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Introduction: Extracorporeal membrane oxygenation (ECMO) assisted CPR (ECPR) can improve outcomes after prolonged or unsuccessful resuscitative efforts, but neurological injury remains common in survivors. The lack of routine neuromonitoring during ECPR and ECMO prohibits brain-targeted management to help improve neurological outcomes. In this study, we examine the association of non-invasive, frequency-domain diffuse optical spectroscopy (FD-DOS) measurements of cerebral tissue oxygen extraction fraction (OEF), an indicator of metabolic stress, with invasively collected brain injury biomarkers to explore the utility of this monitoring modality during ECPR. Hypothesis: FD-DOS measurement of cerebral OEF is positively correlated with biomarkers of brain injury (lactate-pyruvate ratio, LPR; glycerol). Methods: Cerebral OEF was continuously monitored by FD-DOS in nine pediatric swine (8-11 kg) who underwent 30-60 minutes of manual CPR, were cannulated for ECMO, and remained on ECMO for 22-24 hours. Cerebral pyruvate, lactate, glycerol and glucose content were measured from cerebral microdialysate samples collected hourly. The correlation between OEF and microdialysis parameters were assessed using a linear mixed-effects model incorporating subject-specific random slope and intercept effects. Significance was determined at p Results: Microdialysis parameters from 192 samples were compared against non-invasive OEF values. OEF was significantly correlated with LPR (p=0.001), and relative change in glycerol (p=0.005) and glucose (p=0.020) concentrations from baseline. Conclusions: Non-invasive FD-DOS neuromonitoring of OEF demonstrated significant correlations with invasive brain injury biomarkers; increasing OEF was associated with elevated LPR and glycerol, and diminished glucose. FD-DOS detection of critical neurometabolic stress at the bedside may facilitate brain-targeted ECMO management after cardiac arrest.

The development of massively parallel sequencing (MPS) has revolutionized molecular genetic diagnostics in monogenic disorders. The present review gives a brief overview of different MPS-based approaches used in clinical diagnostics of neuromuscular disorders (NMDs) and highlights their advantages and limitations.MPS-based approaches like gene panel sequencing, (whole) exome sequencing, (whole) genome sequencing, and RNA sequencing have been used to identify the genetic cause in NMDs. Although gene panel sequencing has evolved as a standard test for heterogeneous diseases, it is still debated, mainly because of financial issues and unsolved problems of variant interpretation, whether genome sequencing (and to a lesser extent also exome sequencing) of single patients can already be regarded as routine diagnostics. However, it has been shown that the inclusion of parents and additional family members often leads to a substantial increase in the diagnostic yield in exome-wide/genome-wide MPS approaches. In addition, MPS-based RNA sequencing just enters the research and diagnostic scene.Next-generation sequencing increasingly enables the detection of the genetic cause in highly heterogeneous diseases like NMDs in an efficient and affordable way. Gene panel sequencing and family-based exome sequencing have been proven as potent and cost-efficient diagnostic tools. Although clinical validation and interpretation of genome sequencing is still challenging, diagnostic RNA sequencing represents a promising tool to bypass some hurdles of diagnostics using genomic DNA.

BACKGROUND Placebo-controlled and open-label studies have demonstrated the safety and efficacy of daily oral preexposure prophylaxis (PrEP) in preventing HIV infection, but data are limited on real-world PrEP use. METHODS We conducted a cohort study from July 2012 through June 2015 of Kaiser Permanente Northern California members initiating PrEP. We assessed pharmacy refill adherence and discontinuation, decreases in estimated glomerular filtration rate (eGFR), and sexually transmitted infection (STI)/HIV incidence. RESULTS Overall, 972 individuals initiated PrEP, accumulating 850 person-years of PrEP use. Mean adherence was 92% overall. Black race/ethnicity [adjusted risk ratio (aRR) 3.0; 95% confidence interval: 1.7 to 5.1, P < 0.001], higher copayments (aRR 2.0; 1.2 to 3.3, P = 0.005), and smoking (aRR 1.6; 1.1 to 2.3, P = 0.025) were associated with

