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PurposeThis study is an empirical exploration of the tech-based transformation strategies being adopted by luxury hotels in India to assuage the fear psychosis and restore guest confidence in the context of the COVID-19 pandemic. It sheds light on the “new normal” and its overarching implications for hotel operations from the user experience perspective.Design/methodology/approachA mixed method strategy was adopted for data collection. Qualitative data was gathered from a video analysis of two webinars with high-profile panels of thought leaders about the challenges arising from the global health crisis and related post-pandemic recovery strategies. This data has been triangulated with desk research and data collected through an online survey which sought to map guest sentiments with respect to resuming the use of hospitality services and their attitude towards the proposed tech transformation initiatives in the Indian luxury hospitality industry.FindingsThe research data indicates that despite their pandemic-related trepidations, people still have a strong urge to be social and to travel. Technology can play a pivotal role in creating safe spaces for social distancing, facilitating a contactless guest interface to alleviate guest concerns for safe hygiene and rebuilding customer confidence to address the trust deficit.Practical implicationsHospitality organisations must be discerning in the investments they make in new technology and contactless experiences because hasty investments in extensive automation may be perceived as gimmicky by guests. Intelligent and astute use of technology tools can minimise human error, optimise service efficiency and enhance guest experience through elevated levels of personalised hospitality in luxury hotels by judiciously marrying high touch with high tech.Originality/valueThis study is the one of the first empirical explorations of the tech transformation strategies adopted by luxury hotels in the Indian context in response to the COVID-19 pandemic. It explores their efforts for the continued co-creation of high value experiences based on consumer perspectives, with implications for both hospitality and tourism theory and practice.

Purpose This research aims at understanding techno-based strategies deployed by the hospitality industry by exploring the emerging technological product and process innovations that are actively being used in the hospitality space to deliver enhanced guest experiences. It also aims at gaining perspective about the challenges of technology adoption faced by the Indian luxury hotels that have traditionally been driven by high-touch, unscripted and personalised service. Design/methodology/approach This paper adopted a two-pronged methodology for data collection – in-depth semi-structured interviews with General Managers of Luxury Hotels in India and literature-based innovation output (LBIO). NVivo12 software was used to carry out a qualitative thematic analysis of the data. The primary data collected was then triangulated with secondary data gathered through literature review of academic papers, industry reports and studies on the use of technology for enhancing and co-creating customer experience in luxury hotels. Findings The research brings in to focus the importance of technology and high-tech, state-of-the-art tools in facilitating the co-creation and delivery of experiences in the context of luxury hospitality. However, it also emphasises that the high-touch dimension is the core of hospitality in luxury and premium hotels and should remain the primary driver of this segment. Luxury hotels will have to fine-tune and tailor their services and provide the right mix of high-tech and high-touch, depending on the micro-niche segments to which they cater. Practical implications Practitioners, researchers and educationists in the hospitality industry would find the implications of this study useful in context of the evolving technology imperative and the present customer-centric business environment where hotels are constantly striving to meet the exponentially rising bar of guest expectations. Originality/value This study is the one of the few empirical explorations of the techno-based strategies adopted by luxury hotels for co-creating enhanced and high-value experiences leading to critical implications for both hospitality and tourism theory and practice.

Purpose This study aims to explore the reasons for the rise of independent, stand-alone restaurants and ascertains the benefits of outsourcing food and beverage (F&B) in luxury hotels in India from the perspectives of the strategic partners involved in such an alliance. The study also proposes different formats for F&B outsourcing in luxury hotels. Design/methodology/approach An exploratory study was carried out by collecting primary data from 16 Hotel General Managers and F&B operations experts through qualitative, semi-structured, personal and in-depth interviews. NVivo12 software was used to carry out a qualitative thematic analysis of the data. The primary data collected were triangulated with secondary data gathered through literature review of academic papers, industry reports and studies on the trends of restaurants in luxury hotels being outsourced. Findings The study focusses on the antecedents of the rise of stand-alone restaurants in the Indian hospitality industry. To combat the competitive disruption arising because of this trend, the study posits the business model innovation of outsourcing F&B operations in luxury hotels. Practical implications The benefits of a strategic alliance from the perspective of both parties – the luxury hotel and Michelin-star chef or branded/marquee restaurant – are elucidated. Further, three broad formats, which can be adopted for speciality restaurant outsourcing are also proposed. Practitioners, researchers and educationists in the hospitality industry would find the implications of this study useful in the context of the present customer-centric business environment where hotels are constantly striving to meet the exponentially rising bar of guest expectations in an increasingly globalised milieu. Originality/value The study proposes a preliminary road map for internationalisation of F&B operations through the business model innovation of outsourcing operations of in-house specialty restaurants by luxury hotels in the Indian context.

