Implementing a specialist paediatric clinical pharmacology service in a UK children's hospital.

AIMS: Royal College of Paediatrics and Child Health subspecialist training in Paediatric Clinical Pharmacology and Therapeutics has been delivered in the UK for 20 years, but no specialist clinical services have been set up previously. METHODS: Prospective audit and service evaluation of paediatric clinical pharmacology service pilot phase and dedicated service at a UK children's hospital. RESULTS: Pilot scheme (May-October 2019), then weekly service (established June 2020). Service covers the High Dependency Unit, and inpatients with polypharmacy. The pilot demonstrated high levels of acceptance, with 89% of suggested medication changes agreed by lead clinical team, and success, with 97.5% of suggested changes continued until discharge/pilot completion. Economic analysis estimated direct annualised cost savings on medications of up to £10 000. After 20 ward rounds of the established service, 270 potential medication changes were identified, 213 were carried out (78.9%). The most common were deprescribing (n = 143), prescribing (n = 47) and dose adjustment (n = 8). Seventy-five different medications were deprescribed, most commonly chloral hydrate (n = 12), Lactulose, ibuprofen, Bio-Kult and sodium alginate (all n = 4). The percentage of inpatients prescribed ≥10 medications decreased from 38.5 to 32.1%, while the subset prescribed ≥20 medications decreased from 11.0 to 5.67%. The mean number of medicines prescribed decreased from 9.0 to 8.0, while the median was unchanged at 7. Annual Yellow Card reports of suspected adverse drug reactions more than doubled (n = 66). CONCLUSION: A UK model for subspecialist paediatric clinical pharmacology service delivery has demonstrated a positive clinical impact and could be replicated at other UK secondary/tertiary children's hospitals.

Pharmacokinetic and pharmacodynamic evidence of adrenaline administered via auto-injector for anaphylactic reactions: A review of literature.

Anaphylaxis is a severe allergic reaction that can lead to death if not treated quickly. Adrenaline (epinephrine) is the first-line treatment for anaphylaxis and its prompt administration is vital to reduce mortality. Following a number of high-profile cases, serious concerns have been raised, both about the optimal dose of intramuscular adrenaline via an auto-injector and the correct needle length to ensure maximal penetration every time. To date, the public data are sparse on the pharmacokinetics-pharmacodynamics of adrenaline administered via an auto-injector. The limited available literature showed a huge variation in the plasma concentrations of adrenaline administered through an auto-injector, as well as variations in the auto-injector needle length. Hence, delivering an effective dose during an anaphylaxis remains a challenge for both patients and healthcare professionals. Collaborative work between pharmacokinetics-pharmacodynamics experts, clinical triallists and licence holders is imperative to address this gap in evidence so that we can improve outcomes of anaphylaxis. In addition, we advise inclusion of expertise of human factors in usability studies given the necessity of carer or self-administration in the uniquely stressful nature of anaphylaxis.

Effects of sex on response of the bovine preimplantation embryo to insulin-like growth factor 1, activin A, and WNT7A.

BACKGROUND: Alterations in maternal environment can sometimes affect embryonic development in a sexually-dimorphic manner. The objective was to determine whether preimplantation bovine embryos respond to three maternally-derived cell signaling molecules in a sex-dependent manner. RESULTS: Actions of three embryokines known to increase competence of bovine embryos to develop to the blastocyst stage, insulin-like growth factor 1 (IGF1), activin A, and WNT member 7A (WNT7A), were evaluated for actions on embryos produced in vitro with X- or Y- sorted semen from the same bull. Each embryokine was tested in embryos produced by in vitro fertilization of groups of oocytes with either pooled sperm from two bulls or with sperm from individual bulls. Embryos were treated with IGF1, activin A, or WNT7A on day 5 of culture. All three embryokines increased the proportion of cleaved zygotes that developed to the blastocyst stage and the effect was similar for female and male embryos. As an additional test of sexual dimorphism, effects of IGF1 on blastocyst expression of a total of 127 genes were determined by RT-qPCR using the Fluidigm Delta Gene assay. Expression of 18 genes was affected by sex, expression of 4 genes was affected by IGF1 and expression of 3 genes was affected by the IGF1 by sex interaction. CONCLUSION: Sex did not alter how IGF1, activin A or WNT7A altered developmental competence to the blastocyst stage. Thus, sex-dependent differences in regulation of developmental competence of embryos by maternal regulatory signals is not a general phenomenon. The fact that sex altered how IGF1 regulates gene expression is indicative that there could be sexual dimorphism in embryokine regulation of some aspects of embryonic function other than developmental potential to become a blastocyst.

