Characterizing sleep disorders in an autism-specific collection of electronic health records.

OBJECTIVE/BACKGROUND: Sleep problems are common in people on the autism spectrum. This study reviews one detailed approach to querying the electronic health record (EHR) in a large tertiary care center. PATIENTS/METHODS: We developed methods for identifying people on the autism spectrum and defined their sleep problems using the key words, "sleep" or "melatonin", or International Classification of Diseases (ICD) codes. We examined treatment responses of these individuals to melatonin supplementation. RESULTS: Sleep problems were documented in 86% of patients with ages ranging from 6 to 30 years old. Our specific keyword search yielded more patients with sleep diagnoses than ICD codes alone. About two-thirds of patients who received melatonin supplementation reported benefit from its use. CONCLUSIONS: Our study provides a framework for using deidentified medical records to characterize sleep, a common co-occurring condition, in people on the autism spectrum. Using specific keywords could be helpful in future work that queries the EHR.

Consensus exercise identifying priorities for research in the field of general surgery of childhood in the UK.

BACKGROUND: The evidence base underlying clinical practice in children's general surgery is poor and high-quality collaborative clinical research is required to address current treatment uncertainties. The aim of this study was, through a consensus process, to identify research priorities for clinical research in this field amongst surgeons who treat children. METHODS: Questions were invited in a scoping survey amongst general surgeons and specialist paediatric surgeons. These were refined by the study team and subsequently prioritized in a two-stage modified Delphi process. RESULTS: In the scoping survey, a total of 226 questions covering a broad scope of children's elective and emergency general surgery were submitted by 76 different clinicians. These were refined to 71 research questions for prioritization. A total of 168 clinicians took part in stage one of the prioritization process, and 157 in stage two. A 'top 10' list of priority research questions was generated for both elective and emergency general surgery of childhood. These cover a range of conditions and concepts, including inguinal hernia, undescended testis, appendicitis, abdominal trauma and enhanced recovery pathways. CONCLUSION: Through consensus amongst surgeons who treat children, 10 priority research questions for each of the elective and emergency fields have been identified. These should provide a basis for the development of high-quality multicentre research projects to address these questions, and ultimately improve outcomes for children requiring surgical care.

Virtual consultations: delivering outpatient clinics in paediatric surgery during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic has resulted in many changes to clinical practice, including the introduction of remote clinics. Those familiar with remote clinics have reported benefits to their use, such as patient satisfaction and cost benefits; however, ongoing challenges exist, including delivering optimal patient-centred care. As a tertiary paediatric surgery unit in the UK, completing remote clinics was a new experience for most of our surgical team. We completed a service evaluation early into the COVID-19 pandemic aiming to define and address issues when delivering remote clinics in paediatric surgery. Remote clinics were observed (telephone and video), with follow-up calls to families following the consultations. RESULTS: Eight paediatric surgeons were observed during their remote clinics (telephone n = 6, video n = 2). Surgeons new to remote clinics felt their consultations took longer and were reluctant to discharge patients. The calls did not always occur at the appointed time, causing some upset by parents. Prescription provision and outpatient investigations led to some uncertainty within the surgical team. Families (n = 11) were called following their child's appointment to determine how our remote clinics could be optimised. The parents all liked remote clinics, either as an intermediate until a face-to-face consultation or for continued care if appropriate.Our findings, combined by discussions with relevant managers and departments, led to the introduction of recommendations for the surgical team. An information sheet was introduced for the families attending remote clinics, which encouraged them to take notes before and during their consultations. CONCLUSIONS: There must be strong support from management and appropriate departments for successful integration of remote clinics. Surgical trainees and their training should be considered when implementing remote clinics. Our learning from the pandemic may support those considering integrating remote clinics in the future.

Assessment of corrosion in retrieved spine implants.

Recently the use of dissimilar metals in spine instrumentation has increased, especially in the case of adult deformities, where rods made from Cobalt Chrome alloys (CoCr) are used with Titanium (Ti) screws. The use of dissimilar metals increases the risk of galvanic corrosion and patients have required revision spine surgery due to severe metallosis that may have been caused by corrosion. We aimed to assess the presence of corrosion in spine implant retrievals from constructs with two types of material combinations: similar (Ti/Ti) and dissimilar (CoCr/Ti). First, we devised a grading score for corrosion of the rod-fixture junctions. Then, we applied this score to a collection of retrieved spine implants. Our proposed corrosion grading score was proven reliable (kappa > 0.7). We found no significant difference in the scores between 4 CoCr and 11 Ti rods (p = 0.0642). There was no indication that time of implantation had an effect on the corrosion score (p = 0.9361). We recommend surgeons avoid using implants designs with dissimilar metals to reduce the risk of corrosion whilst a larger scale study of retrieved spine implants is conducted. Future studies can now use our scoring system for spine implant corrosion. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 632-638, 2018.

