Complement factor B is critical for sub-RPE deposit accumulation in a model of Doyne honeycomb retinal dystrophy with features of age-related macular degeneration.

EFEMP1 R345W is a dominant mutation causing Doyne honeycomb retinal dystrophy/malattia leventinese (DHRD/ML), a rare blinding disease with clinical pathology similar to age-related macular degeneration (AMD). Aged Efemp1  R345W/R345W knock-in mice (Efemp1ki/ki) develop microscopic deposits on the basal side of retinal pigment epithelial cells (RPE), an early feature in DHRD/ML and AMD. Here, we assessed the role of alternative complement pathway component factor B (FB) in the formation of these deposits. RNA-seq analysis of the posterior eyecups revealed increased unfolded protein response, decreased mitochondrial function in the neural retina (by 3 months of age) and increased inflammatory pathways in both neural retina and posterior eyecups (at 17 months of age) of Efemp1ki/ki mice compared with wild-type littermate controls. Proteomics analysis of eye lysates confirmed similar dysregulated pathways as detected by RNA-seq. Complement activation was increased in aged Efemp1ki/ki eyes with an approximately 2-fold elevation of complement breakdown products iC3b and Ba (P < 0.05). Deletion of the Cfb gene in female Efemp1ki/ki mice partially normalized the above dysregulated biological pathway changes and oral dosing of a small molecule FB inhibitor from 10 to 12 months of age reduced sub-RPE deposits by 65% (P = 0.029). In contrast, male Efemp1ki/ki mice had fewer sub-RPE deposits than age-matched females, no elevation of ocular complement activation and no effect of FB inhibition on sub-RPE deposits. The effects of FB deletion or inhibition on Efemp1ki/ki mice supports systemic inhibition of the alternative complement pathway as a potential treatment of dry AMD and DHRD/ML.

User-Centered Design of a Machine Learning Dashboard for Prediction of Postoperative Complications.

BACKGROUND: Machine learning models can help anesthesiology clinicians assess patients and make clinical and operational decisions, but well-designed human-computer interfaces are necessary for machine learning model predictions to result in clinician actions that help patients. Therefore, the goal of this study was to apply a user-centered design framework to create a user interface for displaying machine learning model predictions of postoperative complications to anesthesiology clinicians. METHODS: Twenty-five anesthesiology clinicians (attending anesthesiologists, resident physicians, and certified registered nurse anesthetists) participated in a 3-phase study that included (phase 1) semistructured focus group interviews and a card sorting activity to characterize user workflows and needs; (phase 2) simulated patient evaluation incorporating a low-fidelity static prototype display interface followed by a semistructured interview; and (phase 3) simulated patient evaluation with concurrent think-aloud incorporating a high-fidelity prototype display interface in the electronic health record. In each phase, data analysis included open coding of session transcripts and thematic analysis. RESULTS: During the needs assessment phase (phase 1), participants voiced that (a) identifying preventable risk related to modifiable risk factors is more important than nonpreventable risk, (b) comprehensive patient evaluation follows a systematic approach that relies heavily on the electronic health record, and (c) an easy-to-use display interface should have a simple layout that uses color and graphs to minimize time and energy spent reading it. When performing simulations using the low-fidelity prototype (phase 2), participants reported that (a) the machine learning predictions helped them to evaluate patient risk, (b) additional information about how to act on the risk estimate would be useful, and (c) correctable problems related to textual content existed. When performing simulations using the high-fidelity prototype (phase 3), usability problems predominantly related to the presentation of information and functionality. Despite the usability problems, participants rated the system highly on the System Usability Scale (mean score, 82.5; standard deviation, 10.5). CONCLUSIONS: Incorporating user needs and preferences into the design of a machine learning dashboard results in a display interface that clinicians rate as highly usable. Because the system demonstrates usability, evaluation of the effects of implementation on both process and clinical outcomes is warranted.

Evaluation of adenosine A1 receptor agonists as neuroprotective countermeasures against Soman intoxication in rats.