Angelman syndrome imprinting center encodes a transcriptional promoter.

Clusters of imprinted genes are often controlled by an imprinting center that is necessary for allele-specific gene expression and to reprogram parent-of-origin information between generations. An imprinted domain at 15q11-q13 is responsible for both Angelman syndrome (AS) and Prader-Willi syndrome (PWS), two clinically distinct neurodevelopmental disorders. Angelman syndrome arises from the lack of maternal contribution from the locus, whereas Prader-Willi syndrome results from the absence of paternally expressed genes. In some rare cases of PWS and AS, small deletions may lead to incorrect parent-of-origin allele identity. DNA sequences common to these deletions define a bipartite imprinting center for the AS-PWS locus. The PWS-smallest region of deletion overlap (SRO) element of the imprinting center activates expression of genes from the paternal allele. The AS-SRO element generates maternal allele identity by epigenetically inactivating the PWS-SRO in oocytes so that paternal genes are silenced on the future maternal allele. Here we have investigated functional activities of the AS-SRO, the element necessary for maternal allele identity. We find that, in humans, the AS-SRO is an oocyte-specific promoter that generates transcripts that transit the PWS-SRO. Similar upstream promoters were detected in bovine oocytes. This result is consistent with a model in which imprinting centers become DNA methylated and acquire maternal allele identity in oocytes in response to transiting transcription.

Effect of age on cutaneous vasomotor responses during local skin heating.

This study examined the effect of ageing on the low-frequency oscillations (vasomotion) of skin blood flow in response to local heating (LH). Skin blood flow was assessed by laser-Doppler flowmetry on the forearm at rest (33°C) and in response to LH of the skin to both 42°C and 44°C in 14 young (24±1years) and 14 older (64±1years) participants. Vasomotion was analyzed using a wavelet transform to investigate power of the frequency intervals associated with endothelial, neural, myogenic, respiratory, and cardiac activities of the laser-Doppler signal. Laser-Doppler flux increased in both groups with LH (both d>1.8, p<0.001). Endothelial activity increased in both groups following LH to 42°C (young d=1.4, p<0.001; older d=1.2, p=0.005) and 44°C (young d=1.4, p=0.001; older d=1.5, p=0.005). Endothelial activity was higher in the young compared to older group during LH to 42°C (d=1.4, p=0.017) and 44°C (d=1.5, p=0.004). In response to LH to 42°C and 44°C, neural activity in both groups was decreased (both groups and conditions: d>1.2, p<0.001). Myogenic activity increased in the younger group following LH to 44°C (d=1, p=0.042), while in the older group, myogenic activity increased following LH to 42°C (d=1.2, p=0.041) and 44°C (d=1.1, p=0.041). Respiratory and cardiac activities increased in both groups during LH to 42°C and 44°C (All: d>0.9, p<0.017). There were no differences in wavelet amplitude between younger and older in the neural (d=0.1, p>0.7), myogenic (d=0.3, p>0.7), respiratory (d=0.4, p>0.6), and cardiac (d=0.1, p>0.7) frequency intervals. These data indicate that LH increases cutaneous endothelial and myogenic activity, while decreasing neural activity. Furthermore, ageing reduces the increase in cutaneous endothelial activity in response to LH.