Autism and autism spectrum disorders are complex neurodevelopmental disorders characterized by deficits in social interaction, communication, and behavioral flexibility. The complex phenotypic presentation of these disorders suggests that multiple genetic and environmental factors contribute to risk, and gene-environment interactions are widely believed to underlie autism spectrum disorders. Few studies have addressed joint risk from specific genetic susceptibility in combination with a specific environmental exposure or class of exposures.1 In previous independent studies, we have identified (1) increased autism spectrum disorder risk among children exposed to high levels of local near-roadway traffic-related air pollution and regional particulate matter near the time of birth2,3; (2) increased autism spectrum disorder risk among children with the C allele of the MET gene promoter variant rs1858830,4,5 which is associated with decreased expression of MET protein in brain6 and immune system7; and (3) decreased MET protein expression in brain and altered behavior in offspring of mouse dams exposed during pregnancy to the polycyclic aromatic hydrocarbon benzo(a)pyrene (a component of traffic-related air pollution and particulate matter).8 Based on these independent autism spectrum disorder associations and the biological link between benzo(a)pyrene and MET, we hypothesized that a gene-environment interaction contributes to autism spectrum disorder risk. In children, as in animals, prenatal polycyclic aromatic hydrocarbon exposure has been associated with intelligence (IQ) deficits at age 5 years as well as with increased anxiety, depression, and inattention at age 6–7.8–10 In this study we investigated the relationship of air pollution exposure and genotype at the MET rs1858830 locus with autism spectrum disorder.

Intermittent dosing of pre-exposure prophylaxis (iPrEP) has potential to decrease costs, improve adherence, and minimize toxicity. Practical event-based dosing of iPrEP requires men who have sex with men (MSM) to be sexually active on fewer than 3 days each week and plan for sexual activity. MSM who may be most suitable for event-based dosing were older, more educated, more frequently used sexual networking websites, and more often reported that their last sexual encounter was not with a committed partner. A substantial proportion of these MSM endorse high-risk sexual activity, and event-based iPrEP may best target this population.

Wegener's granulomatosis is characterized by vasculitis and necrotizing granulomatous inflammation that classically affects the upper respiratory tract and lungs, and frequently involves the kidneys with pauci-immune glomerulonephritis.' Almost any organ may be involved, and eye, skin, nervous system and inner ear involvement are not uncommon. Involvement of the lower urinary tract is unusual.l.* To our knowledge we report the first case in which the initial presenting sign of Wegener's granulomatosis was a urethral diverticulum. CASE RE PORT A 56-year-old white woman presented with vaginal spotting. Full evaluation was unrevealing except for a nontender fluctuant area in the distal anterior vaginal wall, which had been incised transvaginally elsewhere. Some pus had been expressed and the incision was closed but the area soon became tender and indurated. The patient was placed on antibiotics and referred for further definitive evaluation and treatment. Urethroscopy revealed inflammatory changes as well as an ostium in the ventral distal urethra. Voiding cystourethrography confirmed a urethral diverticulum at the corresponding location (fig. 1). At surgery it was noted that the distal anterior vaginal wall had become much more indurated with pronounced inflammatory changes. Frozen sections of the distal anterior vaginal wall and tissue beneath it revealed no malignant elements. After meticulous dissection we removed a large doughnut-shaped urethral diverticulum circumferentially surrounding the distal half of the urethra with a portion of the anterior vaginal wall. A firm yellowish material was contained within the diverticulum. The anterior vaginal wall was reconstructed by advancing vaginal wall flaps to surround the urethra and cover the distal anterior vagina. Final pathological evaluation revealed a 4.5 x 3.8 x 1.4 cm. urethral diverticulum with a mass of necrotizing granulomatous inflammation (fig. 2). All tissue cultures and a purified protein derivative tuberculin test were negative. The patient did well until 1 month later, when a macular rash, arthralgia and chondritis of the right ear developed. Additional evaluations demonstrated superficial nasal septa1 ulceration, bilateral scleritis, nodules on the legs, fever of 101F. and paresthesia of the hands and feet. Chest x-ray showed a right lower lobe infiltrate and computerized tomography revealed 3 focal lung infiltrates consistent with local vasculitis. Bronchoscopy excluded infection. Antineutrophil cytoplasmic antibodies with anti-proteinase 3 specificity were present. Serum creatinine and urinalysis (catheterized sample) were normal. Based on the histological findings, laboratory data, constellation of symptoms and signs, and radiological findings Wegener's granulomatosis was diagnosed. A regimen of prednisone and methotrexate was initiated. During the ensuing 8 weeks symptoms resolved, the radiological findings disappeared and the anterior vaginal wall healed completely. Currently the patient is asymptomatic. Prednisone will be ta