Soman, an organophosphorus (OP) compound, disrupts nervous system function through inactivation of acetylcholinesterase (AChE), the enzyme that breaks down acetylcholine at synapses. Left untreated, a state of prolonged seizure activity (status epilepticus, SE) is induced, causing widespread neuronal damage and associated cognitive and behavioral impairments. Previous research demonstrated that therapeutic stimulation of A1 adenosine receptors (A1ARs) can prevent or terminate soman-induced seizure. This study examined the ability of three potent A1AR agonists to provide neuroprotection and, ultimately, prevent observable cognitive and behavioral deficits following exposure to soman. Sprague Dawley rats were challenged with a seizure-inducing dose of soman (1.2 x LD50) and treated 1 min later with one of the following A1AR agonists: (6)-Cyclopentyladenosine (CPA), 2-Chloro-N6-cyclopentyladenosine (CCPA) or N-bicyclo(2.2.1)hept-2-yl-5'-chloro-5'-deoxyadenosine (cdENBA). An active avoidance shuttle box task was used to evaluate locomotor responses to aversive stimuli at 3, 7 and 14 days post-exposure. Animals treated with CPA, CCPA or cdENBA demonstrated a higher number of avoidance responses and a faster reaction to the aversive stimulus than the soman/saline control group across all three sessions. Findings suggest that A1AR agonism is a promising neuroprotective countermeasure, capable of preventing the long-term deficits in learning and memory that are characteristic of soman intoxication.

Effect of electroencephalogram-guided anaesthesia administration on 1-yr mortality: follow-up of a randomised clinical trial.

BACKGROUND: Intraoperative EEG suppression duration has been associated with postoperative delirium and mortality. In a clinical trial testing anaesthesia titration to avoid EEG suppression, the intervention did not decrease the incidence of postoperative delirium, but was associated with reduced 30-day mortality. The present study evaluated whether the EEG-guided anaesthesia intervention was also associated with reduced 1-yr mortality. METHODS: This manuscript reports 1 yr follow-up of subjects from a single-centre RCT, including a post hoc secondary outcome (1-yr mortality) in addition to pre-specified secondary outcomes. The trial included subjects aged 60 yr or older undergoing surgery with general anaesthesia between January 2015 and May 2018. Patients were randomised to receive EEG-guided anaesthesia or usual care. The previously reported primary outcome was postoperative delirium. The outcome of the current study was all-cause 1-yr mortality. RESULTS: Of the 1232 subjects enrolled, 614 subjects were randomised to EEG-guided anaesthesia and 618 subjects to usual care. One-year mortality was 57/591 (9.6%) in the guided group and 62/601 (10.3%) in the usual-care group. No significant difference in mortality was observed (adjusted absolute risk difference, -0.7%; 99.5% confidence interval, -5.8% to 4.3%; P=0.68). CONCLUSIONS: An EEG-guided anaesthesia intervention aiming to decrease duration of EEG suppression during surgery did not significantly decrease 1-yr mortality. These findings, in the context of other studies, do not provide supportive evidence for EEG-guided anaesthesia to prevent intermediate term postoperative death. CLINICAL TRIAL REGISTRATION: NCT02241655.

Longitudinal changes in glucose metabolism in women with gestational diabetes, from late pregnancy to the postpartum period.

AIMS/HYPOTHESIS: This study aimed to determine, in women with gestational diabetes (GDM), the changes in insulin sensitivity (Matsuda Insulin Sensitivity Index; ISOGTT), insulin response and disposition index (DI) from late pregnancy (34-37 weeks gestation, T1), to early postpartum (1-5 days, T2) and late postpartum (6-12 weeks, T3). A secondary aim was to correlate the longitudinal changes in maternal lipids, adipokines, cytokines and weight in relation to the changes in ISOGTT, insulin response and DI. METHODS: ISOGTT, insulin response and DI were calculated at the three time points (T1, T2 and T3) using the results of a 75 g OGTT. Adipokines, cytokines and lipids were measured prior to each OGTT. Linear mixed-effects models were used to compare changes across each time point. Changes in ISOGTT, insulin response and DI were correlated with changes in maternal adipokines, cytokines and lipids at each time point. RESULTS: A total of 27 women completed all assessments. Compared with T1, ISOGTT was 11.20 (95% CI 8.09, 14.31) units higher at 1-5 days postpartum (p < 0.001) and was 5.49 (95% CI 2.38, 8.60) units higher at 6-12 weeks postpartum (p < 0.001). Compared with T1, insulin response values were 699.6 (95% CI 957.5, 441.6) units lower at T2 (p < 0.001) and were 356.3 (95% CI 614.3, 98.3) units lower at T3 (p = 0.004). Compared with T1, the DI was 6434.1 (95% CI 2486.2, 10,381.0) units higher at T2 (p = 0.001) and was 4262.0 (95% CI 314.6, 8209.3) units higher at T3 (p = 0.03). There was a decrease in mean cholesterol, triacylglycerol, LDL-cholesterol and VLDL-cholesterol from T1 to T2 (all p < 0.001), and an increase in mean C-reactive protein, IL-6 and IL-8 from T1 to T2 (all p < 0.001). Mean leptin decreased from T1 to T2 (p = 0.001). There was no significant change in mean adiponectin (p = 0.99) or TNF-α (p = 0.81) from T1 to T2. The mean maternal BMI decreased from T1 to T2 (p = 0.001) and T3 (p < 0.001). There were no significant correlations between any measure of change in ISOGTT, insulin response and DI and change in maternal cytokines, adipokines, lipids or weight from T1 to T2. CONCLUSIONS/INTERPRETATION: In women with GDM, delivery was associated with improvement in both insulin sensitivity and insulin production within the first few days. Improvement in insulin production persisted for 6-12 weeks, but insulin sensitivity deteriorated slightly. These changes in glucose metabolism were not associated to changes in lipids, leptin, inflammation markers or body weight. TRIAL REGISTRATION: ClinicalTrials.gov NCT02082301.

