effects on disease. METHODS: Thirty-nine outpatients with mild to moderate COVID-19 were recruited at Santa Casa de Misericordia de Santos in Sao Paulo State, Brazil. Patients were randomized to three cohorts: 1) Control, no Foralumab (n=16); 2) Nasal Foralumab (100ug/day) given for 10 consecutive days with 6 mg dexamethasone given on days 1-3 (n=11); and 3) Nasal Foralumab alone (100ug/day) given for 10 consecutive days (n=12). Patients continued standard of care medication. RESULTS: We observed reduction of serum IL-6 and C-reactive protein in Foralumab alone vs. untreated or Foralumab/Dexa treated patients. More rapid clearance of lung infiltrates as measured by chest CT was observed in Foralumab and Foralumab/Dexa treated subjects vs. those that did not receive Foralumab. Foralumab treatment was well-tolerated with no severe adverse events. CONCLUSIONS: This pilot study suggests that nasal Foralumab is well tolerated and may be of benefit in treatment of immune hyperactivity and lung involvement in COVID-19 disease and that further studies are warranted.

Corrigendum: Nasal Administration of Anti-CD3 Monoclonal Antibody (Foralumab) Reduces Lung Inflammation and Blood Inflammatory Biomarkers in Mild to Moderate COVID-19 Patients: A Pilot Study.

[This corrects the article DOI: 10.3389/fimmu.2021.709861.].

Comparing quality of reporting between preprints and peer-reviewed articles in the biomedical literature.

BACKGROUND: Preprint usage is growing rapidly in the life sciences; however, questions remain on the relative quality of preprints when compared to published articles. An objective dimension of quality that is readily measurable is completeness of reporting, as transparency can improve the reader's ability to independently interpret data and reproduce findings. METHODS: In this observational study, we initially compared independent samples of articles published in bioRxiv and in PubMed-indexed journals in 2016 using a quality of reporting questionnaire. After that, we performed paired comparisons between preprints from bioRxiv to their own peer-reviewed versions in journals. RESULTS: Peer-reviewed articles had, on average, higher quality of reporting than preprints, although the difference was small, with absolute differences of 5.0% [95% CI 1.4, 8.6] and 4.7% [95% CI 2.4, 7.0] of reported items in the independent samples and paired sample comparison, respectively. There were larger differences favoring peer-reviewed articles in subjective ratings of how clearly titles and abstracts presented the main findings and how easy it was to locate relevant reporting information. Changes in reporting from preprints to peer-reviewed versions did not correlate with the impact factor of the publication venue or with the time lag from bioRxiv to journal publication. CONCLUSIONS: Our results suggest that, on average, publication in a peer-reviewed journal is associated with improvement in quality of reporting. They also show that quality of reporting in preprints in the life sciences is within a similar range as that of peer-reviewed articles, albeit slightly lower on average, supporting the idea that preprints should be considered valid scientific contributions.

Safety, tolerability, and pharmacokinetics of allopregnanolone as a regenerative therapeutic for Alzheimer's disease: A single and multiple ascending dose phase 1b/2a clinical trial.

