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Introduction Carotid webs are a rare form of focal fibromuscular dysplasia and a possible cause of ischaemic stroke. They are defined as an abnormal shelf-like projection of intimal fibrous tissue into the carotid bulb. We reviewed patients found to have carotid webs at our unit over a 12-year period. Methods Radiology reports of all cross-sectional imaging from 2010-2021 were searched for the phrase carotid web. Images were reviewed to confirm the finding. Patients with previous carotid intervention were excluded. Electronic patient records were reviewed to establish presenting symptoms, diagnosis, management and stroke recurrence. Results 60 patients with carotid webs were identified. Ages ranged from 36-92 years. The gender ratio was 31 male:29 female. 29 patients had left-sided carotid webs, 22 right-sided and 9 bilateral. No patients had a pre-event diagnosis of fibromuscular dysplasia. 27 patients had an ischaemic intracerebral event - 18 in the territory relevant to the web location and nine in other territories. 1 patient was treated with thrombolysis, 1 with thrombectomy and 1 with thrombolysis and thrombectomy. None underwent carotid intervention. Of the 18 patients with a carotid web on the ipsilateral side to their ischaemic event, none had a repeat event recorded. Conclusion 30% of patients had an ischaemic event corresponding to the territory supplied by a carotid artery with a web. Current management of carotid webs favours conservative management with antiplatelet therapy. However, these data suggest carotid intervention should be considered in selected patients where stroke symptoms correlate to the laterality of the carotid web.

The Fort Cobb Reservoir Experimental Watershed (FCREW) and Little Washita River Experimental Watershed (LWREW), located within the Upper Washita Basin (UWB) in Oklahoma, are part of the Agricultural Research Service (ARS) Benchmark Conservation Effects Assessment Project (CEAP)–Watershed Assessment Studies locations. The CEAP was created in 2003 by the USDA Natural Resources Conservation Service (NRCS) in partnership with USDA ARS and many other partners to quantify the environmental effects of conservation practices (CPs) and programs and to develop the science base for managing the agricultural landscape for environmental quality. The ultimate goal of this study was to present CPs that are expected to work at respective spatial scales, based on the findings of research that has been carried out in these CEAP and other watersheds within the UWB in the last 15 years. A summary of research findings indicates that the effects of CPs on soil and water resources were simulated at various spatial scales. At the large watershed scale, average annual suspended sediment yield at the 786 km2 (303 mi2) FCREW outlet was reduced by 86% based on multiple CPs implemented from the 1950s to 2008 by NRCS. Specific quantified effects of studied CPs are presented herein. With the exception of red cedar (Juniperus virginiana L.) removal, single CPs were expected to show improvement of soil and water resources in smaller-scale watersheds. Practices that are expected to improve soil and water resources include grassland conservation from red cedar encroachment (brush control), combined streambank stabilization practices, riparian and filter strip buffer practices, and conversion of cropped area to Bermuda grass (Cynodon dactylon [L.] Pers.).

BACKGROUND: We implemented an observation unit and home oxygen therapy (OU-HOT) protocol at our children’s hospital during the 2010-2011 winter season to facilitate earlier discharge of children hospitalized with bronchiolitis. An earlier study demonstrated substantial reductions in inpatient length of stay and costs in the first year after implementation. OBJECTIVE: Evaluate long-term reductions in length of stay and cost. DESIGN, SETTING, AND PARTICIPANTS: Interrupted time-series analysis, adjusting for patient demographic factors and disease severity. Participants were children aged 3 to 24 months and hospitalized with bronchiolitis from 2007 to 2019. INTERVENTION: OU-HOT protocol implementation. MAIN OUTCOME AND MEASURES: Hospital length of stay. Process measures were the percentage of patients discharged from the OU; percentage of patients discharged with HOT. Balancing measures were 7-day hospital revisit rates; annual per-population bronchiolitis admission rates. Secondary outcomes were inflation-adjusted cost per episode of care and discharges within 24 hours. RESULTS: A total of 7,116 patients met inclusion criteria. The OU-HOT protocol was associated with immediate decreases in mean length of stay (–30.6 hours; 95% CI, –37.1 to –24.2 hours) and mean cost per episode of care (–$4,181; 95% CI, –$4,829 to –$3,533). These findings were sustained for 9 years after implementation. Hospital revisit rates did not increase immediately (–1.1% immediate change; 95% CI, –1.8% to –0.4%), but a small increase in revisits was observed over time (change in slope 0.4% per season, 95% CI, 0.1%-0.8%). CONCLUSION: The OU-HOT protocol was associated with sustained reductions in length of stay and cost, representing a promising strategy to reduce the inpatient burden of bronchiolitis.

Aims Tildrakizumab, an interleukin (IL)-23 inhibitor, is indicated for the treatment of moderate to severe chronic plaque psoriasis. Although tildrakizumab is not metabolized by, and does not alter, cytochrome P450 (CYP) expression in vitro, clinically significant pharmacokinetic effects through changes in systemic inflammation, which alters CYP metabolism, have been well documented. At the time of study conduct, the effect of modulation of inflammation/cytokines, including IL-23 inhibition with tildrakizumab, on CYP metabolism, and therefore the potential for disease-drug interactions, in psoriasis patients was unknown. We therefore assessed whether tildrakizumab alters CYP metabolism in subjects with moderate to severe psoriasis. Methods This was an open-label, fixed-sequence, two-period trial. In Period 1 (Day 1), subjects received an oral CYP probe cocktail of up to five drugs (midazolam 2 mg [3A4], caffeine 200 mg [1A2], warfarin 10 mg [2C9], omeprazole 40 mg [2C19] and dextromethorphan 30 mg [2D6]), followed by a 7-day washout. In Period 2, subjects received tildrakizumab 200 mg subcutaneously on Days 1 and 29 and a second CYP probe cocktail on Day 57. Substrate or metabolite pharmacokinetics, safety and changes in Psoriasis Severity Area Index (PASI), interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hs-CRP), were assessed. Results Twenty subjects (13 men, 7 women) were enrolled. Tildrakizumab had no clinically relevant effect on the pharmacokinetics of any of the probe substrates tested. On Day 57 of Period 2, the median percentage decrease from baseline in PASI score following tildrakizumab was ~93%. There were no clinically relevant changes in IL-6 or hs-CRP. Treatment with tildrakizumab was generally well tolerated. Conclusion In subjects with moderate to severe psoriasis, tildrakizumab 200 mg did not have a discernible effect on CYP metabolism. The potential for clinically significant drug-drug interactions (DDIs) with tildrakizumab in patients with psoriasis is low. The difference in the occurrence of DDIs seen with anti-inflammatory agents in rheumatoid arthritis patients compared with psoriasis patients may be due to the much greater extent of systemic inflammation in rheumatoid arthritis as compared to psoriasis.