Objectives: Longer retention in treatment is associated with positive outcomes. For women, who suffer worse drug-related problems than men, social technologies, which are more readily adopted by women, may offer promise. This naturalistic study examined whether a smartphone-based relapse-prevention system, A-CHESS (Addiction-Comprehensive Health Enhancement Support System), could improve retention for women with substance use disorders in an impoverished rural setting. Methods: A total of 98 women, age 18 to 40, in southeastern Kentucky and mandated to treatment, received A-CHESS with intensive outpatient treatment for 6 months. For comparison, data were obtained for a similar but non-equivalent group of 100 same-age women also mandated to treatment in the same clinics during the period. Electronic medical record data on length-of-stay and treatment service use for both groups were analyzed, with A-CHESS use data, to determine whether those using A-CHESS showed better retention than those without. Results: Women with A-CHESS averaged 780 service units compared with 343 for the comparison group. For those with discharge dates prior to the study’s end, A-CHESS patients stayed in treatment a mean of 410 vs 262 days for the comparison group. Conclusions: Given associations between retention and positive outcomes, mobile health technology such as A-CHESS may help improve outcomes among women, especially in settings where access to in-person services is difficult. The findings, based on a non-equivalent comparison, suggest the need for further exploration with rigorous experimental designs to determine whether and to what degree access to a smartphone with A-CHESS may extend and support recovery for women.

This case asks the student to take a stance on whether an portfolio manager should take a long or short position in the equity of Universal Display Corporation (PANL). The stock is polarizing, in that reasonable arguments could be made for both long and short positions. The case suggests a number of steps that an analyst might follow when valuing a companyDiscounted cash flow valuation, comparables valuation, short selling. After students have analyzed the case they will be able to value the equity of a publicly traded company and take a position on whether a portfolio manager should buy or sell the stock.

Purpose The hospitality industry the world over is transforming from a product-focused, physical-asset-intensive business to a customer-focused, experience-centric one. This research aims at evolving a typology of customer-centric hospitality innovations. It attempts to explicitly capture the intrinsic DNA of hospitality innovations in the Indian context by exemplifying the typology posited with customer service innovations adopted by contemporary hoteliers that provide new ways of managing and enhancing customer experience. Design/methodology/approach This study is based on primary research through qualitative interviews conducted with select hospitality professionals, supplemented by secondary research in the form of a review of academic literature, as well as other secondary data sources such as company websites and travel websites which shed light on customer service innovations in the Indian context. Findings To develop and sustain competitive advantage, hospitality businesses are increasingly channelizing their efforts to provide innovative and holistic experiential service offerings. Service innovations are being tailored to cater to the unique personal tastes and requirements of hotel guests to connect with individual guests on a personal and emotional level to create memorable hospitality experiences. Research limitations/implications Practitioners, researchers and educationists in the hospitality industry would find the implications of this study useful in the context of the present customer-centric business environment where hotels are constantly striving to meet the exponentially rising bar of guest expectations. Originality/value The research highlights that it is critical to keep the customers’ perspectives central while designing innovative hospitality products. Further, it is important to create a cadre of innovation champions and service enthusiasts who can engender a culture of service innovation within the organisation.

Potential effects of supratherapeutic doses of intravenous (IV) ceftazidime-avibactam and ceftaroline fosamil-avibactam on cardiac repolarization were assessed in a thorough QT/QTc study. This was a double-blind, randomized, placebo-controlled, four-period crossover Phase I study (NCT01290900) in healthy males (n = 51). Subjects received, in randomized order and separated by ≥3 days washout: single doses of IV ceftaroline fosamil 1,500 mg with avibactam 2,000 mg; IV ceftazidime 3,000 mg with avibactam 2,000 mg; oral moxifloxacin 400 mg (open-label positive control); and IV placebo (saline). Least square mean and two-sided 90% confidence intervals (CI) for change from baseline in Fridericia-corrected QT interval (ΔQTcF) for active treatments versus placebo were estimated at 10 time points over 24 hours. The upper bound of the two-sided 90% CI for placebo-corrected ΔQTcF did not exceed 10 milliseconds at any time point over 24 hours for ceftaroline fosamil-avibactam or ceftazidime-avibactam. The lower bound of the two-sided 90% CI for the difference between moxifloxacin and placebo in ΔQTcF over 1-4 hours was >5 milliseconds, confirming assay sensitivity. Pharmacokinetics results confirmed achievement of supratherapeutic plasma concentrations. No safety concerns were raised. In conclusion, supratherapeutic doses of ceftaroline fosamil-avibactam or ceftazidime-avibactam were not associated with QT/QTc prolongation in this study population.

BACKGROUND: Intimate partner violence (IPV) is an important health issue. Many medical students and residents have received training relating to IPV, but previous studies show that many students feel that their training has been inadequate. Our objective was to assess the knowledge, attitudes and perceptions about IPV among university medical students and surgical residents. METHODS: We administered an online survey to a sample of Ontario medical students and surgical residents. The survey instrument was a modified version of the Provider Survey. RESULTS: Two hundred medical students and surgical residents participated in the survey (response rate: 29%). Misperceptions about IPV among respondents included the following: 1) victims must get something from the abusive relationships (18.2%), 2) physicians should not interfere with a couple’s conflicts (21%), 3) asking about IPV risks offending patients (45%), 4) Victims choose to be victims (11.1%), 5) it usually takes ‘two to tango’ (18.3%), and 6) some patients’ personalities cause them to be abused (41.1%). The majority of respondents (75.0%) believed identifying IPV was very relevant to clinical practice. The majority of medical students (91.2%) and surgical residents (96.9%) estimated the IPV prevalence in their intended practice to be 10% or less. Most of the medical students (84%) and surgical residents (60%) felt that their level of training on IPV was inadequate and over three quarters of respondents (77.2%) expressed a desire to receive additional education and training on IPV. CONCLUSIONS: There are misconceptions among Canadian medical students and surgical residents about intimate partner violence. These misconceptions may stem from lack of education and personal discomfort with the issue or from other factors such as gender. Curricula in medical schools and surgical training programs should appropriately emphasize educational opportunities in the area of IPV.© 2011 KUMS, All right reserved

