Small Molecule Antagonists of the DNA Repair ERCC1/XPA Protein-Protein Interaction.

The DNA excision repair protein ERCC1 and the DNA damage sensor protein, XPA are highly overexpressed in patient samples of cisplatin-resistant solid tumors including lung, bladder, ovarian, and testicular cancer. The repair of cisplatin-DNA crosslinks is dependent upon nucleotide excision repair (NER) that is modulated by protein-protein binding interactions of ERCC1, the endonuclease, XPF, and XPA. Thus, inhibition of their function is a potential therapeutic strategy for the selective sensitization of tumors to DNA-damaging platinum-based cancer therapy. Here, we report on new small-molecule antagonists of the ERCC1/XPA protein-protein interaction (PPI) discovered using a high-throughput competitive fluorescence polarization binding assay. We discovered a unique structural class of thiopyridine-3-carbonitrile PPI antagonists that block a truncated XPA polypeptide from binding to ERCC1. Preliminary hit-to-lead studies from compound 1 reveal structure-activity relationships (SAR) and identify lead compound 27 o with an EC50 of 4.7 µM. Furthermore, chemical shift perturbation mapping by NMR confirms that 1 binds within the same site as the truncated XPA67-80 peptide. These novel ERCC1 antagonists are useful chemical biology tools for investigating DNA damage repair pathways and provide a good starting point for medicinal chemistry optimization as therapeutics for sensitizing tumors to DNA damaging agents and overcoming resistance to platinum-based chemotherapy.

Robotic-assisted Laparoscopic Supracervical Repair of a Chronic Puerperal Uterine Inversion.

Surgical correction of a chronic puerperal uterine inversion traditionally requires an anterior or posterior cervical incision to relieve the constricting band. This case is only the second reported case of robotic-assisted correction of a chronic puerperal uterine inversion and the first to avoid a cervical incision. The patient was 5 months postpartum and desired future pregnancy. After a laparoscopic Huntington technique was unsuccessful, a vertical hysterotomy was created in the anterior lower uterine segment and extended toward the fundus until the inversion could be relieved. The incision was repaired in 3 layers and a round ligament plication was performed to provide additional support within the pelvis. The patient's symptoms gradually improved during her postoperative course, and ultrasound 2 weeks after the procedure revealed the uterus in anatomic position in the pelvis. With a paucity of reported cases of laparoscopic correction of chronic puerperal uterine inversion, the present case offers a novel surgical approach that maintains cervical integrity and thereby minimizes long-term effects of the procedure on future pregnancies.

Multimodal analgesia is superior to opiates alone after tibial fracture in patients with substance abuse history.

Objectives: To evaluate the effectiveness of multimodal analgesia in patients with a tibial shaft fracture. Design: Retrospective review. Setting: Large, urban, academic center. Patients: One hundred thirty-eight patients were evaluated before implementation of multimodal analgesia. Thirty-four patients were evaluated after implementation. All patients were treated operatively with internal fixation for their tibial shaft fracture. Patients with polytrauma were excluded. Intervention: Multimodal analgesia. Main Outcome Measures: Pain levels at rest and with movement were assessed. Morphine milligram equivalents (MMEs) dosed per patient were calculated each day. Length of stay was also documented. Results: After implementation of a multimodal analgesic program, there was a statistically significant decrease in pain score at rest (4.7-4.0, P = 0.034) and with movement (5.8-4.8, P = 0.007). MMEs dosed in the multimodal analgesic program correlated with pain score (R2 = 0.5), whereas before implementation of the program, MMEs dosed were not dependent on pain score (R2 = 0.007). Patients with a history of substance abuse had the most profound effect from this paradigm change. For those with a history of substance abuse, treatment of pain using a multimodal approach reduces MMEs dosed and length of stay (5.7-3.1 days, P = 0.016). Conclusions: Multimodal analgesia improves patient pain scores both at rest and during movement. In patients with a history of substance abuse, multimodal analgesia not only decreases pain but also decreases length of stay and MMEs dosed to levels consistent with someone who does not have a substance abuse history. Level of Evidence: Therapeutic Level III.

Robotic hysterectomy compared with laparoscopic hysterectomy: is it still more costly to perform?