Medical students must gain proficiency with the complex skill of case presentations, yet current approaches to instruction are fragmented and often informal, resulting in suboptimal transfer of this skill into clinical practice. Whole task approaches to learning have been proposed to teach complex skill development. The authors describe a longitudinal case presentation curriculum developed using a whole task approach known as four-component instructional design (4-C/ID). 4‑C/ID is based on cognitive psychology theory, and carefully attends to titrating a learner’s cognitive load, aiming to always keep students in their zone of proximal development. A multi-institutional group of medical educators convened to develop expert consensus regarding case presentation instruction using the 4‑C/ID model. A curriculum consisting of 1) learning tasks, 2) supportive information, 3) just-in-time information, and 4) part-task practice was developed. Domains were identified that make the task of delivering a case presentation complex. A simplifying conditions approach was applied to each domain to develop sequential task class descriptions. Examples of the four components are given to facilitate understanding of the 4‑C/ID model, making it more accessible to medical educators. Applying 4‑C/ID to curriculum development for the complex skill of case presentation delivery may optimize instruction. The provision of the complete curricular outline may facilitate transfer and implementation of this case presentation curriculum, as well as foster the application of 4‑C/ID to other complex skill development in medical education. Electronic supplementary material The online version of this article (10.1007/s40037-018-0443-8) contains supplementary material, which is available to authorized users.

Background In Australia, Hepatitis C Virus (HCV) treatment is declining, despite broad access to direct-acting antiviral medication. People who inject drugs are proportionally over-represented in emergency department presentations. Emergency department assessment of people who have injected drugs for HCV presents an opportunity to engage this marginalised population with treatment. We describe the outcomes of risk-based screening and point-of-care anti-HCV testing for emergency department patients, and linkage to outpatient antiviral treatment. Methods During the three-month study period, consecutive adult patients who presented to the emergency department during the study times were screened for risk factors and offered the OraQuick oral HCV antibody test. Those with reactive results were offered venepuncture in the emergency department for confirmatory testing and direct-acting antiviral treatment in clinic. The main outcome measures were the number and proportion of viremic participants that were linked to the hepatitis clinic, commenced treatment and achieved a sustained viral response. Secondary outcome measures were the proportion (%) of presentations screened that were oral antibody reactive, and the prevalence and type of HCV risk factors. Results During the study period, 2408 of the 3931 (61%) presentations to the emergency department were eligible for screening. Of these 2408 patients, 1122 (47%) participated, 307 (13%) declined participation and 977 (41%) could not be approached during their time in the emergency department. Among the 1122 participants, 378 (34%) reported at least one risk factor. Subsequently, 368 (97%) of the 378 participants underwent OraQuick anti-HCV test, and 50 (14%) had a reactive result. A risk factor of ever having injected drugs was present in 44 (88%) of participants who were sero-positive. Of the 45 that had blood tested, 30 (67%) were HCV ribonucleic acid (RNA) positive. Three participants died. Of the 27 remaining participants, 10 (37%) commenced treatment and 7 of these 10 (70%) obtained a cure. There was a high rate of homelessness (24%) among anti-HCV positive participants. Conclusion Among emergency department participants with a risk factor for HCV, positive serology was common using a rapid point-of-care test. A history of injecting drug use was identified as the risk factor with highest yield for positive HCV serology, and is suitable as a single screening question. However, linkage to care post ED presentation was low in this marginalised population. There is a need for new pathways to improve the care cascade for marginalised individuals living with HCV infection.

The pharmacokinetics (PK), and pharmacodynamics (PD) of omarigliptin, a novel once-weekly DPP-4 inhibitor, were assessed following single and multiple doses in healthy subjects. Absorption was rapid and food did not influence single dose PK. Accumulation was minimal and steady state was reached after 2-3 weeks. Weekly AUC and Cmax displayed dose proportionality within the dose range studied at steady state. The average renal clearance of omarigliptin was ~2 L/h. DPP-4 inhibition ranged from ~77-89% at 168 hours following the last of 3 once-weekly doses over the dose range studied. Omarigliptin resulted in ~2-fold increases in weighted average post-prandial active GLP-1. Omarigliptin acts by stabilizing active GLP-1, which is consistent with its mechanism of action as a DPP-4 inhibitor. Administration of omarigliptin was generally well tolerated in healthy subjects, and both the PK and PD profile support once-weekly dosing. A model-based assessment of QTc interval risk from the single ascending dose study indicated low risk of QTc prolongation within the likely clinical dose range ispartof: Journal of Clinical Pharmacology vol:56 issue:12 pages:1528-1537 ispartof: location:England status: published