WNT regulation of embryonic development likely involves pathways independent of nuclear CTNNB1.

The bovine was used to examine the potential for WNT signaling to affect the preimplantation embryo. Expression of seven key genes involved in canonical WNT signaling declined to a nadir at the morula or blastocyst stage. Expression of 80 genes associated with WNT signaling in the morula and inner cell mass (ICM) and trophectoderm (TE) of the blastocyst was also evaluated. Many genes associated with WNT signaling were characterized by low transcript abundance. Seven genes were different between ICM and TE, and all of them were overexpressed in TE as compared to ICM, including WNT6, FZD1, FZD7, LRP6, PORCN, APC and SFRP1 Immunoreactive CTNNB1 was localized primarily to the plasma membrane at all stages examined from the 2-cell to blastocyst stages of development. Strikingly, neither CTNNB1 nor non-phospho (i.e., active) CTNNB1 was observed in the nucleus of blastomeres at any stage of development even after the addition of WNT activators to culture. In contrast, CTNNB1 associated with the plasma membrane was increased by activators of WNT signaling. The planar cell polarity pathway (PCP) could be activated in the embryo as indicated by an experiment demonstrating an increase in phospho-JNK in the nucleus of blastocysts treated with the non-canonical WNT11. Furthermore, WNT11 improved development to the blastocyst stage. In conclusion, canonical WNT signaling is attenuated in the preimplantation bovine embryo but WNT can activate the PCP component JNK. Thus, regulation of embryonic development by WNT is likely to involve activation of pathways independent of nuclear actions of CTNNB1.

Identification of Beef Heifers with Superior Uterine Capacity for Pregnancy.

Infertility and subfertility represent major problems in domestic animals and humans, and the majority of embryonic loss occurs during the first month of gestation that involves pregnancy recognition and conceptus implantation. The critical genes and physiological pathways in the endometrium that mediate pregnancy establishment and success are not well understood. In study one, predominantly Angus heifers were classified based on fertility using serial embryo transfer to select animals with intrinsic differences in pregnancy loss. In each of the four rounds, a single in vitro-produced, high-quality embryo was transferred into heifers on Day 7 postestrus and pregnancy was determined on Days 28 and 42 by ultrasound and then terminated. Heifers were classified based on pregnancy success as high fertile (HF), subfertile (SF), or infertile (IF). In study two, fertility-classified heifers were resynchronized and bred with semen from a single high-fertility bull. Blood samples were collected every other day from Days 0 to 36 postmating. Pregnancy rate was determined on Day 28 by ultrasound and was higher in HF (70.4%) than in heifers with low fertility (36.8%; SF and IF). Progesterone concentrations in serum during the first 20 days postestrus were not different in nonpregnant heifers and also not different in pregnant heifers among fertility groups. In study three, a single in vivo-produced embryo was transferred into fertility-classified heifers on Day 7 postestrus. The uteri were flushed on Day 14 to recover embryos, and endometrial biopsies were obtained from the ipsilateral uterine horn. Embryo recovery rate and conceptus length and area were not different among the heifer groups. RNA was sequenced from the Day 14 endometrial biopsies of pregnant HF, SF, and IF heifers (n = 5 per group) and analyzed by edgeR-robust analysis. There were 26 differentially expressed genes (DEGs) in the HF compared to SF endometrium, 12 DEGs for SF compared to IF endometrium, and three DEGs between the HF and IF endometrium. Several of the DEG-encoded proteins are involved in immune responses and are expressed in B cells. Results indicate that preimplantation conceptus survival and growth to Day 14 is not compromised in SF and IF heifers. Thus, the observed difference in capacity for pregnancy success in these fertility-classified heifers is manifest between Days 14 and 28 when pregnancy recognition signaling and conceptus elongation and implantation must occur for the establishment of pregnancy.