Preoperative Cognitive Abnormality, Intraoperative Electroencephalogram Suppression, and Postoperative Delirium: A Mediation Analysis.

BACKGROUND: Postoperative delirium is a common complication that hinders recovery after surgery. Intraoperative electroencephalogram suppression has been linked to postoperative delirium, but it is unknown if this relationship is causal or if electroencephalogram suppression is merely a marker of underlying cognitive abnormalities. The hypothesis of this study was that intraoperative electroencephalogram suppression mediates a nonzero portion of the effect between preoperative abnormal cognition and postoperative delirium. METHODS: This is a prespecified secondary analysis of the Electroencephalography Guidance of Anesthesia to Alleviate Geriatric Syndromes (ENGAGES) randomized trial, which enrolled patients age 60 yr or older undergoing surgery with general anesthesia at a single academic medical center between January 2015 and May 2018. Patients were randomized to electroencephalogram-guided anesthesia or usual care. Preoperative abnormal cognition was defined as a composite of previous delirium, Short Blessed Test cognitive score greater than 4 points, or Eight Item Interview to Differentiate Aging and Dementia score greater than 1 point. Duration of intraoperative electroencephalogram suppression was defined as number of minutes with suppression ratio greater than 1%. Postoperative delirium was detected via Confusion Assessment Method or chart review on postoperative days 1 to 5. RESULTS: Among 1,113 patients, 430 patients showed evidence of preoperative abnormal cognition. These patients had an increased incidence of postoperative delirium (151 of 430 [35%] vs.123 of 683 [18%], P < 0.001). Of this 17.2% total effect size (99.5% CI, 9.3 to 25.1%), an absolute 2.4% (99.5% CI, 0.6 to 4.8%) was an indirect effect mediated by electroencephalogram suppression, while an absolute 14.8% (99.5% CI, 7.2 to 22.5%) was a direct effect of preoperative abnormal cognition. Randomization to electroencephalogram-guided anesthesia did not change the mediated effect size (P = 0.078 for moderation). CONCLUSIONS: A small portion of the total effect of preoperative abnormal cognition on postoperative delirium was mediated by electroencephalogram suppression. Study precision was too low to determine if the intervention changed the mediated effect.

Should women with gestational diabetes be screened at delivery hospitalization for type 2 diabetes?

BACKGROUND: Less than one-half of women with gestational diabetes mellitus are screened for type 2 diabetes postpartum. Other approaches to postpartum screening need to be evaluated, including the role of screening during the delivery hospitalization. OBJECTIVE: To assess the performance of an oral glucose tolerance test administered during the delivery hospitalization compared with the oral glucose tolerance test administered at a 4- to 12-week postpartum visit. STUDY DESIGN: We conducted a combined analysis of patient-level data from 4 centers (6 clinical sites) assessing the utility of an immediate postpartum 75-g oral glucose tolerance test during the delivery hospitalization (PP1) for the diagnosis of type 2 diabetes compared with a routine 4- to 12-week postpartum oral glucose tolerance test (PP2). Eligible women underwent a 75-g oral glucose tolerance test at both PP1 and PP2. Sensitivity, specificity, and negative and positive predictive values of the PP1 test were estimated for diagnosis of type 2 diabetes, impaired fasting glucose, or impaired glucose tolerance. RESULTS: In total, 319 women completed a PP1 screening, with 152 (47.6%) lost to follow-up for the PP2 oral glucose tolerance test. None of the women with a normal PP1 oral glucose tolerance test (n=73) later tested as having type 2 diabetes at PP2. Overall, 12.6% of subjects (n=21) had a change from normal to impaired fasting glucose/impaired glucose tolerance or a change from impaired fasting glucose/impaired glucose tolerance to type 2 diabetes. The PP1 oral glucose tolerance test had 50% sensitivity (11.8-88.2), 95.7% specificity (91.3-98.2%) with a 98.1% (94.5-99.6%) negative predictive value and a 30% (95% confidence interval, 6.7-65.3) positive predictive value for type 2 diabetes vs normal/impaired fasting glucose/impaired glucose tolerance result. The negative predictive value of having type 2 diabetes at PP2 compared with a normal oral glucose tolerance test (excluding impaired fasting glucose/impaired glucose tolerance) at PP1 was 100% (95% confidence interval, 93.5-100) with a specificity of 96.5% (95% confidence interval, 87.9-99.6). CONCLUSION: A normal oral glucose tolerance test during the delivery hospitalization appears to exclude postpartum type 2 diabetes mellitus. However, the results of the immediate postpartum oral glucose tolerance test were mixed when including impaired fasting glucose or impaired glucose tolerance. As a majority of women do not return for postpartum diabetic screening, an oral glucose tolerance test during the delivery hospitalization may be of use in certain circumstances in which postpartum follow-up is challenging and resources could be focused on women with an abnormal screening immediately after the delivery hospitalization.