PurposeThis paper aims to identify the key risks which are endemic to the hospitality industry and considered as important by hoteliers in today's growing global context, with particular reference to the Indian context. It also seeks to propose a generic model for risk management.Design/methodology/approachPrimary data collection using questionnaires and semi‐structured qualitative interviews with hospitality professionals was supplemented by secondary research in the field of risk and uncertainty management.FindingsTo secure competitive advantage and develop business resilience, it is becoming increasingly important for hospitality organisations to shift their focus from merely responding and reacting to crises and emergency situations, to proactively identifying, analysing and assessing risks while formulating their business strategies. The paper identifies the most commonly addressed areas of risk in the Indian hospitality industry, which include competition, seasonality of business and changes in customer preferences and demand.Practical implicationsPractitioners, researchers and educationists in the hospitality industry will find the implications of this study useful in the context of the present complex business environment which is fraught with risks.Originality/valueGiven the dearth of research in the field of risk and uncertainty management in the hospitality industry, especially in the Indian context, the paper explores various aspects of hospitality operations prone to risk and proposes a framework for identifying the key risks in hospitality organisations. It also puts forward a generic model of the process of risk management.

Three phase 1 studies of eliglustat tartrate (Genz-112638), an oral inhibitor of glucosylceramide synthase under development for treating Gaucher disease type 1 (GD1), evaluated the safety, tolerability, and pharmacokinetics in healthy volunteers after escalating single doses (n = 99), escalating multiple doses (n = 36), and food (n = 24). Eliglustat tartrate was well tolerated at single doses ≤ 20 mg/kg and multiple doses ≤ 200 mg bid, with 50 mg bid producing plasma concentrations in the predicted therapeutic range. No serious adverse events occurred. Mild to moderate events of nausea, dizziness, and vomiting increased in frequency with escalating single and multiple doses. Single doses ≥ 10 mg/kg caused mild increases in electrocardiogram PR, QRS, and QT/QTc intervals. Single-dose pharmacokinetics showed dose linearity but not proportionality. Maximum plasma concentrations occurred at ~2 hours, followed by a monophasic decline with a ~6-hour terminal half-life. Unchanged drug in 8-hour urine collections was

이 논문은 󰡔비전󰡕이 창조과정에 대해서 드러내는 것이 무엇인지 찾기 위해서 󰡔비전󰡕의 신비주의적 요소들 초월하려고 한다. 󰡔비전󰡕은 예이츠의 신비주의에 대한 관심과 인간의식의 가장자리 넘어 존재하는 것에 대한 세속적 설명(이를테면, 프로이드의 무의식) 사이에 끼인, 중요한 시기에 나타난다. 예이츠의 "안내자"가 말하는, "시를 위한 메타포"를 제공하는 것 이상으로 󰡔비전󰡕은 시적 영감이 생성하는 과정에 대한 통찰을 보여준다.

Several studies have explored the disproportionate number of children of color involved in child protective services, raising concerns that racial bias in the system results in more women of color being referred to child protection. The authors conducted a case series to analyze whether a woman's race and ethnicity influenced referrals to child protective services in a domestic violence context. Data were obtained through interview records of 263 women (38% women of color) at a Minneapolis-based advocacy and therapy organization. The findings suggest that women who face multiple forms of oppressions may have greater risk of being involved with child protection services.

Objective The aim of this study is to assess chiropractors' attitudes, beliefs, knowledge, and experience about intimate partner violence (IPV). Methods This cross-sectional survey was developed by members of the Violence Against Women Health Research Collaborative. The survey was disseminated to a voluntary, nonrandom convenience sample of chiropractors attending a 3-day continuing education seminar. Surveys were distributed at the entrances of the seminar session rooms and placed on luncheon tables. Respondents returned surveys to collection boxes. Results Ninety-three doctors of chiropractic completed the survey. Respondents estimated that only 5.2% (95% confidence interval, 3.3%-7.0%) of their female patients were victims of IPV. General knowledge of IPV was good among respondents. Knowledge of clinical indicators and victim's management was fair to poor. Only 22% of respondents identified the most commonly injured body regions among battered women. Lack of knowledge, personal discomfort, and time constraints were all cited as barriers to IPV screening. Conclusions Our survey indicates that doctors of chiropractic underestimate the prevalence of IPV among their female patients. Like other health care specialists, chiropractors cite multiple IPV screening barriers, especially lack of knowledge. Doctors of chiropractic would benefit from education and training in IPV to enable them to better identify and assist patients who are victims of IPV.