To establish the economic value of simple robotic hysterectomy vs laparoscopic hysterectomy and assess the impact of surgeon's experience. Retrospective cohort study. University-affiliated US regional healthcare system. Reproductive and post-menopausal women undergoing hysterectomy for benign indications. Robotic or laparoscopic hysterectomy. Between January 2018 and December 2019, a total of 985 simple laparoscopic and robotic hysterectomies were performed by 47 different gynecologists. Overall, the mean payment, direct cost, and profit were comparable (p value > 0.05) among simple robotic and laparoscopic hysterectomy. However, the mean operative time was significantly shorter for robotic hysterectomy compared to laparoscopic hysterectomy (106 min vs 127 min, respectively, p < 0.05). Operative time decreased as a surgeon's annual robotic case volume increased. Per-minute profitability of robotic hysterectomy increased significantly when a surgeon performed greater than 45 cases annually (p = 0.04). This effect became most pronounced when a surgeon performed 60 or more cases per year (p = 0.01). Simple robotic hysterectomy has shorter operative time compared to laparoscopic hysterectomy, with direct costs being similar. Robotic hysterectomy has higher per-minute profit compared to laparoscopic hysterectomy when a surgeon performs > 45 cases per year.

Robotic-assisted laparoscopic Essure removal: a novel surgical approach.

Primary objective was to evaluate safety and feasibility of robotic-assisted Essure removal while describing the procedure. Secondary objective was to assess improvement of symptoms post-operatively. The design was retrospective cohort study. Patients included were those who underwent robotic-assisted Essure removal between June, 2015 and December, 2020 for symptomatic relief. Interventions are robotic-assisted laparoscopic removal of Essure devices. A retrospective chart review was conducted. Phone survey of pain scores and quality-of-life ratings were performed. Twenty-one women underwent robotic-assisted removal of Essure devices. Two cases were excluded from analysis due to concomitant procedures. All devices were removed intact (19/19). The mean time from placement to removal was 5.3 years. Safety and feasibility were demonstrated, mean operating time was 43.1 ± 12 min, mean length of stay (LOS) was 11 h, and no complications occurred. Mean pain scores (0-10) improved from 8.5 before surgery to 0.75 at 1 month after surgery (p < 0.005). Mean Quality-of-Life (QOL) scores (0-7) improved from 5.9 prior to surgery to 1.5 at 1 month after surgery (p < 0.005). To our knowledge, this is the first report of the use of robotic assistance for Essure removal. Robotic-assisted laparoscopic Essure removal appears safe, feasible, and potentially superior to other surgical approaches. Despite discontinuation of the device in 2018, Essure removal is likely to remain needed. Robotic-assisted laparoscopic Essure removal appears effective in treating pain and various other symptoms attributed to Essure devices.

Robotic-assisted laparoscopic tubal anastomosis: Single institution analysis.

BACKGROUND: Tubal anastomosis has similar pregnancy rates regardless of approach. Historically, robotic anastomosis has been associated with increased cost and operative time. We sought to perform a contemporary study of these metrics. METHODS: One hundred and nine patients were identified who underwent robotic-assisted laparoscopic tubal anastomosis. Retrospective analysis of medical records was performed. Phone survey was conducted. RESULTS: The mean operative time decreased from 140.7 ± 27.0 min in 2013 to 60.0 ± 9.1 min in 2018, with significant downward trend (p < 0.001). The mean cost was $7153.46 ± $1484.41. The pregnancy rate was 59% (35/59), and tubal patency rate was 81% (42/52). Seventy-two percent of patients under 37 years became pregnant. CONCLUSIONS: There is significant improvement in operative time of robotic-assisted tubal anastomosis with surgical experience. Robotic tubal anastomosis outperformed historical metrics of laparoscopy and laparotomy with regard to operative time and cost in this series.

Opioid Avoidance in Liver Transplant Recipients: Reduction in Postoperative Opioid Use Through a Multidisciplinary Multimodal Approach.

The prevalence of substance use disorder in the liver transplantation (LT) population makes postoperative pain management challenging. We report our initial experience with a novel, comprehensive, multidisciplinary opioid avoidance pathway in 13 LT recipients between January 2018 and September 2019. Patients received comprehensive pre-LT education on postoperative opioid avoidance by the surgeon, pharmacist, and psychologist at the time of listing. Immediately after LT, patients received a continuous incisional ropivacaine infusion, ketamine, acetaminophen, and gabapentin as standard nonopioid medications; rescue opioids were used as needed. We compared outcomes with a historical cohort of 27 LT recipients transplanted between August 2016 and January 2018 managed primarily with opioids. On average, opioid avoidance patients used 92% fewer median (interquartile range [IQR]) morphine milligram equivalents (MMEs) versus the historical cohort (7 [1-11] versus 87 [60-130] MME; P < 0.001) per postoperative day over a similar length of stay (8 [7-10] versus 6 [6-10] days; P = 0.14). Fewer outpatient MMEs were prescribed within the first 60 days after LT in the opioid avoidance group versus the historical cohort: 125 (25-150) versus 270 (0-463) MME (P = 0.05). This proof-of-concept study outlines the potential to profoundly reduce opioid utilization in the LT population using a comprehensive multidisciplinary approach.

