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Mucoadhesive dosage forms, which are used for topical application in the oral cavity, are currently a very intensively developing field in pharmaceutical technology. Considering the physiological conditions of the oral cavity, the formulation of these mucoadhesive forms is still a challenge. Various types and forms of polymers are used in the experiments, in combination with a large number of drugs, while the achieved effect can be local or systemic and the release rate can be controlled. For many drugs, buccal application is one of the ways to increase their bioavailability.

Background Severe acne vulgaris has limited therapeutic options. Objectives To evaluate photodynamic therapy ( PDT) using topical methyl aminolaevulinate ( MAL, 80 mg g −1) as the photosensitizer in severe facial acne. Methods A double-blind, randomized, vehicle-controlled multicentre trial in 153 patients (aged 12-35 years) with severe facial acne [Investigator's Global Assessment ( IGA) score 4; 25-75 inflammatory lesions with ≤ 3 nodules; 20-100 noninflammatory lesions]. Treatment (four treatments 2 weeks apart) involved incubation with MAL ( n = 100) or vehicle cream ( n = 53) for 1·5 h under occlusion, then illumination (635-nm red light, total dose 37 J cm −2). IGA assessment and standardized lesion counts were performed before each treatment and 12 weeks after the first treatment. Treatment success was defined as improvement from baseline in IGA by ≥ 2 grades at 12 weeks. Safety assessments were for pain (10-cm visual analogue scale, immediately after illumination), erythema (four-point rating scale) and adverse events. Results At 12 weeks, PDT using MAL 80 mg g −1 reduced inflammatory lesions vs. vehicle PDT (mean change −15·6 vs. −7·8, P = 0·006; mean percentage change −37·3% vs. −16·2%, P = 0·003). However, noninflammatory lesions did not decrease significantly (mean change −11·8 vs. −10·7, P = 0·85; mean percentage change −28·6% vs. −24·9%, P = 0·72). Treatment success rates were greater with MAL- PDT 80 mg g−1 (44% vs. 26%, P = 0·013). Pain was low and manageable by briefly pausing illumination. There was similar pain or erythema with successive treatments. Conclusions PDT using topical MAL 80 mg g−1 and red light may offer promise for severe acne vulgaris. [ABSTRACT FROM AUTHOR]

Purpose: The 2024 ASHP Pharmacy Forecast identifies and contextualizes emerging issues and trends that will influence healthcare, health systems, and the pharmacy profession and provides recommendations to inform long-term strategic planning that should prompt action by pharmacists and health-system leaders., Methods: Drawing on the “wisdom of crowds” concept, a survey was constructed with 6 general themes, each with 6 to 9 focused statements and a seventh theme on preparedness (58 survey items in total). The size of and representation within the survey panel were intended to capture opinions from a wide range of pharmacy leaders. The survey instructed panelists to consider the likelihood of the events/scenarios described in the statements occurring in the next 5 years as being likely, somewhat likely, somewhat unlikely, or very unlikely. Then, survey panelists assessed the preparedness (from very unprepared to very prepared) for 12 of the statements., Results: The 6 survey themes identified were Urgent Public Health Priorities, Responding to the Mental Health Crisis, Achieving Care Equity, New Disease Paradigms and Treatment Innovations, Workforce: Focus on Culture for the Future, and Artificial Intelligence: Can Ethics and Regulators Catch Up? The survey was completed by 250 respondents, yielding an 88% response rate. Analysis of survey results was provided by chapter authors along with strategic recommendations to guide actions for each theme., Conclusion: The focus of the Pharmacy Forecast is on large-scale, long-term trends that will influence healthcare and the pharmacy profession over months and years and not on day-to-day situational dynamics. The report provides insight to stimulate thinking and discussion and provides a starting point to proactively position leaders, their teams, and departments for potential future events and trends.