Public accountability is a hallmark of modern democratic governance and the foundation of the popular performance management movement. Democracy is just an empty exercise if those in power cannot be held accountable in public for their acts and omissions, for their decisions, their policies, and their expenditures. This book offers a finely detailed and richly informed consideration of accountability in both government and the contemporary world of governance. Twenty-five leading experts cover varying aspects of the accountability movement, including multiple and competing accountabilities, measuring accountability, accountability and democratic legitimacy, and accountability and information technology, and apply them to governments, quasi-governments, non-government organizations, governance organizations, and voluntary organizations. Together they provide the most comprehensive consideration of accountability currently available, with a blend of theoretical, empirical, and applied approaches.

Vandetanib is a selective inhibitor of vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR) and rearranged during transfection (RET) signalling, indicated for the treatment of medullary thyroid cancer. We investigated potential drug–drug interactions between vandetanib and metformin [organic cation transporter 2 (OCT2) substrate; NCT01551615]; digoxin [P-glycoprotein (P-gp) substrate; NCT01561781]; midazolam [cytochrome P450 (CYP) 3A4 substrate; NCT01544140]; omeprazole (proton pump inhibitor) or ranitidine (histamine H2-receptor antagonist; both NCT01539655). Four open-label, phase I studies were conducted in healthy volunteers: n = 14 (metformin), n = 14 (digoxin), n = 17 (midazolam), n = 16 (omeprazole), n = 18 (ranitidine). Three of these comprised the following regimens: metformin 1000 mg ± vandetanib 800 mg, midazolam 7.5 mg ± vandetanib 800 mg, or digoxin 0.25 mg ± vandetanib 300 mg. The randomized study comprised vandetanib 300 mg alone and then either (i) omeprazole 40 mg (days 1–4), and omeprazole + vandetanib (day 5); or (ii) ranitidine 150 mg (day 1), and ranitidine + vandetanib (day 2). The primary objective assessed metformin, digoxin, midazolam and vandetanib pharmacokinetics. Vandetanib + metformin increased metformin area under the plasma concentration–time curve from zero to infinity (AUC0–∞) and maximum observed plasma concentration (Cmax) by 74 and 50 %, respectively, and decreased the geometric mean metformin renal clearance (CLR) by 52 % versus metformin alone. Vandetanib + digoxin increased digoxin area under the concentration-time curve from zero to the last quantifiable concentration (AUC0–last) and Cmax by 23 and 29 %, respectively, versus digoxin alone, with only a 9 % decrease in CLR. Vandetanib had no effect on midazolam exposure. Vandetanib exposure was unchanged during co-administration with omeprazole/ranitidine. Treatment combinations were generally well tolerated. Patients receiving vandetanib with metformin/digoxin may require additional monitoring of metformin/digoxin, with dose adjustments where necessary. Vandetanib with CYP3A4 substrates or omeprazole/ranitidine is unlikely to result in clinically relevant drug–drug interactions.

This paper reports on a continuing development of an abstract algebra course that was first implemented in the summer of 1990. This course was designed to address discrepancies between how students learn and how they were traditionally being taught. Based on results from the first implementation, pedagogical changes were made, including increased computer programming activities and other exercises which were designed to give the students the opportunity to build experience to draw on in order to construct understanding of the topics in class. A second experimental course was run. To assess the impact of these methods, and to continue to better understand how students go about learning, test results from the latter class and interviews with students from both experimental courses and a lecture-based class were analyzed. The students in the second experimental course demonstrated a deep understanding of the title concepts, especially cosets and normality. We discuss the details of the revised experimental course; the epistemological theory behind its design; and the framework used to analyze the results. We demonstrate through examples from interviews and test results the applicability of this analysis to the data, and the strides made by the students in comparison with the students from the lecture-based course, and with the students from the first experimental course. We hope to illustrate difficulties students face in learning abstract algebra, and to discuss instructional strategies to help students overcome these difficulties.

Communities are stronger when they have an active, engaged citizenry — a public. The challenge to putting the public back into community — and finding a responsible public voice — is changing private individuals into responsible public citizens.

A new politics is emerging that embraces a broader range of choices than the polarized liberal and conservative options of the conventional political system. It is personal, reflective and deliberative, nurturing true “public opinion” and generating true “public will.”

The use of warfarin has a well-known bleeding risk. Recombinant activated factor VII (rFVIIa) is a non–plasma-derived, rapid-acting, and rapidly infused potential treatment. This randomized, single-center, placebo-controlled, double-blinded, dose-escalation, exploratory phase 1 trial assessed safety and effects of rFVIIa in reversing warfarin-induced changes in bleeding and coagulation parameters, using a punch biopsy–induced bleeding model in healthy subjects. The effects of warfarin (experiment 1) and rFVIIa (5-80 μg/kg; experiment 2) were evaluated. Outcomes were bleeding duration, blood loss, coagulation parameters, and safety. Warfarin treatment significantly increased bleeding duration and blood loss from pretreatment (experiment 1, 12 subjects). However, these parameters after rFVIIa treatment were not significantly different from placebo (experiment 2, 85 subjects). Mean activated partial thromboplastin time, prothrombin time, and international normalized ratio were reduced from warfarin-elevated levels. rFVIIa (80 μg/kg) significantly reversed warfarin effects on all thromboelastography parameters, compared with placebo (P < .05), and returned the thrombin generation speed to baseline. There were no thromboembolic or serious adverse events. In this exploratory trial, the reversal of warfarin effects was observed in the thromboelastography, thrombin generation, and clotting assays. However, this reversal did not translate to improvements in the bleeding model parameters evaluated in the punch biopsy model. Trial registration is exempt (phase 1).