Variation in C-reactive protein at 1 month post-partum by etiology of preterm birth: selective identification of those at risk for both poor pregnancy outcome and future health complications.

Objective To assess post-partum inflammation for patients delivering prior to 34 6/7 weeks by birth etiology. Methods This was an observational study of early preterm birth (PTB) occurring between 20 0/7 and 34 6/7 weeks of gestation. Serum C-reactive protein (CRP) levels were measured 1 month post-partum. CRP measurements were compared by birth etiology. Results A total of 399 women were analyzed. Distribution of birth etiology was 35% (n = 138) preterm labor (PTL), 28% (n = 115) preterm premature rupture of membranes (pPROM), and 37% (n = 141) indicated preterm birth (IPTB). Serum CRP varied by birth etiology (P = 0.036). Women with pPROM had elevated median CRP levels compared to women with PTL (P = 0.037). IPTB demonstrated elevated CRP levels when compared to PTL (P = 0.019). Pre-eclamptic/eclamptic subjects exhibited increased median CRP levels compared to PTL (P = 0.04). Conclusion Post-partum inflammation varies by birth etiology. Such variation may serve as identification of subjects whose future pregnancies and, ultimately, overall health status may benefit from inter-pregnancy interventions aimed at reducing inflammatory-associated risk factors.

Effect of Electroencephalography-Guided Anesthetic Administration on Postoperative Delirium Among Older Adults Undergoing Major Surgery: The ENGAGES Randomized Clinical Trial.

Importance: Intraoperative electroencephalogram (EEG) waveform suppression, often suggesting excessive general anesthesia, has been associated with postoperative delirium. Objective: To assess whether EEG-guided anesthetic administration decreases the incidence of postoperative delirium. Design, Setting, and Participants: Randomized clinical trial of 1232 adults aged 60 years and older undergoing major surgery and receiving general anesthesia at Barnes-Jewish Hospital in St Louis. Recruitment was from January 2015 to May 2018, with follow-up until July 2018. Interventions: Patients were randomized 1:1 (stratified by cardiac vs noncardiac surgery and positive vs negative recent fall history) to receive EEG-guided anesthetic administration (n = 614) or usual anesthetic care (n = 618). Main Outcomes and Measures: The primary outcome was incident delirium during postoperative days 1 through 5. Intraoperative measures included anesthetic concentration, EEG suppression, and hypotension. Adverse events included undesirable intraoperative movement, intraoperative awareness with recall, postoperative nausea and vomiting, medical complications, and death. Results: Of the 1232 randomized patients (median age, 69 years [range, 60 to 95]; 563 women [45.7%]), 1213 (98.5%) were assessed for the primary outcome. Delirium during postoperative days 1 to 5 occurred in 157 of 604 patients (26.0%) in the guided group and 140 of 609 patients (23.0%) in the usual care group (difference, 3.0% [95% CI, -2.0% to 8.0%]; P = .22). Median end-tidal volatile anesthetic concentration was significantly lower in the guided group than the usual care group (0.69 vs 0.80 minimum alveolar concentration; difference, -0.11 [95% CI, -0.13 to -0.10), and median cumulative time with EEG suppression was significantly less (7 vs 13 minutes; difference, -6.0 [95% CI, -9.9 to -2.1]). There was no significant difference between groups in the median cumulative time with mean arterial pressure below 60 mm Hg (7 vs 7 minutes; difference, 0.0 [95% CI, -1.7 to 1.7]). Undesirable movement occurred in 137 patients (22.3%) in the guided and 95 (15.4%) in the usual care group. No patients reported intraoperative awareness. Postoperative nausea and vomiting was reported in 48 patients (7.8%) in the guided and 55 patients (8.9%) in the usual care group. Serious adverse events were reported in 124 patients (20.2%) in the guided and 130 (21.0%) in the usual care group. Within 30 days of surgery, 4 patients (0.65%) in the guided group and 19 (3.07%) in the usual care group died. Conclusions and Relevance: Among older adults undergoing major surgery, EEG-guided anesthetic administration, compared with usual care, did not decrease the incidence of postoperative delirium. This finding does not support the use of EEG-guided anesthetic administration for this indication. Trial Registration: ClinicalTrials.gov Identifier: NCT02241655.