Background: In youth with type 1 diabetes (T1D), high haemoglobin A1c (HbA1c) levels are associated with an increased risk for diabetic ketoacidosis (DKA)., Aims: This study examined whether daily school-supervised basal insulin injections were feasible and if they reduced the risk of morning ketosis in children and adolescents with high HbA1c levels. We hypothesized that supervised glargine and degludec would reduce the risk of ketosis and that the prolonged action of degludec would protect from ketosis after consecutive days of unsupervised injections., Materials & Methods: After a 2-4-week run-in, youth (10-18 years, HbA1c ≥ 8.5%) managing T1D with injections were randomized to school-supervised administration of degludec or glargine for 4 months. School nurses observed daily blood β-hydroxybutyrate (BHB) and glucose checks. During COVID closures, the research team supervised procedures remotely., Results: Data from 28 youth (age 14.3 ± 2.3 years, HbA1c 11.4 ± 1.9%, 64% F) were analysed. School-supervised injections of both basal insulins for 1-4 days progressively lowered the percent of participants with elevated BHB. The percent of participants with elevated BHB (≥0.6 mmol/L) after 2 days of unsupervised basal insulin doses at home was greater in the glargine than degludec group but had a high p-value (17.2% vs. 9.0%, p = 0.3). HbA1c was unchanged in both groups., Discussion: In youth with T1D at high risk for DKA, daily supervised long-acting insulin administration decreased the probability of elevated ketone levels on subsequent school days, regardless of basal insulin type. A larger sample size may have demonstrated that the longer action profile of degludec would offer additional protection from ketosis during days of not attending school., Conclusion: Engaging school-based caregivers in management of youth with T1D on injected insulin may decrease clinically significant ketosis and minimize acute complications of diabetes., (© 2023 Diabetes UK.)

Objective: To quantify the economic burden of bacterial antimicrobial resistance in Thailand and estimate potential savings from improving the rate of appropriate empiric treatment, where effective coverage is provided within the first days of infection., Design: Cost-of-illness study., Methods: A cost-calculator, decision-tree model was developed using published data and records from 3 Thai hospitals for patients hospitalized with antimicrobial-resistant infections between 2015 and 2019. Direct and indirect costs of antimicrobial-resistant infections were assessed over a 5-year time horizon, with outcomes derived separately for cases having received appropriate empiric treatment versus inappropriate empiric treatment. In a real-world scenario, outcomes were estimated using actual rates of inappropriate empiric treatment, and in a hypothetical scenario, outcomes were estimated using decreased rates of inappropriate empiric treatment., Results: Over 5 years, in-hospital antimicrobial-resistant infections produced costs of approximately Thai baht (THB) 66.4 billion (USD 2.1 billion) in the real-world scenario and THB 65.8 billion (USD 2.1 billion) in the hypothetical scenario (0.9% cost savings relative to the real-world scenario). Most costs were attributable to income loss due to in-hospital mortality (real world: THB 53.7 billion [USD 1.7 billion]; 80.9% of costs; hypothetical: THB 53.2 billion [USD 1.7 billion]; 80.8% of costs) and hospitalization (real world: THB 10.3 billion [USD 330.8 million]; 15.5% of costs; hypothetical: THB 10.2 billion [USD 328.9 million]; 15.5% of costs)., Conclusions: In-hospital antimicrobial-resistant infections produced a substantial economic toll in Thailand. This public health burden could be reduced with a strategy aimed at decreasing the rate of patients receiving inappropriate empiric treatment., Competing Interests: A.A.T., C.P., P.S., and N.K. are or have been employees of Pfizer and may own Pfizer stock. E.T. and TK are employees of Evidera, which received financial support from Pfizer. in connection with the study and the development of this manuscript. K.K. is an employee of University of Phayao and received financial support from Pfizer in connection with the study and the development of this manuscript., (© The Author(s) 2023.)