INTRODUCTION: Allopregnanolone is an endogenous neurosteroid with the potential to be a novel regenerative therapeutic for Alzheimer's disease (AD). Foundations of mechanistic understanding and well-established preclinical safety efficacy make it a viable candidate. METHODS: A randomized, double-blinded, placebo-controlled, single and multiple ascending dose trial was conducted. Intravenous allopregnanolone or placebo was administered once-per-week for 12 weeks with a 1-month follow-up. Participants with early AD (mild cognitive impairment due to AD or mild AD), a Mini-Mental State Examination score of 20-26 inclusive, and age ≥55 years were randomized (6:2 to three allopregnanolone dosing cohorts or one placebo cohort). Primary endpoint was safety and tolerability. Secondary endpoints included pharmacokinetic (PK) parameters and maximally tolerated dose (MTD). Exploratory endpoints included cognitive and imaging biomarkers. RESULTS: A total of 24 participants completed the trial. Allopregnanolone was safe and well tolerated in all study participants. No differences were observed between treatment arms in the occurrence and severity of adverse events (AE). Most common AE were mild to moderate in severity and included rash (n = 4 [22%]) and fatigue (n = 3 [17%]). A single non-serious AE, dizziness, was attributable to treatment. There was one serious AE not related to treatment. Pharmacokinetics indicated a predictable linear dose-response in plasma concentration of allopregnanolone after intravenous administration over 30 minutes. The maximum plasma concentrations for the 2 mg, 4 mg, 6 mg, and 10 mg dosages were 14.53 ng/mL (+/-7.31), 42.05 ng/mL (+/-14.55), 60.07 ng/mL (+/-12.8), and 137.48 ng/mL (+/-38.69), respectively. The MTD was established based on evidence of allopregnanolone-induced mild sedation at the highest doses; a sex difference in the threshold for sedation was observed (males 10 mg; females 14 mg). No adverse outcomes on cognition or magnetic resonance imaging-based imaging outcomes were evident. CONCLUSIONS: Allopregnanolone was well tolerated and safe across all doses in persons with early AD. Safety, MTD, and PK profiles support advancement of allopregnanolone as a regenerative therapeutic for AD to a phase 2 efficacy trial. TRIAL REGISTRATION: ClinicalTrials.gov-NCT02221622.

Auditory cognitive training improves prepulse inhibition in serine racemase mutant mice.

Evidence indicates that neuroplasticity-based cognitive training can improve cognition in patients with schizophrenia, but the individual response to training varies greatly between subjects. Hence, there is a need to understand the neurological underpinnings of cognitive training to reveal predictors of treatment response. D-serine is a crucial modulator of neuroplasticity, and decreased levels of D-serine may contribute to deficits in neuroplasticity in schizophrenia. Interestingly, we observed that training mice to identify auditory oddballs increased extracellular levels of D-serine in the hippocampus during training. Serine racemase (Srr) is the only source of brain D-serine; thus, it is possible that Srr may mediate the response to training. To test this hypothesis, we trained mice that have a mutated version of Srr (SrrY269*/SrrY269*) and reduced levels of D-serine in the same auditory training. SrrY269*/SrrY269* mice showed decreased performance during auditory training (defined as the capacity to discriminate an oddball during a sequence of tones). Importantly, auditory training improved prepulse inhibition (PPI) in SrrY269*/SrrY269* but not in wild-type mice. Finally, D-serine (100 mg/kg i.p.) given 30 min before training sessions to SrrY269*/SrrY269* mice improved training performance, but it did not enhance PPI. Taken together, our results show that D-serine is involved in the response to neuroplasticity-based auditory training and that PPI deficits can be improved by auditory oddball training even in the presence of neuroplasticity deficits.

IMP dehydrogenase rod/ring structures in acral melanomas.

Acral lentiginous melanoma (ALM) is a rare subtype of melanoma with aggressive behavior. IMPDH enzyme, involved in de novo GTP biosynthesis, has been reported to assemble into large filamentary structures called rods/rings (RR) or cytoophidium (cellular snakes). RR assembly induces a hyperactive state in IMPDH, usually to supply a high demand for GTP nucleotides, such as in highly proliferative cells. We investigate whether aggressive melanoma tumor cells present IMPDH-based RR structures. Forty-five ALM paraffin-embedded tissue samples and 59 melanocytic nevi were probed with anti-IMPDH2 antibody. Both the rod- and ring-shaped RR could be observed, with higher frequency in ALM. ROC curve analyzing the proportions of RR-positive cells in ALM versus nevi yielded a 0.88 AUC. Using the cutoff of 5.5% RR-positive cells, there was a sensitivity of 80% and specificity of 85% for ALM diagnosis. In ALM, 36 (80%) showed RR frequency above the cutoff, being classified as RR-positive, compared with only 9 (15%) of the nevi (p < .001). Histopathology showed that 71% of the RR-positive specimens presented Breslow thickness > 4.0mm, compared with only 29% in the RR-low/negative (p = .039). We propose that screening for RR structures in biopsy specimens may be a valuable tool helping differentiate ALM from nevi and accessing tumor malignancy.

Evidence of Hyperacusis in Adult Rats Following Non-traumatic Sound Exposure.