Systemic Medication Associations with Presumed Advanced or Uncontrolled Primary Open-Angle Glaucoma.

PURPOSE: To identify associations between systemic medications and primary open-angle glaucoma (POAG) requiring a procedure using United States insurance claims data in a hypothesis-generating study. DESIGN: Database study. PARTICIPANTS: In total, 6130 POAG cases (defined as patients with POAG undergoing a glaucoma procedure) were matched to 30 650 controls (defined as patients undergoing cataract surgery but without a coded glaucoma diagnosis, procedure, or medication) by age, gender, and region of residence. METHODS: Participant prescription drug use was calculated for the 5-year period before the glaucoma procedure or cataract surgery. Separately for individual generic drugs and drug classes, logistic regression was used to assess the association with POAG status. This was done across all generic drugs and drug classes that were prescribed in at least 1% of cases and controls. Analyses were adjusted for age, sex, region of residence, employment status, insurance plan type, and the total number of drugs prescribed. MAIN OUTCOME MEASURES: Odds ratio (OR) and 95% confidence intervals (CIs) for the association between each drug or drug class and POAG. RESULTS: The median age of participants was 72 years, and 52% were women. We tested for associations of POAG with 423 drug classes and 1763 generic drugs, resulting in a total of 2186 statistical tests and a Bonferroni-adjusted significance threshold of P < 2.3 × 10-5. Selective serotonin reuptake inhibitors (SSRIs) were strongly associated with a reduced risk of POAG (OR, 0.70; 95% CI, 0.64-0.76; P = 1.0 × 10-15); the most significant drug in this class was citalopram (OR, 0.66; 95% CI, 0.57-0.77; P = 1.2 × 10-7). Calcium channel blockers were strongly associated with an increased risk of POAG (OR, 1.26; 95% CI, 1.18-1.35; P = 1.8 × 10-11); the most significant drug in this class was amlodipine (OR, 1.27; 95% CI, 1.18-1.37; P = 5.9 × 10-10). CONCLUSIONS: We present data documenting potential associations of SSRIs and calcium channel blockers with POAG requiring a procedure. Further research may be indicated to better evaluate any associates of serotonin metabolism or calcium channels in glaucoma, or establish whether the associations are due to variations in the patterns for prescribing these drugs.

Mild Complications or Unusual Persistence of Porcine Collagen and Hyaluronic Acid Gel Following Periocular Filler Injections.

The purpose of this study was to describe the histopathologic appearance of dermal eyelid fillers that were unexpectedly encountered in ophthalmic plastic surgery samples from patients with mild eyelid disfigurements, and to review eyelid cases with complications that had previously been described in the literature. A retrospective histopathologic study with Alcian blue, elastic, and Masson trichrome stains of 2 cases that were submitted to the Ocular Pathology Department was conducted, and a critical review of previously published cases of the histopathologic characteristics of dermal filler material in the periocular region was also conducted. Two periocular tissue samples were found to contain dermal filler material. In one case, porcine collagen appeared as amorphous or indistinctly microfibrillar aggregates that stained light blue with the Masson trichrome method. In the other case, hyaluronic acid gel appeared as vivid blue amorphous pools of material in extracellular locules after staining with the Alcian blue method. An inflammatory response was not observed in either case. Patients who undergo facial filler procedures may, at a later time, require a surgical excisional procedure from which a specimen is generated. Previously injected dermal filler that the patient neglected to mention may be present in the pathologic sample, potentially perplexing the unsuspecting pathologist. Both ophthalmic plastic surgeons and ocular pathologists should be aware of the histopathologic features of dermal fillers. It is helpful if a surgeon who submits a specimen to the pathology service makes note of any known prior use of facial filler material or is alert to its possible presence when unfamiliar foreign material is discovered in the dermis of the eyelids.