Udgivelsesdato: 2008-Jul BACKGROUND: Domestic violence is the most common cause of nonfatal injury to women in North America. In a review of 144 such injuries, the second most common manifestation of intimate partner violence was musculoskeletal injuries (28%). The American Academy of Orthopaedic Surgeons is explicit that orthopaedic surgeons should play a role in the screening and appropriate identification of victims. We aimed to identify the perceptions, attitudes, and knowledge of Canadian orthopaedic surgeons with regard to intimate partner violence. METHODS: We surveyed members of the Canadian Orthopaedic Association to identify attitudes toward intimate partner violence. With use of a systematic random sample, 362 surgeons were mailed questionnaires. The questionnaire consisted of three sections: (1) the general attitude of the orthopaedic surgeon toward intimate partner violence, (2) the attitude of the orthopaedic surgeon toward victims and batterers, and (3) the clinical relevance of intimate partner violence in orthopaedic surgery. Up to three follow-up mailings were performed to enhance response rates. RESULTS: A total of 186 orthopaedic surgeons responded (a response rate of 51%), and 167 (91%) of them were men. Most orthopaedic surgeons (95%) estimated that

Abstract 3210 5-HMF (5-hydroxymethyl-2-furfural; Aes-103) is a breakdown product of glucose that has potent anti-sickling properties in vitro and in vivo (transgenic sickle cell mice) and produces concentration-dependent left shifts in p50 values of the oxygen equilibrium curve (OEC), indicating increased oxygen affinity. These pharmacological properties are likely based on the binding of 5-HMF to the valine residue of alpha globin chains of HbS and possibly to lysine. Increasing the oxygen affinity of HbS is known to reduce sickling. Aes-103 is being developed as a potential treatment for sickle cell disease (SCD). The current first in man study was a double-blind, placebo-controlled, ascending single dose evaluation of the safety, pharmacokinetics and pharmacodynamics of 5-HMF given as an oral solution at 300 mg, 1000 mg, 2000 mg and 4000 mg to healthy normal subjects. In each dosing cohort, 6 subjects received 5-HMF and 2 received placebo. A total of 20 adult subjects of African descent with normal hemoglobin (Hb), received a single dose of study drug or placebo on up to 2 occasions separated by 2–4 weeks. The mean age of the subjects was 28 years, mean BMI was 25.8, and 13 were males, 7 were females. Written informed consent was obtained. Safety measures consisted of adverse events (AEs), vital signs, ECG, clinical chemistry, hematology, urinalysis and physical exams. No subjects were discontinued from the study due to an AE. During the day of dosing a total of 14 AEs occurred. All were mild, with 3 occurring in the placebo arm (constipation, dry mouth, dizziness), none at 300 mg, 2 at 1000 mg (diarrhea, headache), 3 at 2000 mg (feeling hot, somnolence, dyspnea—during hypoxia testing) and 6 at 4000 mg (nausea (2), abdominal pain, dizziness, somnolence (2)). Following dosing, there were no clinically significant differences between drug and placebo treated subjects in respect to heart rate, blood pressure, ECG, physical exams, clinical chemistry, hematology and urinalysis results. The pharmacokinetic profile of 5-HMF in plasma showed dose-proportional kinetics with an upward trend towards higher Cmax and AUC at higher doses. Mean plasma Cmax concentrations ranged from 34 to 699 ng/ml, Tmax ranged from 0.42 to 0.67 h, AUC ranged from 33 to 875 ng.ml/hr and t1/2 ranged from 0.38–0.76 h. 5-HMF levels in RBC hemolysate were typically 5–15 times that of corresponding plasma levels with Cmax ranging from 152–3640 ng/ml, Tmax ranging from 0.71–0.83 h, AUC ranging from 473–10103 ng/ml/h and half-life ranging from 1.61–2.13 h. Measurements of RBC hemolysate levels did not include the 5-HMF bound to hemoglobin. The elevated levels and longer half-life of 5-HMF in RBCs relative to plasma probably reflects the binding affinity of Hb for 5-HMF and the equilibrium between Hb bound 5-HMF, free 5-HMF in the RBC and in plasma. The main pharmacodynamic endpoint was the change in blood oxygen level (SpO2) during a 5-minute hypoxia challenge test in which 12% O2 was inhaled. The hypoxia challenge was administered prior to dosing and then at 0.75, 2, 4 and 8 h post-dose. Results showed an appreciable attenuation of the drop in SpO2 values due to hypoxia. For example, at 2 hours post-dose for the placebo treated subjects the mean SpO2 values declined by an average of 12.3% after 5 minutes of hypoxia. In contrast, the 2000 mg 5-HMF treated subjects had a mean decline in SpO2 of 8.7%. The attenuation of hypoxia effects was dose-dependent (minimal effect at 300 mg of 5-HMF) and was time-dependent following 5-HMF dosing (largest protection seen at 2–4 h post-dose, no protection at 8 h post dose). At 2 hours after 5-HMF doses of 1000–4000 mg, the SpO2 values from 18 hypoxia test sessions showed significantly (p In summary, single oral doses of 300–4000 mg of 5-HMF given to healthy normal volunteers were well tolerated, rapidly absorbed and preferentially taken up into RBCs relative to plasma, had a dose-proportional pharmacokinetic profile and showed a pharmacodynamic change (protection against desaturation during hypoxia) consistent with the expected increase in oxygen affinity and with the compound's proposed mechanism of action in SCD patients. A similar ascending single dose, placebo controlled, double-blind study in patients with SCD at steady state is currently ongoing at the NIH (see www.clinicaltrials.gov). Disclosures: Stern: AesRx, LLC: Employment, Equity Ownership.