Omarigliptin is a dipeptidyl peptidase-4 inhibitor being developed as a once-weekly treatment for type 2 diabetes. This double-blind, double-dummy, randomized, 3-period balanced crossover study definitively evaluated the effects of a supratherapeutic omarigliptin dose on QTc interval. Population-specific correction of QT interval (QTcP) was used for the primary analysis. Healthy subjects (n = 60) were enrolled and received treatments separated by a ≥4-week washout: (1) single-dose 25 mg omarigliptin (day 1), single-dose 175 mg omarigliptin (day 2); (2) placebo (day 1) followed by single-dose 400 mg moxifloxacin (day 2); (3) placebo (days 1 and 2). Day 2 QTcP intervals were analyzed. The primary hypothesis was supported if the 90%CIs for the least-squares mean differences between omarigliptin 175 mg and placebo in QTcP interval change from baseline were all < 10 milliseconds at every postdose point on day 2. The upper bounds of the 90%CIs for the differences (omarigliptin-placebo) in QTcP change from baseline for omarigliptin 175 mg were < 10 milliseconds at all postdose times on day 2. In conclusion, a supratherapeutic dose of omarigliptin does not prolong the QTcP interval to a clinically meaningful degree relative to placebo, confirming the results of the earlier concentration-QTc analysis.

Omarigliptin is being developed as a potent, once-weekly, oral dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes. This double-blind, randomized, placebo-controlled study evaluated the effects of age, sex, and obesity on the pharmacokinetics of omarigliptin in healthy subjects. A single oral dose of omarigliptin 10 mg (n = 6/panel) or placebo (n = 2/panel) was administered in the fasted state to elderly nonobese men and women, young obese (30 ≤ body mass index [BMI] ≤ 35 kg/m(2) ) men and women, and young nonobese women of nonchildbearing potential. Plasma was collected at selected postdose times for evaluation of omarigliptin concentrations. Pharmacokinetic parameters were compared with historical data from a previously-conducted single-dose study in young, healthy, nonobese men. There were no clinically significant differences in omarigliptin AUC0-∞ , the primary pharmacokinetic parameter for assessing efficacy and safety, based on age, sex, or BMI (pooled nonobese elderly versus pooled nonobese young, young nonobese female versus young nonobese male, and pooled young obese versus pooled young nonobese). There were no serious adverse events or hypoglycemic events attributable to omarigliptin administration. Demographic factors and BMI had no meaningful effect on omarigliptin pharmacokinetics, suggesting that dose adjustment based on age, sex, or obesity is not required.

Purpose Omarigliptin (MK-3102) is a potent, oral, long-acting dipeptidyl peptidase (DPP)-4 inhibitor approved in Japan and in global development as a once-weekly treatment for type 2 diabetes mellitus (T2DM). The aim of this study was to investigate the pharmacokinetic (PK) and pharmacodynamic (PD) effects of omarigliptin in obese participants with and without T2DM. Methods This was a Phase I, randomized, double-blind, placebo-controlled, multiple-dose study of 50-mg omarigliptin administered once weekly for 4 weeks. Participants included 24 obese but otherwise healthy subjects (panel A; omarigliptin, n=18; placebo, n=6) and 8 obese patients with T2DM (treatment naive, hemoglobin A 1c ≥6.5% and ≤10.0% [panel B]; omarigliptin, n=6; placebo, n=2). Participants were 45 to 65 years of age with a body mass index of ≥30 and ≤40 kg/m 2 . Blood sampling occurred at select time points, depending on the study panel, to evaluate the PK properties of omarigliptin, DPP-4 activity, active glucagon-like peptide 1 levels, and plasma glucose concentrations. Body weight was an exploratory end point. Due to sparse sampling in panel A, a thorough PK analysis was performed in obese patients with T2DM (panel B) only. PD analyses were performed in the overall study population (pooled panels A and B). Findings PK profiles in obese participants with and without T2DM were similar to those observed in nonobese reference subjects (historical data). Steady state was achieved after 1 or 2 weekly doses in obese participants with and without T2DM. In obese patients with T2DM, omarigliptin was rapidly absorbed, with a median T max of 1 to 2.5 hours (days 1 and 22). Compared with those in reference subjects, the geometric mean ratios (95% CI) (Obese T2DM/reference) for steady-state plasma AUC 0–168h , C max, and C 168h were 0.80 (0.65–0.98), 0.86 (0.53–1.41), and 1.08 (0.88–1.33), respectively. Trough DPP-4 activity was inhibited by ~90%; postprandial (PP) 4-hour weighted mean active GLP-1 concentrations were increased ~2-fold; and PP glucose was significantly reduced with omarigliptin versus placebo in the pooled population. Omarigliptin was generally well-tolerated in the pooled population, and there were no hypoglycemic events. Consistent with other DPP-4 inhibitors, omarigliptin had no effect on body weight in this short-duration study. Implications The administration of omarigliptin was generally well-tolerated in obese participants with and without T2DM, and the favorable PK and PD profiles support once-weekly dosing. Omarigliptin may provide an important once-weekly treatment option for patients with T2DM. ClinicalTrials.gov identifier: NCT01088711.