A combined Haemophilus influenzae type b (Hib)/meningococcal serogroup C (MenC) vaccine will soon be unavailable in the UK immunisation schedule due to discontinuation by the manufacturer. An interim statement by the Joint Committee on Vaccination and Immunisation (JCVI) advises stopping MenC immunisation at 12 months of age when this occurs. We undertook an analysis of the public health impact of various potential meningococcal vaccination strategies in the UK in the absence of the Hib/MenC vaccine. A static population-cohort model was developed evaluating the burden of IMD (using 2005-2015 epidemiological data) and related health outcomes (e.g., cases, cases with long-term sequelae, deaths), which allows for the comparison of any two meningococcal immunisation strategies. We compared potential strategies that included different combinations of infant and/or toddler MenACWY immunisations with the anticipated future situation in which a 12-month MenC vaccine is not used, but the MenACWY vaccine is routinely given in adolescents. The most effective strategy is combining MenACWY immunisation at 2, 4, and 12 months of age with the incumbent adolescent MenACWY immunisation programme, resulting in the prevention of an additional 269 IMD cases and 13 fatalities over the modelling period; of these cases, 87 would be associated with long-term sequelae. Among the different vaccination strategies, it was observed that those with multiple doses and earlier doses provided the greatest protection. Our study provides evidence suggesting that the removal of the MenC toddler immunisation from the UK schedule would potentially increase the risk of unnecessary IMD cases and have a detrimental public health impact if not replaced by an alternate infant and/or toddler programme. This analysis supports that infant and toddler MenACWY immunisation can provide maximal protection while complementing both infant/toddler MenB and adolescent MenACWY immunisation programmes in the UK.

Healthcare decision-makers face difficult decisions regarding COVID-19 booster selection given limited budgets and the need to maximize healthcare gain. A constrained optimization (CO) model was developed to identify booster allocation strategies that minimize bed-days by varying the proportion of the eligible population receiving different boosters, stratified by age, and given limited healthcare expenditure. Three booster options were included: B 1 , costing US $1 per dose, B 2 , costing US $2, and no booster (NB), costing US $0. B 1 and B 2 were assumed to be 55%/75% effective against mild/moderate COVID-19, respectively, and 90% effective against severe/critical COVID-19. Healthcare expenditure was limited to US$2.10 per person; the minimum expected expense using B 1, B 2, or NB for all. Brazil was the base-case country. The model demonstrated that B 1 for those aged <70 years and B 2 for those ≥70 years were optimal for minimizing bed-days. Compared with NB, bed-days were reduced by 75%, hospital admissions by 68%, and intensive care unit admissions by 90%. Total costs were reduced by 60% with medical resource use reduced by 81%. This illustrates that the CO model can be used by healthcare decision-makers to implement vaccine booster allocation strategies that provide the best healthcare outcomes in a broad range of contexts.

Objective: Very young children with type 1 diabetes often struggle to achieve glycemic targets, putting them at risk for long-term complications and creating an immense management burden for caregivers. We conducted the first evaluation of the Omnipod 5 Automated Insulin Delivery System in this population., Research Design and Methods: A total of 80 children aged 2.0-5.9 years used the investigational system in a single-arm study for 13 weeks following 14 days of baseline data collection with their usual therapy., Results: There were no episodes of severe hypoglycemia or diabetic ketoacidosis. By study end, HbA1c decreased by 0.55% (6.0 mmol/mol) (P < 0.0001). Time with sensor glucose levels in target range 70-180 mg/dL increased by 10.9%, or 2.6 h/day (P < 0.0001), while time with levels <70 mg/dL declined by median 0.27% (P = 0.0204)., Conclusions: Use of the automated insulin delivery system was safe, and participants experienced improved glycemic measures and reduced hypoglycemia during the study phase compared with baseline., (© 2022 by the American Diabetes Association.)

Objective: Many youth do not use the hybrid closed-loop system for type 1 diabetes effectively. This study evaluated the impact of financial incentives for diabetes-related tasks on use of the 670G hybrid closed-loop system and on glycemia., Methods: At auto mode initiation and for 16 weeks thereafter, participants received a flat rate for wearing and calibrating the sensor ($1/day), administering at least 3 mealtime insulin boluses per day ($1/day), and uploading ($5/week). Weekly bonuses were given for maintaining at least 70% of the time in auto mode, which were increased for persistent auto mode use from $3/week to a maximum of $13/week. If a participant failed to maintain auto mode for a week, the rewards were reset to baseline. Data from 17 participants aged 15.9 years ± 2.5 years (baseline hemoglobin A1c [HbA1c] 8.6% ± 1.1%) were collected at 6, 12, and 16 weeks. The reinforcers were withdrawn at 16 weeks, with a follow-up assessment at 24 weeks., Results: With reinforcers, the participants administered an average of at least 3 mealtime insulin boluses per day and wore the sensor over 70% of the time. However, auto mode use waned. HbA1c levels decreased by 0.5% after 6 weeks, and this improvement was maintained at 12 and 16 weeks (P < .05). Upon withdrawal of reinforcers, HbA1c levels increased back to baseline at 24 weeks., Conclusion: Compensation for diabetes-related tasks was associated with lower HbA1c levels, consistent administration of mealtime insulin boluses, and sustained sensor use. These results support the potential of financial rewards for improving outcomes in youth with type 1 diabetes., (Copyright © 2020 AACE. Published by Elsevier Inc. All rights reserved.)