Regulation of pluripotency of inner cell mass and growth and differentiation of trophectoderm of the bovine embryo by colony stimulating factor 2.

Colony-stimulating factor 2 (CSF2) enhances competence of the bovine embryo to establish and maintain pregnancy after the embryo is transferred into a recipient. Mechanisms involved could include regulation of lineage commitment, growth, or differentiation of the inner cell mass (ICM) and trophectoderm (TE). Experiments were conducted to evaluate regulation by CSF2 of pluripotency of the ICM and differentiation and growth of the TE. Embryos were cultured with 10 ng/ml recombinant bovine CSF2 or a vehicle control from Days 5 to 7 or 6 to 8 postinsemination. CSF2 increased the number of putative zygotes that developed to blastocysts when the percent of embryos becoming blastocysts in the control group was low but decreased blastocyst yield when blastocyst development in controls was high. ICM isolated from blastocysts by lysing the trophectoderm using antibody and complement via immunosurgery were more likely to survive passage when cultured on mitomycin C-treated fetal fibroblasts if derived from blastocysts treated with CSF2 than if from control blastocysts. There was little effect of CSF2 on characteristics of TE outgrowths from blastocysts. The exception was a decrease in outgrowth size for embryos treated with CSF2 from Days 5 to 7 and an increase in expression of CDX2 when treatment was from Days 6 to 8. Expression of the receptor subunit gene CSF2RA increased from the zygote stage to the 9-16 cell stage before decreasing to the blastocyst stage. In contrast, CSF2RB was undetectable at all stages. In conclusion, CSF2 improves competence of the ICM to survive in a pluripotent state and alters TE outgrowths. Actions of CSF2 occur through a signaling pathway that is likely to be independent of CSF2RB.

Assessing Paracetamol Overdose in Children: Acceptability and Potential Market for a Non-Invasive Testing Device.

Background: Assessment of paracetamol overdose in children and teenagers in the emergency department (ED) requires blood, taken 4 hours post ingestion. A commercial partner developed transdermal paracetamol measuring technology. This work aims to understand the acceptability of such a device, and potential market size. Methods: A questionnaire study was undertaken with children and parents attending Alder Hey Children's Hospital, and healthcare professionals (HCP) involved in their care. A retrospective audit of paracetamol ingestion presenting to a paediatric ED was undertaken. Results: One hundred forty-three questionnaires were distributed, and 139 returned (response rate 97.2%), comprising 55 children, 52 parents and 32 HCP (recruited between August-October 2019). Overall device acceptability, assessed by favourability of appearance and willingness to wear was high, at 60.0% and 81.5% respectively. Concerns raised included bulky size and weight, and concern regarding the duration younger children would tolerate wearing the device. All groups, including children, ranked accuracy of results as the most important device feature and device comfort the least important. Parents prioritised avoidance of blood tests more than children. One hundred twenty-seven children presented to ED with paracetamol ingestion (September 2017-August 2018), with 57 (44.9%) categorised as accidental overdose. Overall, 106 (83.4%) required paracetamol concentration measuring, and 25 (19.7%) of these required treatment with N-acetylcysteine. Extrapolating nationally, over 7000 children will present with accidental overdose per annum in the UK. Conclusion: Acceptability of a non-invasive paracetamol sensor was high in all groups, provided accuracy could be assured.

Endurance exercise training in patients with small abdominal aortic aneurysm: a randomized controlled pilot study.