Multiple Eyelid Cysts (Apocrine and Eccrine Hidrocystomas, Trichilemmal Cyst, and Hybrid Cyst) in a Patient With a Prolactinoma.

A 53-year-old man presented with smooth-domed, variegated cysts (polycystic disease) of all 4 eyelids, worse on the left side. Some of the cysts were clear, while others were creamy-white colored. In addition, multiple, very fine vesicopapules were noted along the eyelid margins. Histopathologic examination revealed a trichilemmal cyst, several pure apocrine hidrocystomas displaying multiple chambers, a hybrid cyst, and many small eccrine cysts of the deep dermis. The apocrine lesions, including the small ones at the eyelid margins, predominated. Smooth muscle actin sometimes positively stained outer myoepithelial cells in some of the apocrine cysts, which helped to distinguish them from eccrine cysts. Most noteworthy was the fact that the patient had been diagnosed with a prolactinoma 20 years earlier. There is only 1 previous report of multiple apocrine cysts and an antecedent prolactinoma in the dermatologic literature. This syndrome should be separated from that of Schöpf-Schulz-Passarge, which manifests multiple small eyelid apocrine cysts and other ectodermal dysplasias without any association with neoplasia, and from that of focal dermal hypoplasia (Goltz-Gorlin) syndrome with apocrine cysts but again without neoplasia.

Specific correlation between the major chromosome 10q26 haplotype conferring risk for age-related macular degeneration and the expression of HTRA1.

PURPOSE: A region within chromosome 10q26 has a set of single nucleotide polymorphisms (SNPs) that define a haplotype that confers high risk for age-related macular degeneration (AMD). We used a bioinformatics approach to search for genes in this region that may be responsible for risk for AMD by assessing levels of gene expression in individuals carrying different haplotypes and by searching for open chromatin regions in the retinal pigment epithelium (RPE) that might include one or more of the SNPs. METHODS: We surveyed the PubMed and the 1000 Genomes databases to find all common (minor allele frequency > 0.01) SNPs in 10q26 strongly associated with AMD. We used the HaploReg and LDlink databases to find sets of SNPs with alleles in linkage disequilibrium and used the Genotype-Tissue Expression (GTEx) database to search for correlations between genotypes at individual SNPs and the relative level of expression of the genes. We also accessed Encyclopedia of DNA Elements (ENCODE) to find segments of open chromatin in the region with the AMD-associated SNPs. Predicted transcription factor binding motifs were identified using HOMER, PROMO, and RegulomeDB software programs. RESULTS: There are 34 polymorphisms within a 30-kb region that are in strong linkage disequilibrium (r2>0.8) with the reference SNP rs10490924 previously associated with risk for AMD. The expression of three genes in this region, PLEKHA1, ARMS2, and HTRA1 varies between people who have the low-AMD-risk haplotype compared with those with the high-AMD-risk haplotype. For PLEKHA1, 44 tissues have an expression pattern with the high-AMD-risk haplotype associated with low expression (rs10490924 effect size -0.43, p = 3.8 x 10-5 in ovary). With regard to ARMS2, the variation is most pronounced in testes: homozygotes with the high-AMD-risk haplotype express ARMS2 at lower levels than homozygotes with the low-AMD-risk haplotype; expression in heterozygotes falls in between (rs10490924 effect size -0.79, p = 7.5 x 10-24). For HTRA1, the expression pattern is the opposite; the high-AMD-risk haplotype has higher levels of expression in 27 tissues (rs10490924 effect size 0.40, p = 1.5 × 10-7 in testes). None of the other 22 genes within one megabase of rs10490924, or any gene in the entire genome, have mRNA expression levels that correlate with the high-AMD-risk haplotype. More than 100 other SNPs in the 10q26 region affect the expression of PLEKHA1 and ARMS2 but not that of HTRA1; none of these SNPs affects the risk for AMD according to published genome-wide association studies (GWASs). Two of the AMD-risk SNPs (rs36212732 and rs36212733) affect transcription factor binding sites in proximity to a DNase I hypersensitive region (i.e., a region of open chromatin) in RPE cells. CONCLUSIONS: SNPs in chromosome 10q26 that influence the expression of only PLEKHA1 or ARMS2 are not associated with risk for AMD, while most SNPs that influence the expression of HTRA1 are associated with risk for AMD. Two of the AMD-risk SNPs affect transcription factor binding sites that may control expression of one of the linked genes in the RPE. These findings suggest that the variation in the risk for AMD associated with chromosome 10q26 is likely due to variation in HTRA1 expression. Modulating HTRA1 activity might be a potential therapy for AMD.