From January 1982 through December 1988, 150 patients with 153 Winquist Class ITI and IY comminuted diaphyseal femur fractures due to high energy blunt trauma were treated with immediate plate fixation. A total of 260 major gênerai surgical systems were injured in 150 patients. Forty-nine patients did not have adequate preoperative spine radiographs due to positioning or time factors. Nineteen patient« had spine fractures; nine were diagnosed post-femoral fixation. The average injury severity score (ISS) was 22.7. Three patients died (2%). Our institution predicted mortality with this ISS for patients without pelvic or femur fractures at 15% (P= .0003). Six patients moved to other states and three were lost to follow up due to noncompliance. One of us reviewed 141 fractures in 138 patients at a minimum of 12 months follow up and completion of treatment. Forty-nine fractures were open; 8 grade 1, 25 grade ?, 10 grade ???, 4 ???, 2 HIC. A total of 153 pelvic or ipsilateral major orthopedic injuries were present in 141 fractures. An additional 188 major associated orthopedic injuries were noted. The average time to union was 17.2 weeks. One plate was applied in 11° of varus. Five plates failed from fatigue and five from repeat traumas. Seven plate failures were rodded and healed within 8 weeks. There was one persistent nonunion. One fracture, open IIIC, became infected after uniting. One patient has 110° of knee motion and 140 fractures have greater than 130° of knee motion. Plate fixation is a safe technique for immediate femoral stabilization in the face of high energy blunt trauma. Failures occur late and are easy to reconstruct Intramedullary nails are the preferred method of reconstruction. Ultimate knee function is excellent. Infection rates (1/49) in open fractures are acceptably low.

Background/Objective: Antiplatelet drugs and Vitamin-K antagonists are used to reduce thrombosis potential in patients with cardiovascular disease or with hypercoagulable disorders. Such treatments can impair platelet function and can lead to significant reduction in coagulation-related proteins with the resultant increased bleeding risk.1,2 The current study (Novo Nordisk F7HAEM-1825) was designed to evaluate the use of a new bleeding model for determining the effectiveness of haemostatic interventions to mitigate drug-induced bleeds. We sought to determine the feasibility of demonstrating measurable changes in punch biopsy-induced bleeding durations and bleeding volumes in healthy volunteers after receiving warfarin anti-coagulation therapy. Methods: Healthy volunteers received two biopsies using a 5 mm punch biopsy tool with local anesthesia to the posterior thigh - one prior to warfarin administration (Biopsy 1), and a second post-warfarin administration after achieving an international normalized ratio (INR) of 2.5 (± 0.3) (Biopsy 2). Subjects were titrated with warfarin dosing to achieve a stable INR within the designated range (INR=2.5±0.3), at which time the second biopsy was performed. Bleed duration and bleed volumes were measured. Three data analysis methods were used: a generalized linear model with logarithmic link and gamma distribution, paired t-test on log-transformed data, and paired t-test on the original data. Results: Twelve healthy subjects underwent the first baseline biopsy. One subject did not maintain an INR within the specified range, leaving 11 subjects assessed for the impact of warfarin on bleeding. Mean baseline and post-warfarin bleed durations and volumes are shown below. Baseline (Biopsy 1) Mean Values Warfarin (Biopsy 2) Mean Values Day 1 INR Bleed Duration (min:sec) Blood Volume Loss (ml) Warfarin INR Bleed Duration (min: Sec) Blood Volume Loss (ml) Difference in bleed duration (min:sec) 1.08 12:43 2.34 2.48 20:36 3.83 7:53 All participants demonstrated increases in bleeding duration from Biopsy 2 compared to Biopsy 1. All participants demonstrated increases in bleeding duration from Biopsy 2 compared to Biopsy 1. Changes in Bleeding Duration from Biopsy 1 (Baseline) to Biopsy 2 (Post Warfarin) All analysis methods demonstrated a mean increase in bleeding duration and blood volume loss by at least 60%, and all gave approximately the same estimate of the ratio Mean Bleeding duration at Biopsy 2/ Biopsy 1 (1.60–1.63) as well as approximately the same estimate of the ratio Mean Blood Loss at Biopsy 2/Biopsy 1 (1.64). Conclusion: The method described here is a reproducible technique for evaluating the impact of anticoagulation products in altering bleed durations and volumes and may be useful for evaluating hemostatic agents to control anticoagulation-related bleeding. Additionally, this method may be useful for assessing anticoagulation reversal/mitigation strategies in clinically relevant hemorrhage.