Evidence for Sticky-Trap Avoidance by Stable Fly, Stomoxys calcitrans (Diptera: Muscidae), in Response to Trapped Flies.

Populations of stable flies, Stomoxys calcitrans, and other filth flies are often sampled using sticky traps. We wanted to know whether flies already caught on sticky traps might inhibit to some extent subsequent flies from being caught. To test this, we recorded the number of stable flies landing on white plastic corrugated panels (Coroplast®), which were prepared according to 4 treatments: 12 live stable flies glued to the surface, 12 live house flies (Musca domestica) glued to the surface, 12 black dots, and no treatment. From 160 observations, we found that fewer stable flies landed on panels with either attached stable flies (129) or house flies (133) compared with the number landing on panels with black dots (259) and/or with no treatment (210). This apparent inhibitory effect of trapped flies may explain published trap-catch patterns from field studies.

Technical and Clinical Outcomes Following Colonic Stenting: A Seven-Year Analysis of 268 Procedures.

AIMS: To assess the factors contributing to the technical and clinical success of colorectal stenting for large bowel obstruction. METHODOLOGY: 268 cases of colonic stenting for large bowel obstruction were performed in 249 patients of mean age of 72 years (28-98) between 2006 and 2013. The majority of strictures were due to malignant disease, 244/268 (91 %). Diverticular strictures accounted for 24/268 (9 %). RESULTS: Overall technical success rate was 81 % (217/268), with a clinical success rate of 65 % (174/268). Duration of symptoms ranged from 0 to 180 days (mean 8 days). Technical success rate was seen to decrease with increasing symptom duration. For symptom duration of less than 1 week, technical success was 85.4 % (181/212) versus 69.6 % (39/56) for those with symptoms of greater than a week (p < 0.05). Clinical success rates fell from 71.3 % (107/150) to 59.3 % (70/118) (p < 0.05) when attempting to stent lesions of greater than 5 cm. There was also a significant reduction in clinical success when stenting lesions on a bend rather than a straight segment of colon 75.7 % (109/144) versus 59.7 % (74/124) (p < 0.05). A total of 20 (7.46 %) perforations were identified during the study. Stent migration occurred in 6.6 % of cases. In-stent stenosis occurred in 3.3 %. The overall 30-day all cause mortality rate was 9 %. CONCLUSION: Lesion size, location and duration of obstructive symptoms are statistically significant determinants of patient outcome. These factors could be used to advise patient selection for colonic stenting or direct progression to surgical intervention.

Abnormal connexin expression in human chronic wounds.

BACKGROUND: Regulated alteration of connexin expression has been shown to be integral to acute wound repair. Downregulation of the gap-junction protein connexin 43 at the wound edge has been correlated with keratinocyte and fibroblast migration, while abnormal overexpression of connexin 43 significantly perturbs healing, as shown in the streptozotocin diabetic rodent impaired healing model. OBJECTIVES: To examine the protein expression levels of connexin 43, in addition to connexins 26 and 30, in a variety of human chronic wounds. METHODS: Wound-edge punch biopsies and a matched control from the arm were taken from a cohort of patients with venous leg, diabetic foot or pressure ulcers. Wound connexin expression in each patient was compared with that in a matched, nonwounded arm punch. Tissue was sectioned, stained and imaged by confocal microscopy using identical parameters per patient to permit quantification. RESULTS: Epidermal connexin 43, connexin 26 and connexin 30, and dermal connexin 43 were discovered to be strikingly upregulated in every ulcer from all three wound types, pointing to connexin upregulation as a common feature between chronic wounds. CONCLUSIONS: This result supports efforts to target connexin 43 to promote cell migration and wound healing in chronic ulcers.

Radiology and mesenteric ischaemia.

This review focuses on the radiology of mesenteric ischaemia. Covering the acute and chronic presentations, both of which result from impaired vascularisation of the gastrointestinal tract, we evaluate the role of radiographs, ultrasound, CT, MRI, and catheter angiography in the diagnosis of these conditions. Looking to the future, we also assess some of the emerging imaging techniques. Across medicine and surgery there has been a significant shift towards minimally invasive interventions. Although percutaneous revascularisation of chronic mesenteric ischaemia has been performed for some time, there has been a developing trend for the use of such techniques in acute mesenteric ischaemia. We evaluate the available evidence for the use of these percutaneous interventions and assess how they compare with or in some instances compliment traditional surgical alternatives.

Postoperative complications after reconstructive surgery for cloacal malformations: a systematic review.