Implementation of a Multimodal Pain Management Order Set Reduces Perioperative Opioid Use after Liver Transplantation.

STUDY OBJECTIVE: Nonopioid strategies to optimize pain management in patients after liver transplantation remain underexplored. The purpose of this study was to evaluate whether the use of a multimodal pain management (MPM) order set would reduce postoperative opioid use in adult patients after liver transplantation. DESIGN: Retrospective pre- and post-order set implementation study. SETTING: Large academic tertiary care hospital. PATIENTS: Thirty-one adults who underwent liver transplantation were included; of these, 18 received provider-managed pain regimens (pre-MPM group: August 20, 2016-January 17, 2018), and 13 received the MPM order set (post-MPM group: January 18-July 31, 2018) after implementation of the order set on January 18, 2018. MEASUREMENTS AND MAIN RESULTS: The MPM order set included standardized receipt of acetaminophen 650 mg every 6 hours, gabapentin 300 mg every 8 hours (adjusted for renal function), and opioids for breakthrough pain. Patients managed with the MPM order set received, on average, 30.6 fewer opioid morphine milligram equivalents per day after final extubation than patients who did not receive MPM (median 16, interquartile range [IQR] 4.5-45.6 vs median 46.6, IQR 30.1-75.2; Mann-Whitney U test, p=0.031). Although patients in the post-MPM group had significantly worse renal function at baseline, no other statistically significant differences in baseline characteristics, pain scores, or prescribed outpatient opioids were noted between groups. Patients in the pre-MPM group had a shorter intensive care unit and overall length of stay; however, patients in the post-MPM group may have had more complex postoperative courses contributing to these differences. CONCLUSION: Implementation of the MPM order set significantly reduced postoperative opioid use in liver transplant recipients. Our results provide a compelling rationale to further investigate the use of a non-opioid-centered strategy to optimize pain management in patients recovering from liver transplantation, a population vulnerable to the risks of opioid use such as opioid use disorder, increased susceptibility to adverse effects, and poor allograft and survival outcomes.

Incidence of Visible Hematuria Among Antithrombotic Agents: A Systematic Review of Over 175,000 Patients.

OBJECTIVE: To determine the probability of visible hematuria with antithrombotic agents and to evaluate association of urologic etiology in antithrombotic-related hematuria. METHODS: Preferred Reporting Items in Systematic Reviews and Meta-Analyses guidelines were followed to conduct a systematic review using search engines PUBMED and SCOPUS with the terms "(hematuria) OR (haematuria) OR urinary bleeding)) AND ((anticoagulants) OR anticoagulation) OR noac) OR novel anticoagulants) OR antiplatelet) OR dabigatran) OR rivaroxaban) OR apixaban) OR warfarin) OR aspirin) OR heparin) OR dipyridamole)." Raw data were used to perform a pooled analysis. Chi-square and logistic regression analysis were used for statistical analyses. RESULTS: Twenty-two studies describing 175,114 patients met inclusion criteria. Odds ratio of hematuria with warfarin to rivoraxaban was 33 and warfarin to dabigatran was 16. The odds ratio of hematuria for oral anticoagulant (26.7%) to prophylactic parenteral anticoagulant (1.1%) agents was 9.6. Antiplatelet agents are 76 times less likely to cause hematuria compared to anticoagulants. Odds of hematuria with aspirin were 6.7 times the odds with clopidogrel and 3.5 times the odds with ticagrelor. Dabigatran was 198 times more likely to cause major hematuria compared to warfarin, whereas clopidogrel is 1.2 times more likely to cause major hematuria compared to aspirin. Urologic pathology was identified in 44% (234/532) of cases, malignancy in 24%. CONCLUSION: Warfarin use poses the greatest risk for hematuria but is unlikely to cause major hematuria, whereas novel antithrombotic agents are more commonly associated with major hematuria. This review further characterizes the risk profile of antithrombotic agents and associated hematuria to equip clinicians with knowledge to choose an appropriate antithrombotic agent in patients with high-risk hematuria.