AIMS: Tildrakizumab, an interleukin (IL)‐23 inhibitor, is indicated for the treatment of moderate to severe chronic plaque psoriasis. Although tildrakizumab is not metabolized by, and does not alter, cytochrome P450 (CYP) expression in vitro, clinically significant pharmacokinetic effects through changes in systemic inflammation, which alters CYP metabolism, have been well documented. At the time of study conduct, the effect of modulation of inflammation/cytokines, including IL‐23 inhibition with tildrakizumab, on CYP metabolism, and therefore the potential for disease–drug interactions, in psoriasis patients was unknown. We therefore assessed whether tildrakizumab alters CYP metabolism in subjects with moderate to severe psoriasis. METHODS: This was an open‐label, fixed‐sequence, two‐period trial. In Period 1 (Day 1), subjects received an oral CYP probe cocktail of up to five drugs (midazolam 2 mg [3A4], caffeine 200 mg [1A2], warfarin 10 mg [2C9], omeprazole 40 mg [2C19] and dextromethorphan 30 mg [2D6]), followed by a 7‐day washout. In Period 2, subjects received tildrakizumab 200 mg subcutaneously on Days 1 and 29 and a second CYP probe cocktail on Day 57. Substrate or metabolite pharmacokinetics, safety and changes in Psoriasis Severity Area Index (PASI), interleukin‐6 (IL‐6) and high‐sensitivity C‐reactive protein (hs‐CRP), were assessed. RESULTS: Twenty subjects (13 men, 7 women) were enrolled. Tildrakizumab had no clinically relevant effect on the pharmacokinetics of any of the probe substrates tested. On Day 57 of Period 2, the median percentage decrease from baseline in PASI score following tildrakizumab was ~93%. There were no clinically relevant changes in IL‐6 or hs‐CRP. Treatment with tildrakizumab was generally well tolerated. CONCLUSION: In subjects with moderate to severe psoriasis, tildrakizumab 200 mg did not have a discernible effect on CYP metabolism. The potential for clinically significant drug–drug interactions (DDIs) with tildrakizumab in patients with psoriasis is low. The difference in the occurrence of DDIs seen with anti‐inflammatory agents in rheumatoid arthritis patients compared with psoriasis patients may be due to the much greater extent of systemic inflammation in rheumatoid arthritis as compared to psoriasis.

Non-parasitic splenic cysts are rare entities. In pregnancy, they are rarer still, with as few as seven cases reported in the literature. There is little consensus regarding the optimal management of this condition in pregnancy. Although small, the theoretical risk of intrapartum splenic rupture is associated with a fetal mortality rate as high as 70%. The authors of at least three case reports advocate total splenectomy as first-line management of splenic cyst in pregnancy. Paradoxically, spleen conserving surgery is the recognised gold standard treatment for symptomatic splenic cysts in non-pregnant patients. We present a case of a large maternal splenic cyst that was treated successfully with a laparoscopic cystectomy.

The purpose of this study was to analyse the midterm outcomes of an accelerated rehabilitation programme for unicompartmental knee arthroplasty. One hundred and six patients (187 knees) underwent a minimally invasive Phase 3 Oxford unicompartmental knee arthroplasty with an accelerated rehabilitation programme and were followed over the first 5 years. The emphasis of the programme was pre-operative patient education, multidisciplinary discharge planning and early rehabilitation. On retrospective analysis, patients reported a significant improvement in functional outcomes and quality of life in respect of Oxford knee score, American knee score and short form-12 outcomes (P

Summary Implementation of national guidelines for the prevention of group B streptococcal (GBS) infections has led to an increase in intrapartum antibiotic use and reduction in early-onset GBS infections in newborns. Other outcomes, including the clinical diagnosis of sepsis in term infants, treatment with antibiotics, length of stay, and cost have not been described. To examine these outcomes, we performed an analysis of maternal and newborn data collected between 1998 and 2002 of 130 447 in-hospital births of newborns ≥37 weeks gestation and their mothers from a large vertically integrated healthcare organisation in Utah. The main outcome measures included: (i) the number of women delivering at term who received intravenous antibiotics; (ii) the number of newborns treated for ‘clinical sepsis’, which was defined as receiving antibiotics for >72 h and the number of newborns who received antibiotics for ≤48 h, i.e. a ‘rule-out-sepsis’ course. We also compared the lengths of stay and variable costs of infants whose mothers received antibiotics with those whose mothers did not. We found that the proportion of mothers who received intravenous antibiotics rose from 26.8% in 1998 to 40.6% in 2002 (P

Isolated patellofemoral osteoarthritis is now recognised to be more common than previously thought. The features and management are reviewed, including the various surgical options in symptomatic patients. The evidence base for managing patellofemoral osteoarthritis is behind that for the tibiofemoral joint. All treatments are based on uncontrolled observational case series, typically retrospectively reviewed. Fortunately the majority of patients with isolated patellofemoral degenerative changes do not need surgical treatment. Those who are symptomatic can usually be successfully treated with weight loss and quadriceps strengthening exercises.

Referrals for deformational plagiocephaly (DP) have increased, but estimates of its actual prevalence vary, depending on the population studied and criteria for diagnosis. Few studies employ an objective technique for diagnosis. The objectives of this study were to validate the Transcranial Diameter Difference (TDD) and, using it, determine the prevalence of DP among infants seen by primary care pediatricians. We determined the TDD of 32 infants referred to a craniofacial clinic for DP; blinded to the TDD a craniofacial surgeon assigned a DP severity score. We compared the TDD and severity scores. The TDD of 192 infants presenting to primary care practices (PCP) were determined and their parents completed a DP risk factor questionnaire. Odds ratios for associations of risk factors with DP were calculated. The correlation between TDD and DP severity score was 0.61 (P = 0.002). All infants whose TDD0.6 cm had a severity score2; 18.2% of the 192 infants had DP as defined by a TDD0.6 cm. Significant odds ratios (95% confidence intervals) for the presence of DP were sleeping supine, 3.5; (1.6, 7.5), and infant head position preference 2.2; (1.0, 4.9). Varying the sleep position decreased the risk of DP, OR = 0.40 (0.2, 0.9). We conclude that the TDD is a valid, objective measure of DP for use in research studies. DP is present in nearly one in five PCP infants. Because an infant who prefers to hold his head in one position is more likely to have DP, advising parents to vary the head position may reduce the risk of DP.