Purpose: Ceftazidime/avibactam (CAZ-AVI) is a fixed-dose combination antibiotic approved in Europe and the United States for patients with hospital-acquired pneumonia, including ventilator-associated pneumonia (HAP/VAP). The economic benefits of a new drug such as CAZ-AVI are required to be assessed against those of available comparators, from the perspective of health care providers and payers, through cost-effectiveness and cost-utility analyses. The objective of this analysis was to compare the cost-effectiveness of CAZ-AVI versus meropenem in the empirical treatment of appropriate hospitalized patients with HAP/VAP caused by gram-negative pathogens, from the perspective of publicly funded health care in Italy (third-party perspective, based on the data from the REPROVE (Ceftazidime-Avibactam Versus Meropenem In Nosocomial Pneumonia, Including Ventilator-Associated Pneumonia) clinical study; ClinicalTrials.gov NCT01808092)., Methods: A patient-level, sequential simulation model of the HAP/VAP clinical course was developed using spreadsheet software. The analysis focused on direct medical costs. The time horizon of the model selected was 5 years, with an annual discount rate of 3% on costs and quality-adjusted life-years (QALYs). Clinical inputs for treatment comparisons were mainly obtained from the REPROVE clinical study data. In addition to clinical outcomes observed in the trial, the model incorporated impact of resistance pathogens, based on data from published studies and expert opinion. Certain assumptions were made for some model parameters due to a lack of data., Findings: The analysis demonstrated that the intervention sequence (CAZ-AVI followed by colistin + high-dose meropenem) versus the comparator sequence (meropenem followed by colistin + high-dose meropenem) provided a better clinical cure rate (+13.52%), which led to a shorter hospital stay (-0.40 days per patient), and gains in the number of life-years (+0.195) and QALYs (+0.350) per patient. The intervention sequence had an estimated net incremental total cost of €1254 ($1401) per patient, and the estimated incremental cost-effectiveness ratio was €3581 ($4000) per QALY gained, well below the willingness-to-pay threshold of €30,000 ($33,507) per QALY in Italy., Implications: The model results showed that CAZ-AVI is expected to provide clinical benefits in hospitalized patients with HAP/VAP in Italy at an acceptable cost compared to meropenem., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The rising incidence of resistance to currently available antibiotics among pathogens, particularly Gram-negative pathogens, in complicated intra-abdominal infections (cIAIs) has become a challenge for clinicians. Ceftazidime/avibactam (CAZ-AVI) is a fixed-dose antibiotic approved in Europe and the United States for treating (in combination with metronidazole) cIAI in adult hospitalised patients who have limited or no alternative treatment options. The approval was based on the results of RECLAIM, a Phase III, parallel-group, comparative study (RECLAIM 1 [NCT01499290] and RECLAIM 2 [NCT01500239]). The objective of our study was to assess the cost-effectiveness of CAZ-AVI plus metronidazole compared with 1) ceftolozane/tazobactam plus metronidazole and 2) meropenem, as an empiric treatment for the management of cIAI in Italy., Methods: A sequential, patient-level simulation model, with a 5-year time horizon and 3% annual discount rate (applied to both costs and health benefits), was developed using Microsoft Excel® to demonstrate the clinical course of the disease. The impact of resistant pathogens was included as an additional factor., Results: In the base-case analysis, the CAZ-AVI sequence (CAZ-AVI plus metronidazole followed by a colistin + tigecycline + high-dose meropenem combination after treatment failure), when compared to sequences for ceftolozane/tazobactam (ceftolozane/tazobactam plus metronidazole followed by colistin + tigecycline + high-dose meropenem after treatment failure) and meropenem (meropenem followed by colistin + tigecycline + high-dose meropenem after treatment failure), had better clinical outcomes with higher cure rates (93.04% vs. 91.52%; 92.98% vs. 90.24%, respectively), shorter hospital stays (∆ = - 0.38 and ∆ = - 1.24 days per patient, respectively), and higher quality-adjusted life years (QALYs) gained per patient (4.021 vs. 3.982; 4.019 vs. 3.960, respectively). The incremental cost effectiveness ratio in the CAZ-AVI sequence was €4099 and €15,574 per QALY gained versus each comparator sequence, respectively, well below the willingness-to-pay threshold of €30,000 per QALY accepted in Italy., Conclusions: The model results demonstrated that CAZ-AVI plus metronidazole could be a cost-effective alternative when compared with other antibiotic treatment options, as it is expected to provide better clinical benefits in hospitalised patients with cIAI in Italy., Competing Interests: Competing interestsTK and ET are employees of Evidera, which received funding from Pfizer in connection with conducting the study, developing this manuscript, and medical writing. RDV, NBP, and CC are employees of Pfizer, and hold Pfizer stock and/or stock options. CE is an employee of Klinikum Peine, Academic Hospital of Medical University Hannover, (Hannover, Germany), and MB is an employee of University of Genoa, Genoa and Hospital Policlinico San Martino – IRCCS, Genoa (Italy), each of which received research funding from Pfizer. Outside the submitted work, MB has received funding for scientific advisory boards, travel and speaker honoraria from Angelini, AstraZeneca, Bayer, Cidara, Cepheid, Cubist, Pfizer, Menarini, MSD, Nabriva, Paratek, Roche, Shionogi, Tetraphase, The Medicine Company and Astellas Pharma Inc., (© The Author(s). 2019.)