OBJECTIVE: To investigate the feasibility of endurance exercise training in patients with small abdominal aortic aneurysm (AAA), and to obtain preliminary data of its impact on important health outcomes. DESIGN: Randomized controlled pilot study. SETTING: University rehabilitation facility. PARTICIPANTS: Patients with small AAA (N=28; mean age ± SD, 72±7 y). INTERVENTION: Participants were randomized to a 12-week program of moderate-intensity endurance exercise or standard care control (encouragement to exercise only). MAIN OUTCOME MEASURES: Safety was assessed in terms of the frequency of adverse events and changes in maximum AAA diameter. Outcomes were assessed at baseline and 12 weeks including cardiopulmonary fitness (ventilatory threshold), health-related quality of life (Medical Outcomes Study 36-Item Short-Form Health Survey [version 2]), and markers of vascular risk (eg, blood pressure and high-sensitivity C-reactive protein). RESULTS: Of 545 patients contacted, 28 (5%) entered the trial. There were 3 (11%) dropouts. Adherence to the exercise program was 94%. There were no paradoxical increases in AAA size or adverse clinical events. Ventilatory threshold increased in the exercise group, but not the control group (adjusted mean difference, 2.5 mL·kg(-1)·min(-1); 95% confidence interval, 0.5-4.5; d=.82). Systolic blood pressure and high-sensitivity C-reactive protein decreased in the exercise group compared with the control group (d=.34 and d=.58, respectively). There were no substantial changes in anthropometric variables or quality of life. CONCLUSIONS: Despite a low recruitment rate, the findings suggest that moderate-intensity endurance exercise training is feasible in patients with small AAA, and can evoke improvements in important health outcomes.

Acute inhalation lung injury secondary to zinc and copper aspiration from food contact dust.

A previously healthy boy of preschool age was brought to the emergency department by ambulance with respiratory distress following the accidental inhalation of food contact dust (cake decorating powder). Prehospital oxygen saturations were 80% in room air. Initial treatment was with oxygen, nebulised salbutamol, oral dexamethasone and intravenous amoxicillin/clavulanic acid. Treatment was escalated to nasal high flow oxygen therapy and high dependency care within 8 hours. Lung fields on his initial chest X-ray were clear but the following day showed perihilar infiltrates extending into the lower zones in keeping with inflammation. He was treated with intravenous methylprednisolone, followed by a weaning dose of oral prednisolone over 14 days.He required oxygen therapy for 9 days and remained in hospital for 11 days. Outpatient follow-up, 24 days after the inhalation took place was reassuring with the child showing no signs of abnormal respiratory symptoms.

5-ASA induced interstitial nephritis in patients with inflammatory bowel disease: a systematic review.

BACKGROUND: Acute interstitial nephritis (AIN) is an important cause of kidney injury accounting for up to 27% of unexplained renal impairment. In up to 70% of cases, drugs, including aminosalicylates, are reported as the underlying cause. Following two recent paediatric cases of suspected mesalazine induced AIN within our own department, we performed a systematic review of the literature to address the following question: In patients with inflammatory bowel disease (IBD), is interstitial nephritis associated with 5-aminosalicylate (5-ASA) treatment? Our primary objective was to identify the number of cases reported in the literature of biopsy-proven 5-ASA induced interstitial nephritis, in children and adults with IBD. We also aimed to identify which variables influence the onset, severity and recovery of 5-ASA interstitial nephritis. METHODS: Embase and PubMed databases were searched from inception to 07/10/20. Search terms had three main themes: "inflammatory bowel disease", "interstitial nephritis" and "aminosalicylates". Studies were included if they reported an outcome of AIN, confirmed on biopsy, suspected to be secondary to a 5-ASA drug in those with IBD. A narrative synthesis was performed. RESULTS: Forty-one case reports were identified. Mesalazine was the most frequently reported aminosalicylate associated with AIN (95%). The median duration of treatment before AIN was diagnosed was 2.3 years (Interquartile Range (IQR) 12-48 months). The median rise in creatinine was 3.3 times the baseline measurement (IQR 2.5-5.5). Aminosalicylate withdrawal and steroids were the most frequently used treatments. Despite treatment, 15% of patients developed end-stage renal failure. CONCLUSIONS: AIN is a serious adverse drug reaction associated with aminosalicylates, with mesalazine accounting for most reports. The current guidance of annual monitoring of renal function may not be sufficient to identify cases early. Given the severity of AIN and reports in the literature that early treatment with steroids may be beneficial, we would recommend at least 6 monthly monitoring of renal function. PROSPERO registration number CRD42020205387.