The aim of this comparative study was to examine the potential advantage of the tunnel view radiograph over a series of weight bearing antero-posterior (AP), lateral and skyline radiographs. The study population consisted of 240 subjects with knee pain aged 19 to 93 years. A total of 309 knees had a weight bearing AP in extension, lateral, skyline and tunnel view radiographs. Each radiograph was reported with respect to features related to osteoarthritis, modified from the Ahlback system. Each feature was assessed using the tunnel radiograph alone and then the AP, lateral and skyline views in combination without, and blind to, the information from the tunnel view. On the basis of Bowker's test, the tunnel view was more likely to pick up abnormal intercondylar notch and tibial spine osteophytes but not loose bodies. We conclude that the tunnel view is a valuable addition in the routine assessment of the knee joint in osteoarthritis but not for the diagnosis of loose bodies alone.

Fire has often been shown to promote invasion by non-native plant species, but few studies have examined the process in temperate-zone deciduousforests.Toexaminethepotentialofprescribedfiretofacilitate invasionsintheCentralHardwoodsecosystem,weexperimentallyburned small plots and simulated aspects of fire at a forested site in southeastern Ohio, USA. Treatments included high and low burn intensity, lime addition, and litter removal to test hypotheses of population limitation by fire intensity, fire-caused nutrient release, and removal of leaf litter, respectively. Treatments were arranged in a randomized block design in two landscape positions (dry upland, moist lowland) and two canopy conditions (gap, no gap). The experimental sites were not significantly different from randomly chosen forest sites in any of 12 environmental variables. Seeds of two problematic non-native species (Microstegium vimineum and Rosa multiflora) were sown into plots following treatment to test the possibility of seed limitation. We recorded germination and height growth at three dates 1, 4, and 14 months following burning. Germination was promoted by litter removal and high- and low-intensity fire treatments in M. vimineum, and by high-intensity fire in R. multiflora. Seedling growth of both species was greatest following high-intensity fire under canopy gaps. Germination in the second year showed treatment effects similar to the first year indicating persistence of fire effects. Both species showed stronger recruitment in valleys and in canopy gaps, reflecting an interaction of fire and landscape position. We infer that prescribed burning and canopy-opening management practices have the potential to facilitate invasion of the study area by creating conditions promoting establishment and growth of at least two non-native species. The absence of these species in previous studies appears to be due to a lack of propagules rather than the unsuitability of forest sites for germination or growth.

Omarigliptin is being developed as a potent, once-weekly, oral dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes. This double-blind, randomized, placebo-controlled study evaluated the effects of age, sex, and obesity on the pharmacokinetics of omarigliptin in healthy subjects. A single oral dose of omarigliptin 10 mg (n = 6/panel) or placebo (n = 2/panel) was administered in the fasted state to elderly nonobese men and women, young obese (30 ≤ body mass index [BMI] ≤ 35 kg/m(2) ) men and women, and young nonobese women of nonchildbearing potential. Plasma was collected at selected postdose times for evaluation of omarigliptin concentrations. Pharmacokinetic parameters were compared with historical data from a previously-conducted single-dose study in young, healthy, nonobese men. There were no clinically significant differences in omarigliptin AUC0-∞ , the primary pharmacokinetic parameter for assessing efficacy and safety, based on age, sex, or BMI (pooled nonobese elderly versus pooled nonobese young, young nonobese female versus young nonobese male, and pooled young obese versus pooled young nonobese). There were no serious adverse events or hypoglycemic events attributable to omarigliptin administration. Demographic factors and BMI had no meaningful effect on omarigliptin pharmacokinetics, suggesting that dose adjustment based on age, sex, or obesity is not required.

Objective. Recommendations to prevent vertical transmission of group B Streptococcus (GBS) infections have resulted in many women's receiving antibiotics during labor with an associated reduction in early-onset GBS infections in their newborn infants. However, a potential relationship of intrapartum antibiotics (IPA) to the occurrence of late-onset (7–90 days) serious bacterial infections (SBIs) in term infants has not been reported. The objectives of this study were to determine whether infants with late-onset SBI were more likely than healthy control infants to have been exposed to IPA and whether there was a greater likelihood of antibiotic resistance in bacteria that were isolated from infants who had an SBI and had been exposed to IPA compared with those who had not.Methods. We used a case-control design to study the first objective. Cases were previously healthy full-term infants who were hospitalized for late-onset SBI between the ages of 7 and 90 days. Control subjects were healthy full-term infants who were known not to have an SBI in their first 90 days. Cases and control subjects were matched for hospital of delivery. In the second part of the study, rates of antibiotic resistance of bacteria that were isolated from infected infants were compared for those who had and had not been exposed to IPA.Results. Ninety case infants and 92 control subjects were studied. Considering all types of IPA, more case (41%) than control infants (27%) had been exposed to IPA (adjusted odds ratio [OR]: 1.96; 95% confidence interval [CI]: 1.05–3.66), after controlling for hospital of delivery. The association was stronger when IPA was with broad-spectrum antibiotics (adjusted OR: 4.95; 95% CI: 2.04–11.98), after controlling for hospital of delivery, penicillin IPA, maternal chorioamnionitis, and breastfeeding. Bacteria that were isolated from infected infants who had been exposed to IPA were more likely to exhibit ampicillin resistance (adjusted OR: 5.7; 95% CI: 2.3–14.3), after controlling for hospital of delivery, but not to other antibiotics that are commonly used to treat SBI in infants.Conclusions. After adjusting for potential confounders, infants with late-onset SBI were more likely to have been exposed to IPA than noninfected control infants. Pathogens that cause late-onset SBI were more likely to be resistant to ampicillin when the infant had been exposed to intrapartum antibiotics.