Ceftazidime/avibactam (CAZ-AVI) is a novel, fixed-dose combination antibiotic that has been approved in Europe and the United States for patients with complicated urinary tract infections (cUTIs) based on results of a Phase III, randomized, comparative study (RECAPTURE study). The present analysis evaluated cost-effectiveness of CAZ-AVI as an empirical treatment for hospitalized patients with cUTIs from the Italian publicly funded healthcare (third-party payer) perspective. A sequential, patient-level simulation model was developed that followed the clinical course of cUTI and generated 5000 pairs of identical patients (CAZ-AVI or imipenem as empirical treatment). The model included additional impact of resistant pathogens; patients who did not respond to empirical treatment were switched to second-line treatment of colistin+high dose carbapenem in both groups. The time horizon of the model was five years, with an annual discount rate of 3% applied to both costs and quality-adjusted life-years (QALYs). The analysis demonstrated that an intervention sequence (CAZ-AVI followed by colistin+high dose carbapenem) compared with a comparator sequence (imipenem followed by colistin+high dose carbapenem) was associated with a net incremental cost of €1015 per patient but provided better health outcomes in terms of clinical cure (97.65% vs. 91.08%; ∆ = 6.57%), shorter hospital stays (10.65 vs. 12.55 days; ∆ = 1.90 days), and QALYs gained per patient (4.190 vs. 4.063; ∆ = 0.126). The incremental cost-effectiveness ratio was €8039/QALY, which is well below the willingness-to-pay threshold of €30 000/QALY in Italy. The results showed that CAZ-AVI is expected to be a cost-effective treatment compared with imipenem for cUTI in Italy., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: This randomized, controlled trial evaluated a monetary-based reinforcement intervention for increasing self-monitoring of blood glucose (SMBG) among youth with poorly controlled type 1 diabetes., Methods: After a 2-week baseline, 60 participants were randomized to enhanced usual care (EUC) or Reinforcers. The Reinforcers group earned monetary rewards for SMBG and associated behaviors such as uploading glucose meters. Reinforcers were withdrawn at 24 weeks. A follow-up evaluation occurred at 36 weeks., Results: Participants in the reinforcers group increased the proportion of days they completed ≥4 SMBG from 14.6% at baseline to 64.4%, 47.5%, and 37.8% at 6, 12, and 24 weeks, respectively. In contrast, EUC participants declined from 22.7% at baseline to 17.5%, 10.5%, and 11.1% (Ps < .01 vs EUC at all time points). Group differences were attenuated but remained significant after withdrawal of reinforcers. Effect sizes for SMBG were very large during reinforcement and large after withdrawal of reinforcers. In the reinforcers group, mean A1c dropped from 9.5% ± 1.2% at baseline to 9.0% ± 1.3% at week 6 and 9.0% ± 1.4% at week 12. For EUC, A1c was 9.2% ± 0.2% at baseline and ranged from 9.2% ± 1.5% to 9.6% ± 1.6% throughout the study (P < .05 vs EUC). Group differences in A1c were no longer significant at weeks 24 and 36. Effect sizes for A1c were small during reinforcement and also after withdrawal of reinforcement., Conclusions: Monetary-based reinforcement of adolescents with type 1 diabetes caused durable increases in SMBG. Modification of the reinforcement structure may be needed to sustain improved metabolic control in this challenging age group., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Context: Type 1 diabetes in adolescence is characterized by insulin deficiency and insulin resistance (IR), both thought to increase cardiovascular disease risk. We previously demonstrated that adolescents with type 1 diabetes have adipose, hepatic, and muscle IR, and that metformin lowers daily insulin dose, suggesting improved IR. However, whether metformin improves IR in muscle, hepatic, or adipose tissues in type 1 diabetes was unknown., Objective: Measure peripheral, hepatic, and adipose insulin sensitivity before and after metformin or placebo therapy in youth with obesity with type 1 diabetes., Design: Double-blind, placebo-controlled clinical trial., Setting: Multi-center at eight sites of the T1D Exchange Clinic Network., Participants: A subset of 12- to 19-year-olds with type 1 diabetes (inclusion criteria: body mass index ≥85th percentile, HbA1c 7.5% to 9.9%, insulin dosing ≥0.8 U/kg/d) from a larger trial (NCT02045290) were enrolled., Intervention: Participants were randomized to 3 months of metformin (N = 19) or placebo (N = 18) and underwent a three-phase hyperinsulinemic euglycemic clamp with glucose and glycerol isotope tracers to assess tissue-specific IR before and after treatment., Main Outcome Measures: Peripheral insulin sensitivity, endogenous glucose release, rate of lipolysis., Results: Between-group differences in change in insulin sensitivity favored metformin regarding whole-body IR [change in glucose infusion rate 1.3 (0.1, 2.4) mg/kg/min, P = 0.03] and peripheral IR [change in metabolic clearance rate 0.923 (-0.002, 1.867) dL/kg/min, P = 0.05]. Metformin did not impact insulin suppression of endogenous glucose release (P = 0.12). Adipose IR was not assessable with traditional methods in this highly IR population., Conclusions: Metformin appears to improve whole-body and peripheral IR in youth who are overweight/obese with type 1 diabetes., (Copyright © 2019 Endocrine Society.)