The repair of cloacal malformations is most often performed using a posterior sagittal anorecto-vagino-urethroplasty (PSARVUP) or total urogenital mobilization (TUM) with or without laparotomy. The aim of this study was to systematically review the frequency and type of postoperative complication seen after cloacal repair as reported in the literature. A systematic literature search was conducted according to preferred reporting items for systematic reviews and meta-analyses guidelines (PRISMA). Eight records were eligible for this study which were qualitatively analyzed according to the Rangel score. Overall complication rates reported in included studies ranged from 0 to 57 %. After meta-analysis of data, postoperative complications were seen in 99 of 327 patients (30 %). The most common reported complications were recurrent or persistent fistula (n = 29, 10 %) and rectal prolapse (n = 27, 10 %). In the PSARVUP group, the complication rate was 40 % and in the TUM group 30 % (p = 0.205). This systematic review shows that postoperative complications after cloacal repair are seen in 30 % of the patients. The complication rates after PSARVUP and TUM were not significantly different. Standardization in reporting of surgical complications would inform further development of surgical approaches. Other techniques aiming to lower postoperative complication rates may also deserve consideration.

Antibiotics in interventional radiology.

The range and number of interventional procedures is rapidly increasing each year. A major complication associated with many procedures is infection, which can result in serious adverse outcomes for the patient. Consequently, antibiotics are amongst the most common pharmaceuticals used by the interventionist, particularly for non-vascular procedures, yet almost no randomized controlled trial data exist to inform our decision when formulating appropriate antibiotic prophylaxis regimens. The purpose of this review is to provide an update on the utilization of antibiotics for common interventional radiology procedures, focusing on timing and duration of antibiotic prophylaxis.

SLC6A3 coding variant Ala559Val found in two autism probands alters dopamine transporter function and trafficking.

Emerging evidence associates dysfunction in the dopamine (DA) transporter (DAT) with the pathophysiology of autism spectrum disorder (ASD). The human DAT (hDAT; SLC6A3) rare variant with an Ala to Val substitution at amino acid 559 (hDAT A559V) was previously reported in individuals with bipolar disorder or attention-deficit hyperactivity disorder (ADHD). We have demonstrated that this variant is hyper-phosphorylated at the amino (N)-terminal serine (Ser) residues and promotes an anomalous DA efflux phenotype. Here, we report the novel identification of hDAT A559V in two unrelated ASD subjects and provide the first mechanistic description of its impaired trafficking phenotype. DAT surface expression is dynamically regulated by DAT substrates including the psychostimulant amphetamine (AMPH), which causes hDAT trafficking away from the plasma membrane. The integrity of DAT trafficking directly impacts DA transport capacity and therefore dopaminergic neurotransmission. Here, we show that hDAT A559V is resistant to AMPH-induced cell surface redistribution. This unique trafficking phenotype is conferred by altered protein kinase C ß (PKCß) activity. Cells expressing hDAT A559V exhibit constitutively elevated PKCß activity, inhibition of which restores the AMPH-induced hDAT A559V membrane redistribution. Mechanistically, we link the inability of hDAT A559V to traffic in response to AMPH to the phosphorylation of the five most distal DAT N-terminal Ser. Mutation of these N-terminal Ser to Ala restores AMPH-induced trafficking. Furthermore, hDAT A559V has a diminished ability to transport AMPH, and therefore lacks AMPH-induced DA efflux. Pharmacological inhibition of PKCß or Ser to Ala substitution in the hDAT A559V background restores AMPH-induced DA efflux while promoting intracellular AMPH accumulation. Although hDAT A559V is a rare variant, it has been found in multiple probands with neuropsychiatric disorders associated with imbalances in DA neurotransmission, including ADHD, bipolar disorder, and now ASD. These findings provide valuable insight into a new cellular phenotype (altered hDAT trafficking) supporting dysregulated DA function in these disorders. They also provide a novel potential target (PKCß) for therapeutic interventions in individuals with ASD.

Brain and peripheral pharmacokinetics of levodopa in the cynomolgus monkey following administration of opicapone, a third generation nitrocatechol COMT inhibitor.