Neoadjuvant Platinum-Based Chemotherapy is an Independent Predictor for Preoperative Thromboembolic Events in Bladder Cancer Patients Undergoing Radical Cystectomy.

INTRODUCTION: Neoadjuvant chemotherapy (NAC) confers a significant survival benefit in patients with muscle invasive bladder cancer. Platinum-based chemotherapy increases the risk of thromboembolic events (TEE). We determined the effect of cisplatin-based NAC on the incidence of preoperative TEEs in radical cystectomy patients. MATERIALS AND METHODS: A retrospective matched case-control study was performed on 55 patients undergoing radical cystectomy for muscle invasive bladder cancer. Group 1 (n = 20) included patients that received NAC prior to radical cystectomy and Group 2 (n = 35) included patients that underwent radical cystectomy without NAC. Logistic regression analyses tested potential predictors for TEEs in both groups (age, American Society of Anesthesiologists grade, use of NAC, histological subtype, pathological stage). RESULTS: In total, 6 patients of 55 developed a TEE. Five patients of 20 (25%) treated with NAC prior to radical cystectomy developed TEEs, while 1 of 35 (2.9%) treated with radical cystectomy alone developed a TEE. On univariate and multivariate regression analysis, NAC prior to radical cystectomy was an independent predictor for TEE prior to radical cystectomy (p = 0.033 and p = 0.043, respectively). The effect of perioperative anticoagulation on operative blood loss and postoperative hemoglobin level was not statistically significant between both groups (p = 0.22 and p = 0.08, respectively). CONCLUSION: Neoadjuvant cisplatin-based chemotherapy is a significant predictor for preoperative TEE in patients undergoing radical cystectomy.

Sialylated glycosylphosphatidylinositols suppress the production of toxic amyloid-ß oligomers.

The production of amyloid-ß (Aß) is a key factor driving pathogenesis in Alzheimer's disease (AD). Increasing concentrations of soluble Aß oligomers within the brain lead to synapse degeneration and the progressive dementia characteristic of AD. Since Aß exists in both disease-relevant (toxic) and non-toxic forms, the factors that affected the release of toxic Aß were studied in a cell model. 7PA2 cells expressing the human amyloid precursor protein released Aß oligomers that caused synapse damage when incubated with cultured neurones. These Aß oligomers had similar potency to soluble Aß oligomers derived from the brains of Alzheimer's patients. Although the conditioned media from 7PA2 cells treated with the cellular prion protein (PrPC) contained Aß, it did not cause synapse damage. The loss of toxicity was associated with a reduction in Aß oligomers and an increase in Aß monomers. The suppression of toxic Aß release was dependent on the glycosylphosphatidylinositol (GPI) anchor attached to PrPC, and treatment of cells with specific GPIs alone reduced the production of toxic Aß. The efficacy of GPIs was structure-dependent and the presence of sialic acid was critical. The conditioned medium from GPI-treated cells protected neurones against Aß oligomer-induced synapse damage; neuroprotection was mediated by Aß monomers. These studies support the hypothesis that the ratio of Aß monomers to Aß oligomers is a critical factor that regulates synapse damage.

Sialic Acid within the Glycosylphosphatidylinositol Anchor Targets the Cellular Prion Protein to Synapses.

Although the cellular prion protein (PrP(C)) is concentrated at synapses, the factors that target PrP(C) to synapses are not understood. Here we demonstrate that exogenous PrP(C) was rapidly targeted to synapses in recipient neurons derived from Prnp knock-out((0/0)) mice. The targeting of PrP(C) to synapses was dependent upon both neuronal cholesterol concentrations and the lipid and glycan composition of its glycosylphosphatidylinositol (GPI) anchor. Thus, the removal of either an acyl chain or sialic acid from the GPI anchor reduced the targeting of PrP(C) to synapses. Isolated GPIs (derived from PrP(C)) were also targeted to synapses, as was IgG conjugated to these GPIs. The removal of sialic acid from GPIs prevented the targeting of either the isolated GPIs or the IgG-GPI conjugate to synapses. Competition studies showed that pretreatment with sialylated GPIs prevented the targeting of PrP(C) to synapses. These results are consistent with the hypothesis that the sialylated GPI anchor attached to PrP(C) acts as a synapse homing signal.

Glycosylphosphatidylinositols: More than just an anchor?