In a prospective blinded non-randomised cohort study, 32 patients were assessed following anterior cruciate ligament reconstruction using autograft middle-third bone-patellar tendon-bone, over a period of 10 months. Two experienced surgeons performed the procedures, one using an arthroscopically assisted technique (16 patients) and the other by mini-arthrotomy (16 patients). A comparison was made between the positions of the tunnels as perceived by the surgeon intra-operatively with the actual position as shown on the post-operative X-ray. An independent blinded observer made the latter assessment. Actual vs. expected tunnel placement was analysed using the coefficient of correlation. The anteroposterior femoral tunnel position indicated perfect correlation (R(2)=1.00, P=0), and on the lateral view showed good correlation (R(2)=0.55, P=0.005). However, the tibial tunnel position anteroposteriorly showed poor correlation (R(2)=0.14, P=0.22), and on the lateral view no correlation (R(2)=0.07, P=0.36). The ideal tibial tunnel position is controversial, and in this study, two tibial tunnels were just anterior to the acceptable position and one was posterior. Altogether these three, and one other, were in very different positions to that expected by the surgeon. Surgeons may consider that before drilling the tibial tunnel, intra-operative confirmation of the guide-wire position would be helpful.

Background. Intrapartum antibiotic prophylaxis against group B Streptococcus (GBS) has reduced the occurrence of serious bacterial infections (SBI) in young infants caused by GBS. Recommendations for initial antibiotic therapy for the febrile infant 1 to 90 days old were developed when infections with GBS were common and antibiotic resistance was rare.Objective. To document the pathogens responsible for SBI in recent years in febrile infants 1 to 90 days old and the antibiotic susceptibility of these organisms.Methods. The results of bacterial cultures from infants 1 to 90 days old evaluated for fever at Primary Children’s Medical Center in Salt Lake City, Utah, between July 1999 and April 2002 were analyzed. Antibiotic susceptibility profiles were collected and patient records were reviewed to determine if initial antibiotic therapy was changed following the identification of the organism.Results. Of 1298 febrile infants enrolled from the Primary Children’s Medical Center emergency department, 105 (8%) had SBI. The mean age of the infants with SBI was 39 days (range 2–82 days) and 2 (2%) were Of the 105 pathogens, 56 (53%) were resistant to ampicillin. Of the pathogens causing meningitis, UTI, and bacteremia, 78%, 53%, and 50%, respectively, were resistant to ampicillin. Antibiotic therapy was changed in 54% of cases of SBI following identification of the organism.Conclusions. In Utah, ampicillin-resistant Gram-negative bacteria are the most common cause of SBI in febrile infants

Purpose Bronchiolitis is the most common cause of illness leading to hospitalization in young children. At present, many bronchiolitis management decisions are made subjectively, leading to significant practice variation among hospitals and physicians caring for children with bronchiolitis. To standardize care for bronchiolitis, researchers have proposed various models to predict the disease course to help determine a proper management plan. This paper reviews the existing state of the art of predictive modeling for bronchiolitis. Predictive modeling for respiratory syncytial virus (RSV) infection is covered whenever appropriate, as RSV accounts for about 70% of bronchiolitis cases. Methods A systematic review was conducted through a PubMed search up to April 25, 2014. The literature on predictive modeling for bronchiolitis was retrieved using a comprehensive search query, which was developed through an iterative process. Search results were limited to human subjects, the English language, and children (birth to 18 years). Results The literature search returned 2312 references in total. After manual review, 168 of these references were determined to be relevant and are discussed in this paper. We identify several limitations and open problems in predictive modeling for bronchiolitis, and provide some preliminary thoughts on how to address them, with the hope to stimulate future research in this domain. Conclusions Many problems remain open in predictive modeling for bronchiolitis. Future studies will need to address them to achieve optimal predictive models.

Anterior knee pain due to dysplasia of the extensor mechanism is common. We have studied 137 knees (103 patients) in order to identify a rapid and reproducible radiological feature which would indicate the need for further analysis. Overall, 67 knees (49%) had at least one radiological abnormality; 70 (51%) were considered normal. There were five cases of Dejour type-3 dysplasia of the femoral trochlea, nine of type-2 and 12 of type-1. There were 49 cases of patella alta and five of patella infera. Four knees had an abnormal lateral patellofemoral angle (patellar tilt), and in 15 knees there was more than one abnormality. Classification of trochlear dysplasia was difficult and showed poor reproducibility. This was also true for the measurement of the lateral patellofemoral angle. Patellar height was more easily measured but took time. The sulcus angle is an easily and rapidly measurable feature which was reproducible and was closely related to other features of dysplasia of the extensor mechanism. The finding of a normal sulcus angle suggested that seeking other radiological evidence of malalignment of the extensor mechanism was unlikely to reveal additional useful information. The severity of other features of dysplasia of the extensor mechanism correlated with increasing sulcus angle.

We took posteroanterior weight-bearing radiographs, both with the joint fully extended and in 30° of flexion, in a consecutive series of 50 knees in 37 patients referred for the primary assessment of pain and/or stiffness. These radiographs were reported ‘blind’ both by an orthopaedic surgeon and a radiologist. Direct measurement of the joint space, together with grading of the severity of erosion according to the Ahlback criteria, was undertaken. Any other abnormality present was also documented. The radiographs of the knees in 30° of flexion consistently showed more advanced erosion in both the medial (p = 0.001) and the lateral (p = 0.0001) tibiofemoral compartments, when compared with those of knees in full extension. The Ahlback classification of 25 joints was altered, in some cases by several grades, by the flexed position of the joint. In every case in which another abnormality was identified on the radiograph in full extension, it was also noted on that of the knee in 30° of flexion. In a further four cases, additional pathology could only be seen in the flexed knee. Every patient was able to complete the radiological examination without difficulty. Our study supports the adoption of a weight-bearing view in 30° of flexion as the standard posteroanterior radiograph for the assessment of tibiofemoral osteoarthritis in patients over 50 years of age.