Manipulations that enhance neuroplasticity may inadvertently create opportunities for maladaptation. We have previously used passive exposures to non-traumatic white noise to open windows of plasticity in the adult rat auditory cortex and induce frequency-specific functional reorganizations of the tonotopic map. However, similar reorganizations in the central auditory pathway are thought to contribute to the generation of hearing disorders such as tinnitus and hyperacusis. Here, we investigate whether noise-induced reorganizations are accompanied by electrophysiological or behavioral evidence of tinnitus or hyperacusis in adult Long-Evans rats. We used a 2-week passive exposure to moderate-intensity (70 dB SPL) broadband white noise to reopen a critical period for spectral tuning such that a second 1-week exposure to 7 kHz tone pips produced an expansion of the 7 kHz frequency region in the primary auditory cortex (A1). We demonstrate for the first time that this expansion also takes place in the ventral auditory field (VAF). Sound exposure also led to spontaneous and sound-evoked hyperactivity in the anterior auditory field (AAF). Rats were assessed for behavioral evidence of tinnitus or hyperacusis using gap and tone prepulse inhibition of the acoustic startle response. We found that sound exposure did not affect gap-prepulse inhibition. However, sound exposure led to an improvement in prepulse inhibition when the prepulse was a 7 kHz tone, showing that exposed rats had enhanced sensorimotor gating for the exposure frequency. Together, our electrophysiological and behavioral results provide evidence of hyperacusis but not tinnitus in sound-exposed animals. Our findings demonstrate that periods of prolonged noise exposure may open windows of plasticity that can also be understood as windows of vulnerability, potentially increasing the likelihood for maladaptive plasticity to take place.

Dysregulation of auditory neuroplasticity in schizophrenia.

Schizophrenia is a complex brain syndrome characterized by an array of positive symptoms (delusions, hallucinations, disorganized speech), negative symptoms (alogia, apathy, avolition) and cognitive impairments (memory, executive functions). Although investigations of the cognitive deficits in schizophrenia have primarily concentrated on disturbances affecting higher-order cognitive processes, there is an increasing realization that schizophrenia also affects early sensory processing, which might, in fact, play a significant role in the development of higher-order cognitive impairments. Recent evidence suggests that many of these early sensory processing impairments possibly arise from a dysregulation of plasticity regulators in schizophrenia, resulting in either reduced plasticity or excessive unregulated plasticity. The purpose of the present manuscript is to provide a concise overview of how the dysregulation of cortical plasticity mechanisms contributes to schizophrenia symptoms with an emphasis on auditory dysplasticity and to discuss its relevance for treatment outcomes. The idea that plasticity mechanisms are not constrained only within sensitive periods suggests that many functional properties of sensory neurons can be altered throughout the lifetime.

Interfilament interaction between IMPDH and CTPS cytoophidia.

Inosine monophosphate dehydrogenase (IMPDH) and cytidine triphosphate synthase (CTPS) are two metabolic enzymes that perform rate-limiting steps in the de novo synthesis of purine and pyrimidine nucleotides, respectively. It has been shown that IMPDH and CTPS can comprise a filamentous macrostructure termed the cytoophidium, which may play a role in regulation of their catalytic activity. Although these two proteins may colocalise in the same cytoophidium, how they associate with one another is still elusive. As reported herein, we established a model HeLa cell line coexpressing OFP-tagged IMPDH2 and GFP-tagged CTPS1 and recorded the assembly, disassembly and movement of the cytoophidium in live cells. Moreover, by using super-resolution confocal imaging, we demonstrate how IMPDH- and CTPS-based filaments are aligned or intertwined in the mixed cytoophidium. Collectively, our findings provide a panorama of cytoophidium dynamics and suggest that IMPDH and CTPS cytoophidia may coordinate by interfilament interaction.

Potential and Challenges for the Clinical Use of d-Serine As a Cognitive Enhancer.

After 25 years of its discovery in the rat brain, d-serine is a recognized modulator of synaptic plasticity and cognitive processes through its actions on the NMDA-glutamate receptor. Importantly, cognitive impairment is a core feature of conditions, such as schizophrenia, Alzheimer's disease, depression, and aging, and is associated to disturbances in NMDA-glutamate receptors. The d-serine pathway has been associated with cognitive deficits and these conditions, and, for this reason, d-serine signaling is subject of intense research to probe its role in aiding diagnosis and therapy. Nevertheless, this has not resulted in new therapies being incorporated into clinical practice. Therefore, in this review we will address many questions that need to be solved by future studies, regarding d-serine pharmacokinetics, possible side effects, other strategies to modulate its levels, and combination with other therapies to increase its efficacy.