Context: Postprandial hyperglycemia remains a challenge in type 1 diabetes (T1D) due, in part, to dysregulated increases in plasma glucagon levels after meals., Objective: This study was undertaken to examine whether 3 to 4 weeks of therapy with pramlintide or liraglutide might help to blunt postprandial hyperglycemia in T1D by suppressing plasma glucagon responses to mixed-meal feedings., Design: Two parallel studies were conducted in which participants underwent mixed-meal tolerance tests (MMTTs) without premeal bolus insulin administration before and after 3 to 4 weeks of treatment with either pramlintide (8 participants aged 20 ± 3 years, hemoglobin A1c 6.9 ± 0.5%) or liraglutide (10 participants aged 22 ± 3 years, hemoglobin A1c 7.6 ± 0.9%)., Results: Compared with pretreatment responses to the MMTT, treatment with pramlintide reduced the peak increment in glucagon from 32 ± 16 to 23 ± 12 pg/mL (P < 0.02). In addition, the incremental area under the plasma glucagon curve from 0 to 120 minutes dropped from 1988 ± 590 to 737 ± 577 pg/mL/min (P < 0.001), which was accompanied by a similar reduction in the meal-stimulated increase in the plasma glucose curve from 11,963 ± 1424 mg/dL/min pretreatment vs 2493 ± 1854 mg/dL/min after treatment (P < 0.01). In contrast, treatment with liraglutide had no effect on plasma glucagon and glucose responses during the MMTT., Conclusions: Adjunctive treatment with pramlintide may provide an effective means to blunt postmeal hyperglycemia in T1D by suppressing dysregulated plasma glucagon responses. In contrast, plasma glucose and glucagon responses were unchanged after 3 to 4 weeks of treatment with liraglutide.