A risk of waiting: the weekly incidence of hypertensive disorders and associated maternal and neonatal morbidity in low-risk term pregnancies.

BACKGROUND: Elective induction of labor (eIOL) prior to 39 weeks' gestation is discouraged because of presumed fetal benefits. However, few data exist on the maternal risks of expectant management. To date, no study has evaluated the maternal risk of developing a hypertensive disorder of pregnancy with expectant management of a low-risk gravid at term. OBJECTIVE: We sought to evaluate the development of hypertensive disorders in term low-risk expectantly managed patients. STUDY DESIGN: This is a retrospective cross-sectional study from 19 US hospitals, from 2002 to 2008 (Safe Labor Consortium) including all nonanomalous, cephalic, singleton pregnancies at 37-41 weeks. Women with a history of hypertension, diabetes mellitus, cardiovascular disease, or planned cesarean delivery or from centers with incomplete hypertensive data were excluded. Women with eIOL in each week were compared with women managed expectantly until the next week of gestation or beyond. The primary outcome was the frequency of hypertensive complications. RESULTS: Of 114,651 low-risk deliveries, 12,772 (11.1%) had eIOL. The cohort was 49.2% nulliparous, 51.1% white, and obese (mean body mass index 30.2 kg/m(2)). The risk of developing any hypertension in expectantly managed women was 4.1% after 37 weeks, 3.5% after 38 weeks, 3.2% after 39 weeks, and 2.6% after 40 weeks. Compared with eIOL, women with hypertensive disorders had significantly higher rates of cesarean delivery and maternal morbidities (intensive care unit admission or death, third- or fourth-degree lacerations, maternal infections, and bleeding complications) at each week of gestation and the composite neonatal morbidity at 38 and 39 weeks of gestation. CONCLUSION: For women at low risk expectantly managed at term, there is a risk of developing hypertensive complications for each additional week of pregnancy, with associated increases in maternal and neonatal morbidities.

Evaluation of acetylcholine, seizure activity and neuropathology following high-dose nerve agent exposure and delayed neuroprotective treatment drugs in freely moving rats.

Organophosphorus nerve agents such as soman (GD) inhibit acetylcholinesterase, producing an excess of acetylcholine (ACh), which results in respiratory distress, convulsions and status epilepticus that leads to neuropathology. Several drugs (topiramate, clobazam, pregnanolone, allopregnanolone, UBP 302, cyclopentyladenosine [CPA], ketamine, midazolam and scopolamine) have been identified as potential neuroprotectants that may terminate seizures and reduce brain damage. To systematically evaluate their efficacy, this study employed in vivo striatal microdialysis and liquid chromatography to respectively collect and analyze extracellular ACh in freely moving rats treated with these drugs 20 min after seizure onset induced by a high dose of GD. Along with microdialysis, EEG activity was recorded and neuropathology assessed at 24 h. GD induced a marked increase of ACh, which peaked at 30 min post-exposure to 800% of control levels and then steadily decreased toward baseline levels. Approximately 40 min after treatment, only midazolam (10 mg/kg) and CPA (60 mg/kg) caused a significant reduction of ACh levels, with CPA reducing ACh levels more rapidly than midazolam. Both drugs facilitated a return to baseline levels at least 55 min after treatment. At 24 h, only animals treated with CPA (67%), midazolam (18%) and scopolamine (27%) exhibited seizure termination. While all treatments except for topiramate reduced neuropathology, CPA, midazolam and scopolamine showed the greatest reduction in pathology. Our results suggest that delayed treatment with CPA, midazolam, or scopolamine is effective at reducing GD-induced seizure activity and neuropathology, with CPA and midazolam capable of facilitating a reduction in GD-induced ACh elevation.

A retrospective cohort study of factors relating to the longitudinal change in birth weight.