Anti-rods/rings: a human model of drug-induced autoantibody generation.

In recent years, autoantibodies targeting subcellular structures described as the rods and rings pattern in HEp-2 ANA have been presented as a unique case of autoantibody generation. These rod and ring structures (RR) are at least partially composed of inosine monophosphate dehydrogenase type 2 (IMPDH2), and their formation can be induced in vitro by several small-molecule inhibitors, including some IMPDH2 inhibitors. Autoantibodies targeting these relatively unknown structures have been almost exclusively observed in hepatitis C virus (HCV) patients who have undergone treatment with pegylated interferon-α/ribavirin (IFN/RBV) combination therapy. To date, anti-RR antibodies have not been found in treatment-naïve HCV patients or in patients from any other disease groups, with few reported exceptions. Here, we describe recent advances in characterizing the RR structure and the strong association between anti-RR antibody response and HCV patients treated with IFN/RBV, detailing why anti-RR can be considered a human model of drug-induced autoantibody generation.

Incidence of postoperative acute kidney injury in patients with chronic kidney disease undergoing minimally invasive valve surgery.

BACKGROUND: We hypothesize that minimally invasive valve surgery in patients with chronic kidney disease (CKD) is superior to a conventional median sternotomy. METHODS: We retrospectively analyzed 1945 consecutive patients who underwent isolated valve surgery. Included were patients with CKD stages 2 to 5. In-hospital mortality, composite complication rates, and intensive care unit and total hospital lengths of stay of those who underwent a minimally invasive approach were compared with those who underwent a standard median sternotomy. Resource use was approximated based on intensive care unit and total hospital lengths of stay. RESULTS: There were 688 patients identified; 510 (74%) underwent minimally invasive surgery, and 178 (26%) underwent a median sternotomy. There was no significant difference in mortality. Minimally invasive surgery was associated with fewer composite complications (33.1% vs 49.4%; odds ratio, 0.5; P ≤ .001), shorter intensive care unit (48 [interquartile range {IQR}, 33-74] hours vs 71 [IQR, 42-96] hours; P < .01), and hospital (8 [IQR, 6-9] days vs 10 [IQR, 8-15] days; P < .001) lengths of stay, and a lower incidence of acute kidney injury (8% vs 14.7%; odds ratio, 0.5; P = .01), compared with median sternotomy. In a multivariable analysis, minimally invasive surgery was associated with a 60% reduction in the risk of development of postoperative acute kidney injury. CONCLUSIONS: In patients with CKD undergoing isolated valve surgery, minimally invasive valve surgery is associated with reduced postoperative complications and lower resource use.

Late pregnancy complications can affect risk estimates of elective induction of labor.

OBJECTIVE: Multiple observational studies have emphasized the increased risk of elective induction versus spontaneous labor. We estimated the risks of elective induction before 39 weeks compared to expectant management. METHODS: Using a single institution's delivery data (1996-2004), we identified women with uncomplicated term gestations who underwent elective induction before 39 weeks (Early Induction Group). A comparison group of women eligible for elective induction before 39 weeks but who were managed expectantly was created by identifying the remaining deliveries ≥ 39 weeks and excluding women with "established" pregnancy complications such as diabetes or heart disease (Expectant Management Group), but retaining women with complications that may have developed while waiting, e.g. gestational hypertension or abruption. RESULTS: Pregnancies in the Early Induction Group were generally not at increased risk for morbidity when compared to the entire Expectant Management Group, in whom 49% developed pregnancy complications or went postdates. These pregnancies had poorer maternal and neonatal outcomes when compared to patients who remained uncomplicated with spontaneous labor onset, thus reducing the overall benefit of expectant management. CONCLUSIONS: Failure to account for the large proportion of women who develop late pregnancy complications can falsely elevate the estimated risk of elective induction prior to 39 weeks.