There is increasing interest in the role of glycosylphosphatidylinositol (GPI) anchors that attach some proteins to cell membranes. Far from being biologically inert, GPIs influence the targeting, intracellular trafficking and function of the attached protein. Our recent paper demonstrated the role of sialic acid on the GPI of the cellular prion protein (PrP(C)). The "prion diseases" arise following the conversion of PrP(C) to a disease-associated isoform called PrP(Sc) or "prion". Our paper showed that desialylated PrP(C) inhibited PrP(Sc) formation. Aggregated PrP(Sc) creates a signaling platform in the cell membrane incorporating and activating cytoplasmic phospholipase A2 (cPLA2), an enzyme that regulates PrP(C) trafficking and hence PrP(Sc) formation. The presence of desialylated PrP(C) caused the dissociation of cPLA2 from PrP-containing platforms, reduced the activation of cPLA2 and inhibited PrP(Sc) production. We concluded that sialic acid contained within the GPI attached to PrP(C) modifies local membrane microenvironments that are important in PrP-mediated cell signaling and PrP(Sc) formation.

Does the tail wag the dog? How the structure of a glycosylphosphatidylinositol anchor affects prion formation.

There is increasing interest in the role of the glycosylphosphatidylinositol (GPI) anchor attached to the cellular prion protein (PrP(C)). Since GPI anchors can alter protein targeting, trafficking and cell signaling, our recent study examined how the structure of the GPI anchor affected prion formation. PrP(C) containing a GPI anchor from which the sialic acid had been removed (desialylated PrP(C)) was not converted to PrP(Sc) in prion-infected neuronal cell lines and in scrapie-infected primary cortical neurons. In uninfected neurons desialylated PrP(C) was associated with greater concentrations of gangliosides and cholesterol than PrP(C). In addition, the targeting of desialylated PrP(C) to lipid rafts showed greater resistance to cholesterol depletion than PrP(C). The presence of desialylated PrP(C) caused the dissociation of cytoplasmic phospholipase A2 (cPLA2) from PrP-containing lipid rafts, reduced the activation of cPLA2 and inhibited PrP(Sc) production. We conclude that the sialic acid moiety of the GPI attached to PrP(C) modifies local membrane microenvironments that are important in PrP-mediated cell signaling and PrP(Sc) formation.

Glimepiride protects neurons against amyloid-ß-induced synapse damage.

Alzheimer's disease is associated with the accumulation within the brain of amyloid-ß (Aß) peptides that damage synapses and affect memory acquisition. This process can be modelled by observing the effects of Aß on synapses in cultured neurons. The addition of picomolar concentrations of soluble Aß derived from brain extracts triggered the loss of synaptic proteins including synaptophysin, synapsin-1 and cysteine string protein from cultured neurons. Glimepiride, a sulphonylurea used for the treatment of diabetes, protected neurons against synapse damage induced by Aß. The protective effects of glimepiride were multi-faceted. Glimepiride treatment was associated with altered synaptic membranes including the loss of specific glycosylphosphatidylinositol (GPI)-anchored proteins including the cellular prion protein (PrP(C)) that acts as a receptor for Aß42, increased synaptic gangliosides and altered cell signalling. More specifically, glimepiride reduced the Aß-induced increase in cholesterol and the Aß-induced activation of cytoplasmic phospholipase A2 (cPLA2) in synapses that occurred within cholesterol-dense membrane rafts. Aß42 binding to glimepiride-treated neurons was not targeted to membrane rafts and less Aß42 accumulated within synapses. These studies indicate that glimepiride modified the membrane micro-environments in which Aß-induced signalling leads to synapse damage. In addition, soluble PrP(C), released from neurons by glimepiride, neutralised Aß-induced synapse damage. Such observations raise the possibility that glimepiride may reduce synapse damage and hence delay the progression of cognitive decline in Alzheimer's disease.

Sialic Acid on the Glycosylphosphatidylinositol Anchor Regulates PrP-mediated Cell Signaling and Prion Formation.

The prion diseases occur following the conversion of the cellular prion protein (PrP(C)) into disease-related isoforms (PrP(Sc)). In this study, the role of the glycosylphosphatidylinositol (GPI) anchor attached to PrP(C) in prion formation was examined using a cell painting technique. PrP(Sc) formation in two prion-infected neuronal cell lines (ScGT1 and ScN2a cells) and in scrapie-infected primary cortical neurons was increased following the introduction of PrP(C). In contrast, PrP(C) containing a GPI anchor from which the sialic acid had been removed (desialylated PrP(C)) was not converted to PrP(Sc). Furthermore, the presence of desialylated PrP(C) inhibited the production of PrP(Sc) within prion-infected cortical neurons and ScGT1 and ScN2a cells. The membrane rafts surrounding desialylated PrP(C) contained greater amounts of sialylated gangliosides and cholesterol than membrane rafts surrounding PrP(C). Desialylated PrP(C) was less sensitive to cholesterol depletion than PrP(C) and was not released from cells by treatment with glimepiride. The presence of desialylated PrP(C) in neurons caused the dissociation of cytoplasmic phospholipase A2 from PrP-containing membrane rafts and reduced the activation of cytoplasmic phospholipase A2. These findings show that the sialic acid moiety of the GPI attached to PrP(C) modifies local membrane microenvironments that are important in PrP-mediated cell signaling and PrP(Sc) formation. These results suggest that pharmacological modification of GPI glycosylation might constitute a novel therapeutic approach to prion diseases.