BACKGROUND: Recent reports have shown a decrease in birth weight, a change from prior steady increases. Therefore we sought to describe the demographic and anthropometric changes in singleton term fetal growth. METHODS: This was a retrospective cohort analysis of term singleton deliveries (37-42 weeks) from January 1, 1995 to January 1, 2010 at a single tertiary obstetric unit. We included all 43,217 neonates from term, singleton, non-anomalous pregnancies. Data were grouped into five 3-year intervals. Mean and median birth weight (BW), birth length (BL), and Ponderal Index (PI) were estimated by year, race and gestational age. Our primary outcome was change in BW over time. The secondary outcomes were changes in BL and PI over time. RESULTS: Mean and median BW decreased by 72 and 70 g respectively (p < 0.0001) over the 15 year period while BL also significantly decreased by 1.0 cm (P < 0.001). This contributed to an increase in the neonatal PI by 0.11 kg/m(3) (P < 0.001). Mean gestational age at delivery decreased while maternal BMI at delivery, hypertension, diabetes, and African American race increased. Adjusting for gestational age, race, infant sex, maternal BMI, smoking, diabetes, hypertension, and parity, year of birth contributed 0.1 % to the variance (-1.7 g/year; 26 g) of BW, 1.8% (-0.06 cm/year; 0.9 cm) of BL, and 0.7% (+0.008 kg/m(3)/year; 0.12 kg/m(3)) of PI. These findings were independent of the proportional change in race or gestational age. CONCLUSIONS: We observed a crude decrease in mean BW of 72 g and BL of 1 cm over 15 years. Furthermore, once controlling for gestational age, race, infant sex, maternal BMI, smoking, diabetes, hypertension, and parity, we identified that increasing year of birth was associated with a decrease in BW of 1.7 g/year. The significant increase in PI, despite the decrease in BW emphasizes the limitation of using birth weight alone to define changes in fetal growth.

Maternal and neonatal outcomes in electively induced low-risk term pregnancies.

OBJECTIVE: Elective induction of labor has been discouraged over concerns regarding increased complications. We evaluated the mode of delivery and maternal and neonatal morbidities in low-risk patients whose labor was electively induced or expectantly managed at term. STUDY DESIGN: This was a retrospective cross-sectional study from 12 US institutions (19 hospitals), 2002 through 2008 (Safe Labor Consortium). Healthy women with viable, vertex singleton pregnancies at 37-41 weeks of gestation were included. Women electively induced in each week were compared with women managed expectantly. The primary outcome was mode of delivery. RESULTS: Of 131,243 low-risk deliveries, 13,242 (10.1%) were electively induced. The risk of cesarean delivery was lower at each week of gestation with elective induction vs expectant management regardless of parity and modified Bishop score (for unfavorable nulliparous patients at: 37 weeks = 18.6% vs 34.2%, adjusted odds ratio, 0.40; [95% confidence interval, 0.18-0.88]; 38 weeks = 28.4% vs 35.4%, 0.65 [0.49-0.85]; 39 weeks = 23.6% vs 38.5%, 0.47 [0.38-0.57]; 40 weeks = 32.3% vs 42.3%, 0.70 [0.59-0.81]). Maternal infections were significantly lower with elective inductions. Major, minor, and respiratory neonatal morbidity composites were lower with elective inductions at ≥38 weeks (for nulliparous patients at: 38 weeks = adjusted odds ratio, 0.43; [95% confidence interval, 0.26-0.72]; 39 weeks = 0.75 [0.61-0.92]; 40 weeks = 0.65 [0.54-0.80]). CONCLUSION: Elective induction of labor at term is associated with decreased risks of cesarean delivery and other maternal and neonatal morbidities compared with expectant management regardless of parity or cervical status on admission.

Stimulation of central A1 adenosine receptors suppresses seizure and neuropathology in a soman nerve agent seizure rat model.

The current regimen for treating nerve agent poisoning does not sufficiently suppress the excitotoxic activity that causes severe brain damage, especially in cases where treatment is delayed and nerve agent-induced status epilepticus develops. New therapeutic targets are required to improve survivability and minimize neuropathology after irreversible acetylcholinesterase inactivation. Earlier studies have shown that systemic delivery of adenosine agonists decreases nerve agent lethality; however, the mechanism of protection remains to be understood. The primary aim of this study was to investigate the role of central adenosine receptor (AR) stimulation in neuroprotection by directly injecting (6)-cyclopentyladenosine (CPA), an adenosine agonist specific to the A1 receptor subtype (A1R), into the brain intracerebroventricularly (ICV) in a soman seizure rat model. In addition to general A1R stimulation, we hypothesized that bilateral micro-injection of CPA into the cholinergic basal forebrain (BF) could also suppress excitotoxic activity. The results from these studies demonstrated that centrally administered adenosine agonists are anti-seizure and neuroprotective. CPA-delivered ICV prevented seizure and convulsion in 100% of the animals. Moreover, neuropathological evaluation indicated that adenosine treatments reduced brain damage from severe to minimal. Inhibition of the BF via CPA had varied results. Some animals were protected by treatment; however, others displayed similar pathology to the control. Overall, these data suggest that stimulating central ARs could be an effective target for the next generation countermeasures for nerve agent intoxication.