A 12-year-old boy presented with 3 weeks of calf pain, tripping, and progressive inability to walk. The onset was preceded by a sore throat 4 weeks prior, but no recent immunizations and no sick contacts. He began having problems "catching his toes" for 2 weeks. He had no visual complaints and no bowel or bladder incontinence. He had no recent travel and there were no heavy metal or solvent exposures. He had no prior medical history and he was on no prescription medications. Developmentally, he was on track and had just successfully completed fifth grade. However, he was reported to be behaviorally oppositional, especially regarding his diet which was restricted to beef jerky, yogurt from a squeeze tube, and fruit drinks. Family history included diabetic peripheral neuropathy in his mother, idiopathic peripheral neuropathy in his maternal grandfather, and left lower extremity neuropathy from trauma in his father. There was no known family history of recurrent pressure palsies or cardiac problems.

We retrospectively studied the major complications occurring after one- and two-stage bilateral unicompartmental knee replacements (UKR). Between 1999 and 2008, 911 patients underwent 1150 UKRs through a minimally invasive approach in our unit. Of these, 159 patients (318 UKRs) had one-stage and 80 patients (160 UKRs) had two-stage bilateral UKRs. The bilateral UKR groups were comparable in age and American Society of Anaesthesiology grade, but more women were in the two-stage group (p = 0.019). Mechanical thromboprophylaxis was used in all cases. Major complications were recorded as death, pulmonary embolus, proximal deep-vein thrombosis and adverse cardiac events within 30 days of surgery. No statistical differences between the groups were found regarding the operating surgeon, the tourniquet time or minor complications except for distal deep-vein thrombosis. The anaesthetic times were longer for the two-stage group (p = 0.0001). Major complications were seen in 13 patients (8.2%) with one-stage operations but none were encountered in the two-stage group (p = 0.005). Distal deep-vein thrombosis was more frequent in the two-stage group (p = 0.036). Because of the significantly higher risk of major complications associated with one-stage bilateral UKR we advocate caution before undertaking such a procedure.

Periprosthetic fracture is a recognised complication of joint replacement. Intra-operative fractures of the tibia during total knee replacement have been reported and classified, but there have been no reports in patients undergoing unicompartmental knee replacement. We report a case of intra-operative fracture of the medial tibial plateau during impaction of the tibial component of an Oxford unicompartmental knee replacement. This occurred following a small breach in the posterior tibial cortex during preparation of the tibial plateau for the implant. We therefore advise caution during this stage of the procedure, especially in patients who may already be at risk of intra-operative fracture.

A computationally efficient method to estimate the variance and covariance in piezometric head results computed through MODFLOW 2000 using a first-order second moment (FOSM) approach is presented. This methodology employs a first-order Taylor series expansion to combine model sensitivity with uncertainty in geologic data. MOD-FLOW 2000 is used to calculate both the ground water head and the sensitivity of head to changes in input data. From a limited number of samples, geologic data are extrapolated and their associated uncertainties are computed through a conditional probability calculation. Combining the spatially related sensitivity and input uncertainty produces the variance-covariance matrix, the diagonal of which is used to yield the standard deviation in MODFLOW 2000 head. The variance in piezometric head can be used for calibrating the model, estimating confidence intervals, directing exploration, and evaluating the reliability of a design. A case study illustrates the approach, where aquifer transmis-sivity is the spatially related uncertain geologic input data. The FOSM methodology is shown to be applicable for calculating output uncertainty for (1) spatially related input and output data, and (2) multiple input parameters (trans-missivity and recharge).

The effect of a commercial magnetic water conditioner on the viscosity of a range of aqueous solutions was investigated. In order to measure low viscosities a simple, rolling ball viscometer was constructed. Flight time of the ball was determined by optical sensors and the viscosity computed directly. Significant differences in viscosity were observed in all the magnetically treated solutions except the ion-free milliQ water.

Chiari I malformation is characterized by downward displacement of cerebellar tonsils through the foramen magnum.1-3 In the era of magnetic resonance imaging (MRI), specific radiological criteria for the diagnosis of Chiari I malformation has emerged.1,2 In both children and adults, diagnosis is established by displacement of one or both tonsils 5 mm below the plane of the foramen magnum.4 However, Mikulis et al examined a group of 221 patients ranging from 5 months to 89 years, and found that tonsils tend to ascend with age.5 They recommend that criteria be modified for age, such that younger patients are permitted a higher degree of ectopia. The most commonly reported symptom in both adults and children is headache, occurring in more than half of patients and is often precipitated by Valsalva maneuvers.1,2 Younger children tend to present more commonly with dysphagia and respiratory difficulties.6,7 Before children can communicate verbally, symptoms like headache may present with crying or irritability.2,8 Neurological signs of Chiari I malformation can be codified into 3 categories: a brainstem syndrome (eg, cranial nerve dysfunction, respiratory impairment), a spinal cord syndrome (eg, motor and sensory loss, hyperreflexia or hyporeflexia), and a cerebellar syndrome (eg, ataxia).3 Syringomyelia is associated with Chiari I malformation and deserves special mention as it often warrants surgical intervention.9 We report an unusual presentation of Chiari I in an infant, associated with developmental regression, which resolved on surgical treatment.