Improving the experience of obtaining repeat complex paediatric prescriptions in the UK.

In the UK, medicines for chronic conditions in children and young people (CYP) are typically initiated within secondary or tertiary care, with responsibility for ongoing supply often then passed to the child's general practitioner (GP) and community pharmacist. The patient should then be reviewed in regular specialist clinics, with two-way communication for any changes in medications or clinical status undertaken between primary and secondary/tertiary care. This arrangement allows long-term medications to be obtained close to home.Although this is what parents expect, the reality is often messy, with families regularly needing to source some medicines from the GPs and others via hospitals or homecare services. In addition, these arrangements are not uniform, they vary across different areas of the UK and depend on individual GP or hospital prescriber acceptance. When neither primary, secondary or tertiary care accepts it is their responsibility to prescribe, or patients are under multiple specialists, families often feel left to navigate this complex and variable supply system themselves. Obtaining a prescription is only the start of the process for families as dispensing from a community pharmacy can also be challenging.In this article, we set out the barriers and potential solutions to this complex issue. We use the term specialist prescribers to include not only paediatricians but all other specialists looking after CYP including child and adolescent psychiatrists, ophthalmologists, dermatologists, surgeons, etc, as well as non-medical prescribers.

Reproducibility of cutaneous thermal hyperaemia assessed by laser Doppler flowmetry in young and older adults.

OBJECTIVES: The primary objective of this study was to assess the inter-day reproducibility of cutaneous thermal hyperaemia, as assessed using integrating-probe laser Doppler flowmetry (LDF), in young and older men. A secondary objective was to identify the most reproducible form of data expression. METHODS: Cutaneous thermal hyperaemia was assessed on the forearm in 14 young (25±1 year) and 14 older (65±1 year) men, using integrating-probe LDF. The test was repeated 7-14 days later. The baseline, initial peak, and plateau phases of the data traces were identified and expressed as raw cutaneous vascular conductance (CVC), CVC normalised to baseline (%CVC(BL)), and CVC normalised to 44°C vasodilatation (%CVC(MAX)). Reproducibility was assessed using the coefficient of variation (CV) and intraclass correlation coefficient (ICC) statistics. RESULTS: The inter-day reproducibility was dependent on how the data were expressed. The reproducibility of the initial peak and plateau was equally acceptable in both young and older adults when data were expressed as %CVC(MAX) (e.g., CVs ranging from 4 to 11%). However, the baseline phase was poorly reproducible in both groups irrespective of the data presentation method used (e.g., CVs ranging from 25 to 35%). Furthermore, expressing data as raw CVC or as %CVC(BL) generally showed poor reproducibility for both groups and all phases of the test (e.g., CVs ranging from 15 to 39%). CONCLUSION: Integrating-probe LDF is a reproducible technique to assess cutaneous thermal hyperaemia on the forearm when data are expressed as %CVC(MAX) in healthy young and older adults without history of hypertension or taking system drugs.

Role of sensory nerves in the rapid cutaneous vasodilator response to local heating in young and older endurance-trained and untrained men.