Clinical outcome when left atrial posterior wall box isolation is included as a catheter ablation strategy in patients with persistent atrial fibrillation.

PURPOSE: Isolation of the pulmonary veins alone (PVI) is associated with a 50 to 70 % success rate in paroxysmal atrial fibrillation (AF) but is significantly lower for persistent AF. We sought to evaluate patient outcomes in terms of safety and efficacy when posterior left atrial box isolation is included as a catheter ablation strategy in patients with mainly persistent AF. METHODS: We performed an audit of 100 patients undergoing left atrial (LA) box isolation. Recurrence of arrhythmia was detected by evaluating symptoms and continuous 24 h ECG monitoring at 2, 6 and 12 months post procedure. RESULTS: Seventy-two patients had persistent AF prior to procedure. Average duration of AF was 5.4 ± 5.2 years. All patients underwent circumferential PVI plus linear posterior LA lines to complete box isolation. At a mean follow-up of 12.5 ± 4.2 months, 75 patients were free from atrial fibrillation, 50.6 % of these were taking no antiarrhythmic medication. Twenty-five patients had recurrence of AF, 84 % of whom had previous persistent AF. The average time to recurrence post procedure was 5.9 ± 4.4 months. Thirteen patients underwent repeat procedures for recurrent AF. There were no adverse events relating to the procedure. CONCLUSION: These results suggest that the strategy of left atrial box isolation is safe and effective, worthy of further evaluation in a multicentre registry.

Monoacylated Cellular Prion Proteins Reduce Amyloid-ß-Induced Activation of Cytoplasmic Phospholipase A2 and Synapse Damage.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by the accumulation of amyloid-ß (Aß) and the loss of synapses. Aggregation of the cellular prion protein (PrPC) by Aß oligomers induced synapse damage in cultured neurons. PrPC is attached to membranes via a glycosylphosphatidylinositol (GPI) anchor, the composition of which affects protein targeting and cell signaling. Monoacylated PrPC incorporated into neurons bound "natural Aß", sequestering Aß outside lipid rafts and preventing its accumulation at synapses. The presence of monoacylated PrPC reduced the Aß-induced activation of cytoplasmic phospholipase A2 (cPLA2) and Aß-induced synapse damage. This protective effect was stimulus specific, as treated neurons remained sensitive to α-synuclein, a protein associated with synapse damage in Parkinson's disease. In synaptosomes, the aggregation of PrPC by Aß oligomers triggered the formation of a signaling complex containing the cPLA2.a process, disrupted by monoacylated PrPC. We propose that monoacylated PrPC acts as a molecular sponge, binding Aß oligomers at the neuronal perikarya without activating cPLA2 or triggering synapse damage.

Social skills and executive function among youth with sickle cell disease: a preliminary investigation.

OBJECTIVES: To explore the relationship between executive function (EF) and social skills in youth with sickle cell disease (SCD). METHODS: 20 youth with SCD completed objective tests of EF (Tasks of Executive Control; Animal Sorting subtest from the Developmental Neuropsychological Assessment-Second Edition), an IQ screener, and paper-and-pencil measures of social skills (Social Skills Improvement System [SSIS]). Primary caregivers completed paper-and-pencil measures of EF (Behavior Rating Inventory of Executive Function) and social skills (SSIS). RESULTS: EF scores from the Behavior Rating Inventory of Executive Function related to parent- and child-reported social skills such that EF deficits correlated with poorer overall and domain-specific social skills. Similarly, EF scores from the Animal Sorting test related to child-reported social skills. Worse parent-reported EF predicted worse parent-reported social skills above the variance accounted for by IQ. CONCLUSIONS: EF is related to social skills and may be necessary for successful social interaction among youth with SCD. These results provide rationale and guidance for future larger-scale investigations of EF and social skills among children with SCD.