Plain radiography is the most important primary investigation in the diagnosis and assessment of osteoarthritis of the knee and it is perhaps surprising that a recent survey of practice amongst the British Orthopaedic community has revealed wide variations w x in the radiographs requested 1 . The study identified that many surgeons continue to request non-weight bearing X-ray examinations and that the patellofemoral joint was rarely adequately assessed. There seems to remain some uncertainty as to the X-ray series of choice, resulting in potentially missed pathology and making scientific comparison of data from different units impossible. Standardised techniques would clearly be desirable and this article aims to review the evidence to date. Plain radiography of the knee may be indicated for a variety of reasons

Amongst orthopaedic surgeons there is often debate about which plain X-rays are required in the assessment of knee disorders. To determine which plain knee X-rays are routinely requested by orthopaedic surgeons in the United Kingdom, a postal survey of the 1287 members of the British Orthopaedic Association was conducted, with a response rate of 70.8%. There was broad agreement on the use of anteroposterior and lateral X-rays, despite the fact that 18% do not appreciate the potential value of weight bearing posteroanterior films in older patients. There was less consensus as to the need for skyline X-rays, despite evidence for their value in demonstrating the patellofemoral joint. In arthritis and after knee replacement, over 75% of surgeons do not use this view. The study also revealed various opinions about the most appropriate flexion angle of the knee when taking X-rays. Despite the frequency with which orthopaedic surgeons request knee X-rays, this study suggests that potentially useful information might often be missed. We would recommend that by routinely obtaining weight bearing PA, lateral and skyline views this problem could be addressed. At the same time it would be helpful if there was more awareness of the best methods of taking these views.

So-called "near-term" infants, born between 34 and 36 6/7 completed weeks of gestation, are also referred to as "late-preterm" infants. Whether they are at higher risk than their term counterparts was the subject of this review of birth and death certificate data for infants born in Utah in the years 1999 to 2004. During this period there were 283,975 births of infants whose estimated gestational age (EGA) ranged from 34 to 42 weeks. Early neonatal (first week), neonatal (first 28 days), and infant (first year) mortality rates were calculated for each weekly gestational age cohort from 34 to 42 weeks. Risk ratios for each cohort were estimated using 40 weeks' gestation as the reference. Birth defects were the major cause of death for newborn infants of all gestational ages for all 3 (early neonatal, neonatal, infant) mortality periods. Birth defects were most evident as a cause of death in late-preterm infants. Of infants who died in the first year, nearly two-thirds (63%) of 166 late-preterm (34 to 36 6/7 weeks) neonates compared to 43% of those born at an EGA of 37 weeks died of a birth defect. However, higher mortality rates for all 3 periods were still evident for late-preterm infants after excluding those who died of birth defects. In general, infants born at 34-36 weeks' gestation were likelier than those born at 40 weeks to die within the first year for all reasons except infections and external causes. Mortality rates for infants born at an EGA of 34 to 36 weeks remained significantly higher after excluding deaths from birth defects when 2 further time periods were analyzed: "late neonatal" (days 8-28) and "postneonatal" (days 29-365). These results are clear evidence that, although birth defects are the leading cause of death in near-term infants, the mortality risk is also increased for nonanomalous near-term infants compared to those born at term.

ARTICLE In Reply .— We appreciate the interest of Drs Edwards and Duff in our article. We reported that previously healthy term infants younger than 90 days who were hospitalized because of serious bacterial infections (SBIs) were more likely to have been exposed to intrapartum antibiotics (IPAs) than were age-matched healthy controls. We also found that the causative organisms in infants with an SBI were more likely to be ampicillin-resistant if the infant's mother had been exposed to an IPA, which in our cases was mostly ampicillin.1 We argue that these findings support ascertaining a history of IPA exposure in young infants who are suspected of having an SBI and for recommending that, consistent with national guidelines, penicillin be used as an IPA rather than ampicillin. Edwards and Duff apparently believe that the American College of Obstetricians and Gynecologists, American Academy of Pediatrics, and Centers for Disease Control and Prevention recommendations for penicillin over ampicillin as an IPA …

Introduction We report the impact of host and viral factors on treatment outcome in the first 53 patients who have completed therapy for CHC with either telaprevir or boceprevir, in combination with pegylated-interferon and ribavirin (PEG/R) at our centre. Methods Patients were treatment naive or experienced with F3 or F4 fibrosis, CHC genotype1 and HCV RNA > 10,000 IU/ml. Data were collected on host and viral factors including single nucleotide polymorphisms (SNPs) in the IL28B gene noncoding region at sites rs12979860 and rs8099917. Results 53 patients (42 Caucasian, 32 F4) were treated with TVR (n = 41) and BOC (n = 12). Seven patients were treatment naive. Subtyping was unattainable in 2 patients. Thus far, 18 patients (34%) have failed treatment and the remainder are being evaluated for SVR (24 patients with SVR-4 to date). HCV viral negativity at triple therapy week 4 was associated with treatment success in patients with rs12979860CC and rs8099917TT and rs12979860non-CC and rs8099917non-TT (OR 20.2 P-value Conclusion In our prospective cohort of CHC patients with advanced fibrosis treated with PIs, HCV RNA negativity at triple therapy week 4 and both IL28B genotypes were independent predictors of treatment outcome. Despite similar rates of early viral suppression, our preliminary data indicate more favourable end of treatment results for rs12979860CC and rs8099917TT versus rs12979860non-CC and rs8099917TT. Disclosure of Interest None Declared.

We have treated 69 patients with 72 cystic lateral menisci by arthroscopic surgery. Meniscal tears were observed in all cases, and 69 of these had a horizontal cleavage component. Three types of tear were identified and may be progressive. Treatment was by arthroscopic resection of the meniscal tear, and decompression of the cyst through the substance of the meniscus. After a mean follow-up of 34 months the results were good or excellent in 64 knees (89%) and there were few complications. We recommend this technique as the treatment of choice for cysts of the lateral meniscus.

We studied arthroscopically the meniscal pathology in 100 patients with functional instability of the knee from isolated rupture of the anterior cruciate ligament at an average time of three years after injury. Meniscal tears were observed in 86 patients and multiple lesions of both menisci were common. An incomplete longitudinal cleavage, visible on both surfaces of the posterior horn, was seen in more than half the knees and seemed to indicate progressive meniscal deterioration. Clinical examination was unreliable and we suggest that arthroscopic assessment is necessary for accurate diagnosis and staging.