The ability to increase skin blood flow (SkBF) rapidly in response to local heating is diminished with advanced age; however, the mechanisms are unclear. The primary aim of this study was to investigate the role of sensory nerves in this age-related change. A secondary aim was to investigate the effect of aerobic fitness on sensory nerve-mediated vasodilatation in young and aged skin. We measured SkBF (using laser Doppler flowmetry) in young and older endurance-trained and untrained men (n= 7 in each group) at baseline and during 35 min of local skin heating to 42°C at two sites on the ventral forearm. One site was pretreated with topical anaesthetic cream to block local sensory nerve function. Cutaneous vascular conductance (CVC) was calculated as SkBF divided by mean arterial pressure and normalized to maximal values (CVC(max)) achieved during local heating to 44°C. At the untreated site, the rapid vasodilatation during the first ~5 min of local heating (initial peak) was lower in the older untrained group (68 ± 3%CVC(max)) compared with all other groups (young trained, 76 ± 4%CVC(max); young untrained, 75 ± 5%CVC(max); and older trained, 81 ± 3%CVC(max); P < 0.05). Sensory nerve blockade abolished these differences among the groups (P > 0.05). The contribution of sensory nerve-mediated vasodilatation was lower in the older untrained group compared with all other groups (P< 0.05). Our results suggest that the age-related decline in the rapid vasodilator response to local heating in human skin is explained by diminished sensory nerve-mediated vasodilatation. These findings also indicate that this age-related change can be prevented through participation in regular aerobic exercise.

The impact of paediatric dose range checking software.

OBJECTIVE: Dosing errors can cause significant harm in paediatric healthcare settings. Our objective was to investigate the effects of paediatric dose range checking (DRC) clinical decision support (CDS) software on overdosing-related outcomes. METHODS: A before-after study and a semistructured survey of prescribers was conducted across inpatient wards (excluding intensive care) in a regional children's hospital. DRC CDS software linked to a paediatric drug formulary was integrated into an existing electronic prescribing system. The main outcome measures were; the proportion of prescriptions with overdosing errors; overdosing-related clinical incidents; severity of clinical incidents; and acceptability of the intervention. RESULTS: The prescription overdosing error rate did not change significantly following the introduction of DRC CDS software: in the preintervention period 12/847 (1.4%) prescriptions resulted in prescription errors and in the postintervention period there were 9/684 (1.3%) prescription overdosing errors (n=21, Pearson χ2 value=0.028, p=0.868). However, there was a significant trend towards a reduction in the severity of harm associated with reported overdosing incidents (n=60, Mann-Whitney U value=301.0, p=0.012). Prescribers reported that the intervention was beneficial and they were also able to identify factors that may have contributed to the persistence of overdosing errors. CONCLUSION: DRC CDS software did not reduce the incidence of prescription overdosing errors in a paediatric hospital setting but the level of harm associated with the overdosing errors may have been reduced. Use of the software seemed to be safe and it was perceived to be beneficial by prescribers.

A visual analog scale for the assessment of mild sleepiness in patients with obstructive sleep apnea and healthy participants.

MOTIVATION: Studies have shown poor clinical effectiveness of the Epworth Sleepiness Scale (ESS) due to its ambiguity of items and cultural applicability. This study aimed to investigate the efficacy of a Visual Analog Scale (VAS) to assess sleepiness, compared to ESS. METHODS: Thirty-two obstructive sleep apnea (OSA) patients and 32 healthy participants completed two visits, 1 month apart, during which they completed both ESS and VAS. Patients diagnosed with OSA were treated with Continuous positive airway pressure (CPAP) between visits. The agreement between the ESS and VAS scores in both patients with OSA and healthy participants was investigated using Pearson correlation and Area Under the receiver operating characteristics. RESULTS: The (mean ± standard deviation) Oxygen Desaturation Index for patients with OSA was 18.5 ± 5.7 events/hour and 1.7 ± 1.0 events/hour in the healthy participants. A reduction in sleepiness, following CPAP treatment occurred in patients with OSA, using the ESS (11.2 ± 5.5-4.7 ± 5.0 points, P < 0.001) and the VAS (50.2 ± 3.0-21.9 ± 26.5 mm, P < 0.001). There was no significant change in sleepiness, in healthy participants using the ESS (3.91 ± 3.14-3.34 ± 3.27 points (P < 0.48) or the VAS (15.58 ± 21.21-12.05 ± 14.75 mm, (P < 0.44). A Likert scale showed that the VAS was easier to use compared to ESS in visit 1 (VAS: 8.7 ± 1.9 points, ESS: 7.7 ± 2.6 points, (P < 0.001), and visit 2 (VAS: 9.5 ± 1.4 points, ESS: 8.6 ± 1.5 points, P < 0.001). CONCLUSION: These preliminary results suggest that the VAS can detect a change in sleepiness after CPAP treatment in patients with OSA and that the VAS was also easier to use compared to ESS.