The utility of existing methods for the evaluation of hemostatic agents has been limited. The purpose of this study was to evaluate and optimize the use of a standardized punch biopsy to investigate the effects of hemostatic agents in healthy subjects. Recombinant FVIIa (rFVIIa) is licensed for the treatment of bleeding episodes in patients with hemophilia A or B with inhibitors. Recent reports (anecdotal and from randomized clinical trials) have described the successful use of rFVIIa in patients with liver disease, intracerebral hemorrhage, congenital and acquired coagulation factor deficiency, warfarin-induced bleeding, thrombocytopenia, traumatic brain injury, spinal cord surgery, and platelet disorders using a wide range of doses and dosing regimens. This variety of clinical situations, suggests a need to determine the optimal dose and dosing regime of rFVIIa for use in these potentially new therapeutic areas. A study was designed to evaluate the dose-response of rFVIIa in a controlled manner using a punch biopsy procedure in healthy volunteers that consented to participate in an IRB approved protocol. The study was designed as a three-part trial. Part A (6 subjects) optimized the size of the biopsy needed to create bleeding times and durations appropriate for study purposes. Part B (10 subjects) determined the feasibility of evaluating rFVIIa efficacy and safety in this bleeding model. Part C (48 subjects) examined, in an ascending dose escalation paradigm, the effect of a single dose of rFVIIa on bleeding time, blood loss volume, coagulation parameters and coagulation status in healthy volunteers. In Part C, all patients underwent three punch biopsies: the first (baseline biopsy) with no treatment, the second with either a low or high rFVIIa dose administered prior to biopsy, the third with either a low or high dose of rFVIIa administered prior to biopsy. The treatment pair sequences were placebo/10, 10/20, 20/40, 40/80, 80/120, and 120/160 μg/kg. Blood samples were drawn 15 minutes pre-, 15 minutes post-, and 1 hour post-biopsy to monitor coagulation and conduct ex-vivo assessments of hemostasis [Hemodyne Hemostasis Analyzer (HHA)]. Safety evaluations were conducted by an Independent Safety Officer after each dose tier, and subjects were permitted to enroll in the next higher dose tier only if no significant safety issues were observed. In healthy subjects with no pre-existing coagulopathies, regression analyses indicated that increasing doses of rFVIIa did not have a dose-related linear effect on blood loss volume or duration of bleeding. However, it is of interest that with HHA, a statistically significant impact was noted on the time to 20 mm clot strength, platelet contractile force, and clot elastic modulus, suggesting that rFVIIa does have a measureable and perhaps meaningful effect in individuals with normal coagulation systems. No safety issues were detected during this study. Thus in this model system, designed to evaluate hemostasis, interesting effects were seen with the HHA instrument which suggest that increasing doses of rFVIIa may impact clot stability, but these observations are limited by the significant hetereogeneity which may benefit from improved experimental controls.

The generation of thrombin is a critical step in clot formation and securing hemostasis. Inadequate thrombin generation may result in excessive bleeding, while uncontrolled thrombin production has the potential to induce thromboses. Recombinant FVIIa has been shown to control bleeding in hemophilia patients with inhibitors to coagulation factors VIII and IX, and several other clinical conditions in which life- and limb-threatening bleeding may occur. However, for non-hemophilia patients the dose and dosing regimen still require refinement. The use of ex-vivo assessment systems (Thromboelastograph assay, Hemodyne Hemostasis Analyzer) to generate an in vitro model of hemostasis may be useful to determine the effect of rFVIIa on the dynamics of clot formation, particularly in a patient population where clinical trials are difficult. A series of pilot studies were performed to establish an optimal punch biopsy location and biopsy size to create an effective bleeding site for further study. The current study (48 subjects consented for an IRB approved protocol) examined, in an ascending dose-escalation manner, the effect of an individual dose of rFVIIa on bleeding time, blood loss volume, coagulation parameters and coagulation status in healthy volunteers. All patients underwent three punch biopsies: the first (baseline biopsy) with no treatment, the second and third biopsy with either a low or high rFVIIa dose administered prior to biopsy. The treatment pair sequences were placebo/10, 10/20, 20/40, 40/80, 80/120, and 120/160 μg/kg. Blood samples were drawn 15 minutes pre-, 15 minutes post-, 1 hour and 5 hours post-biopsy to conduct ex-vivo assessments of hemostasis. The results indicate that overall there was a trend towards an increase in platelet contractile force and clot elastic modulus with an apparent maximal effect at 1 hour post-biopsy. At the higher doses this effect, although reduced, does not return to pre-treatment values by 5 hours post-biopsy. For the lower doses these values decreased to levels comparable to those at pre-treatment. These observations are consistent with the reports of a dose-related half-life of rFVIIa. These data imply that the administration of rFVIIa may have an effect in non-coagulopathic individuals. Although the heterogenity observed in this sample of patients may limit interpretations, it is proposed that this ex-vivo model with further refinements may be useful for evaluating the effects of future pro-hemostatic agents. Figure Figure