OBJECTIVE: The present study aimed at evaluating the effect of opicapone, a third generation nitrocatechol catechol-O-methyltransferase (COMT) inhibitor, on the systemic and central bioavailability of 3,4-dihydroxy-l-phenylalanine (levodopa) and related metabolites in the cynomolgus monkey. METHODS: Four monkeys, implanted with guiding cannulas for microdialysis probes, in the substantia nigra, dorsal striatum and prefrontal cortex, were randomized in two groups that received, in a crossover design, vehicle or 100 mg/kg opicapone for 14 days. Twenty-three hours after last administration of vehicle or opicapone, animals were challenged with levodopa/benserazide (12/3 mg/kg). Extracellular dialysate and blood samples were collected over 360 min (at 30 min intervals) for the assays of catecholamine and COMT activity. RESULTS: Opicapone increased levodopa systemic exposure by 2-fold not changing Cmax values and reduced both 3-O-methyldopa (3-OMD) exposure and Cmax values by 5-fold. These changes were accompanied by ∼76-84% reduction in erythrocyte COMT activity. In dorsal striatum and substantia nigra, opicapone increased levodopa exposure by 1.7- and 1.4-fold, respectively, reducing 3-OMD exposure by 5- and 7-fold respectively. DOPAC exposure was increased by 4-fold in the substantia nigra. In the prefrontal cortex, opicapone increased levodopa exposure and reduced 3-OMD levels by 2.3- and 2.4-fold, respectively. CONCLUSIONS: Opicapone behaved as long-acting COMT inhibitor that markedly increased systemic and central levodopa bioavailability. Opicapone is a strong candidate to fill the unmet need for COMT inhibitors that lead to more sustained levodopa levels in Parkinson's disease patients.

De novo mutation in the dopamine transporter gene associates dopamine dysfunction with autism spectrum disorder.

De novo genetic variation is an important class of risk factors for autism spectrum disorder (ASD). Recently, whole-exome sequencing of ASD families has identified a novel de novo missense mutation in the human dopamine (DA) transporter (hDAT) gene, which results in a Thr to Met substitution at site 356 (hDAT T356M). The dopamine transporter (DAT) is a presynaptic membrane protein that regulates dopaminergic tone in the central nervous system by mediating the high-affinity reuptake of synaptically released DA, making it a crucial regulator of DA homeostasis. Here, we report the first functional, structural and behavioral characterization of an ASD-associated de novo mutation in the hDAT. We demonstrate that the hDAT T356M displays anomalous function, characterized as a persistent reverse transport of DA (substrate efflux). Importantly, in the bacterial homolog leucine transporter, substitution of A289 (the homologous site to T356) with a Met promotes an outward-facing conformation upon substrate binding. In the substrate-bound state, an outward-facing transporter conformation is required for substrate efflux. In Drosophila melanogaster, the expression of hDAT T356M in DA neurons-lacking Drosophila DAT leads to hyperlocomotion, a trait associated with DA dysfunction and ASD. Taken together, our findings demonstrate that alterations in DA homeostasis, mediated by aberrant DAT function, may confer risk for ASD and related neuropsychiatric conditions.

Antibacterial activity of eravacycline (TP-434), a novel fluorocycline, against hospital and community pathogens.

Eravacycline (TP-434 or 7-fluoro-9-pyrrolidinoacetamido-6-demethyl-6-deoxytetracycline) is a novel fluorocycline that was evaluated for antimicrobial activity against panels of recently isolated aerobic and anaerobic Gram-negative and Gram-positive bacteria. Eravacycline showed potent broad-spectrum activity against 90% of the isolates (MIC90) in each panel at concentrations ranging from ≤0.008 to 2 µg/ml for all species panels except those of Pseudomonas aeruginosa and Burkholderia cenocepacia (MIC90 values of 32 µg/ml for both organisms). The antibacterial activity of eravacycline was minimally affected by expression of tetracycline-specific efflux and ribosomal protection mechanisms in clinical isolates. Furthermore, eravacycline was active against multidrug-resistant bacteria, including those expressing extended-spectrum ß-lactamases and mechanisms conferring resistance to other classes of antibiotics, including carbapenem resistance. Eravacycline has the potential to be a promising new intravenous (i.v.)/oral antibiotic for the empirical treatment of complicated hospital/health care infections and moderate-to-severe community-acquired infections.

Field measurements of stable fly (Diptera: Muscidae) demography, fecundity, and survival based on daily trap catches at a beef farm in southern Ontario over a 5-yr period.

We sampled stable fly, Stomoxys calcitrans (L.), populations using a CO2 baited cloth trap (Nzi trap) each day throughout the summer and autumn at a beef farm near Peterborough, Ontario, Canada, from 1997 to 2001. Females (2,512) were dissected for ovarian age-grading, to produce a demographic profile of farm populations. The number of follicles were counted to produce fecundity estimates. The developmental periods of adult female stages, measured as accumulated degree-days above 10 degrees C, were determined for a lab colony of stable flies. These measurements were used to calculate survival in terms of degree-days of the farm populations each year. Of the 2,512 females caught, 42.4% were nulliparous on average each year. The median follicle size at insemination was 305 microm in the field populations, and 495 microm in the colony. Farm caught females had an average of 49.15 follicles per ovary overall, with the body size (leg length) and fecundity increasing slightly with age. On average, 44.5% (SE 3.2%) of nulliparous females survived to become parous, and of these, 45.7% (SE 2.1%) survived the uniparous state to become multiparous. Years of higher rainfall had increased fecundity; rainfall did not appear to affect survival.