Open Fractures: Are We Still Treating the Same Types of Infections?

Background: To analyze the rate of methicillin-resistant Staphylococcus aureus (MRSA), gram-negative, and polymicrobial infections in open fractures, measure the efficacy of the current open fracture antibiotic regimen against these infections, identify the most effective agent(s) to cover these infections, and analyze risk factors for infection. Methods: We examined retrospectively 451 patients with open fractures from January 2008 to December 2012 who were treated at our facility. Positive cultures during surgical debridement after wound closure defined an infection. Infecting organisms and their antibiotic sensitivities were identified through microbiology culture reports. Rates of MRSA, gram-negative, and polymicrobial infections were determined. The efficacy of the current regimen (cefazolin and gentamicin) was calculated against gram-positive and gram-negative organisms. Efficacy profiles against infectious organisms were calculated for all commonly tested antibiotics. Patient factors, injury characteristics, and treatment options were analyzed to determine risk factors for infection. Results: Ninety patients (20%) were identified as infected at surgical debridement. Of those 90, 21 (23.3%) were diagnosed with MRSA, 56 (62.2%) were found to have a gram-negative infection, and 46 (51.1%) had polymicrobial infections. Cephalosporins and ß-lactam agents had a 59.2% efficacy rate against gram-positive bacteria and gentamicin showed a 94% sensitivity rate against gram-negative bacteria. Vancomycin (95.8% sensitivity) demonstrated the highest sensitivity for all gram-positive organisms. Amikacin (98.8% sensitivity), meropenem (96.3% sensitivity), and gentamicin (94.2% sensitivity) demonstrated excellent efficacy for all gram-negative organisms. Immuno-compromised status and Gustilo-Anderson type were the only independently predictive risk factors for infection in a multivariable model. Conclusions: Based on this analysis, the rate of MRSA, gram-negative, and polymicrobial infections in open fractures is high and increasing compared with historical cohorts. With the sensitivity of early generation cephalosporins being relatively poor against gram-positive organisms, the present antibiotic regimen for open, long-bone fractures may need to be reconsidered with these emerging trends.

Insulin-like growth factor-1 protects preimplantation embryos from anti-developmental actions of menadione.

Menadione is a naphthoquinone used as a vitamin K source in animal feed that can generate reactive oxygen species (ROS) and cause apoptosis. Here, we examined whether menadione reduces development of preimplantation bovine embryos in a ROS-dependent process and tested the hypothesis that actions of menadione would be reduced by insulin-like growth factor-1 (IGF-1). Menadione caused a concentration-dependent decrease in the proportion of embryos that became blastocysts. All concentrations tested (1, 2.5, and 5.0 microM) inhibited development. Treatment with 100 ng/ml IGF-1 reduced the magnitude of the anti-developmental effects of the two lowest menadione concentrations. Menadione also caused a concentration-dependent increase in the percent of cells positive for the TUNEL reaction. The response was lower for IGF-1-treated embryos. The effects of menadione were mediated by ROS because (1) the anti-developmental effect of menadione was blocked by the antioxidants dithiothreitol and Trolox and (2) menadione caused an increase in ROS generation. Treatment with IGF-1 did not reduce ROS formation in menadione-treated embryos. In conclusion, concentrations of menadione as low as 1.0 muM can compromise development of bovine preimplantation embryos to the blastocyst stage of development in a ROS-dependent mechanism. Anti-developmental actions of menadione can be blocked by IGF-1 through effects downstream of ROS generation.