Purpose Two phase I, open-label trials in healthy subjects assessed whether co-administration with CYP3A4/CYP2C19 inhibitors, itraconazole/fluconazole (study A), or CYP3A4 inducer, rifampicin (study B), affects the exposure, safety/tolerability and pharmacokinetics of selumetinib and its metabolite N-desmethyl selumetinib. Methods In study A (n = 26), subjects received a single dose of selumetinib 25 mg and, after 4 days of washout, were randomized to treatment 1 (itraconazole 200 mg twice daily on days 1–11) or treatment 2 (fluconazole 400 mg on day 1 then 200 mg/day on days 2–11) plus co-administration of single-dose selumetinib 25 mg on day 8 (selumetinib staggered 4 h after itraconazole/fluconazole dose); Twenty-one days after discharge/washout, subjects received the alternate treatment. In study B (n = 22), subjects received a single dose of selumetinib 75 mg (day 1) then rifampicin 600 mg/day (days 4–14) plus a single dose of selumetinib 75 mg on day 12. Pharmacokinetic analysis and safety assessments were performed. Results Selumetinib co-administered with itraconazole, fluconazole (selumetinib staggered 4 h after itraconazole/fluconazole dose), or rifampicin was well tolerated. Selumetinib exposure was higher when co-administered with itraconazole or fluconazole (area under the plasma concentration-time curve (AUC) increased by 49 and 53%, respectively; maximum plasma concentration (C max) increased by 19 and 26%, respectively) but lower when co-dosed with rifampicin (AUC and C max decreased by 51 and 26%, respectively) versus selumetinib dosed alone. Co-administration with itraconazole or rifampicin decreased N-desmethyl selumetinib AUC(0–t) (11 and 55%, respectively), and C max (25 and 18%, respectively), with fluconazole, AUC(0–t) increased by 40%, but there was no effect on C max. Conclusions Co-administration of CYP3A4/CYP2C19 inhibitors will likely increase exposure to selumetinib, while CYP3A4 inducers will likely reduce its exposure. Electronic supplementary material The online version of this article (doi:10.1007/s00228-016-2153-7) contains supplementary material, which is available to authorized users.

Background and objectives Fostamatinib is a spleen tyrosine kinase inhibitor that has been investigated as therapy for rheumatoid arthritis and immune thrombocytopenic purpura. The present studies assessed the potential for pharmacokinetic interaction between fostamatinib and the commonly prescribed medications oral contraceptive (OC), warfarin, and statins (rosuvastatin, simvastatin) in healthy subjects. Methods The OC study was a crossover study over two 28-day treatment periods (Microgynon® 30 plus placebo or fostamatinib). Concentrations of OC constituents (ethinyl estradiol/levonorgestrel) were measured. Effects on warfarin pharmacokinetics and pharmacodynamics were assessed (21-day study). Warfarin was administered on days 1 and 14, fostamatinib on days 8–20. The statin study was a two-period, fixed-sequence study of the effects of fostamatinib on exposure to rosuvastatin or simvastatin (single doses). Safety was assessed throughout. Results Fostamatinib co-administration with OC increased exposure to ethinyl estradiol [area under the plasma concentration–time curve at steady state (AUCss) 28 % [confidence interval (CI 90 %) 21–36]; maximum plasma concentration (Cmax) at steady state (Cmax,ss) 34 % (CI 26–43)], but not levonorgestrel (AUCss 5 %; Cmax,ss −3 %), while exposure to luteinizing hormone and follicle-stimulating hormone decreased (≈20 %). Fostamatinib did not affect the pharmacokinetics/pharmacodynamics of warfarin to a clinically relevant extent, but caused an upward trend in AUC for both R- and S-warfarin [18 % (CI 13–23) and 13 % (CI 7–19)]. Fostamatinib increased rosuvastatin AUC by 96 % (CI 78–115) and Cmax by 88 % (CI 69–110), and increased simvastatin acid AUC by 74 % (CI 50–102) and Cmax by 83 % (CI 57–113). Conclusion Fostamatinib exhibits drug–drug interactions when co-administered with OC, simvastatin, or rosuvastatin, with the AUC of statins almost doubling. Fostamatinib did not exhibit a clinically relevant DDI on warfarin. Electronic supplementary material The online version of this article (doi:10.1007/s40268-015-0120-x) contains supplementary material, which is available to authorized users.

Selection of young people for apprenticeship in the Southampton area is about to experience a major change in the course of a pilot scheme for organising ability‐testing on a common basis. If the scheme is a success, it will be an example of industry‐school cooperation achieving discernible benefits. The initiative has been entirely Southampton's, only some support and expertise being provided from outside the area. Over the last two years, discussion among employers, ITBs and schools has led to the trial, about to take place, of a system in which candidates for apprenticeship take only one set of tests. The scores from the tests will be made available to employers to which the candidate has applied. Such employers will have to be qualified test users. A further part of the scheme is a new form for obtaining references from candidates' schools.