Background and Objectives: Opioid-induced constipation (OIC) is the most common adverse effect reported in patients receiving opioids to manage pain. Initial treatment with laxatives provides inadequate response in some patients. Naloxegol is a peripherally acting µ-opioid receptor antagonist used to treat patients with inadequate response to laxative(s) (laxative inadequate responder [LIR]). A cost-effectiveness model was constructed from the UK payer perspective to compare oral naloxegol 25 mg with placebo in non-cancer LIR patients receiving opioids for chronic pain, and a scenario analysis of naloxegol 25 mg with rescue laxatives compared with placebo with rescue laxatives in the same patient population., Methods: The model comprised a decision tree for the first 4 weeks of treatment, followed by a Markov model with a 4-week cycle length and the following states: 'OIC', 'non-OIC (on treatment)', 'non-OIC (untreated)' and 'death'. Two phase III trials with a follow-up period of 12 weeks provided data on treatment efficacy, transition probabilities, adverse event frequency and patient utility. Resource utilisation data were sourced from a UK-based burden of illness study and physician surveys. A UK National Health Service and Personal Social Service perspective was adopted; costs and health-related quality of life gains were discounted at a rate of 3.5 %. The model was run over a time horizon of 5 years, reflecting the average period of opioid use., Results: Naloxegol has an incremental cost-effectiveness ratio of £10,849 per quality-adjusted life-year gained versus placebo, and £11,179 when rescue laxatives are made available in both arms (2014 values). Model outcomes were only sensitive to variations in utility inputs. However, the probabilistic sensitivity analyses indicate that naloxegol has a 91 % probability of being cost effective at a £20,000 threshold when compared with placebo., Conclusions: Naloxegol is likely a cost-effective treatment option for LIR patients with OIC. This assessment should be supported by further work on the utility of patients with OIC, including how utility varies with more granular measures of OIC.

Objective: To assess the economic value of carfilzomib (Kyprolis), this study developed the Kyprolis Global Economic Model (K-GEM), which examined from a United States (US) payer perspective the cost-effectiveness of carfilzomib-lenalidomide-dexamethasone (KRd) versus lenalidomide-dexamethasone (Rd) in relapsed multiple myeloma (RMM; 1-3 prior therapies) based on results from the phase III ASPIRE trial that directly compared these regimens., Methods: A partitioned survival model that included three health states of progression-free (on or off treatment), post-progression, and death was developed. Using ASPIRE data, the effect of treatment regimens as administered in the trial was assessed for progression-free survival and overall survival (OS). Treatment effects were estimated with parametric regression models adjusting for baseline patient characteristics and applied over a lifetime horizon. US Surveillance, Epidemiology and End Results (1984-2014) registry data were matched to ASPIRE patients to extrapolate OS beyond the trial. Estimated survival was adjusted to account for utilities across health states. The K-GEM considered the total direct costs (pharmacy/medical) of care for patients treated with KRd and Rd., Results: KRd was estimated to be more effective compared to Rd, providing 1.99 life year and 1.67 quality-adjusted life year (QALY) gains over the modeled horizon. KRd-treated patients incurred $179,393 in total additional costs. The incremental cost-effectiveness ratio (ICER) was $107,520 per QALY., Limitations: Extrapolated survival functions present the greatest uncertainty in the modeled results. Utilities were derived from a combination of sources and assumed to reflect how US patients value their health state., Conclusions: The K-GEM showed KRd is cost-effective, with an ICER of $107,520 per QALY gained against Rd for the treatment of patients with RMM (1-3 prior therapies) at a willingness-to-pay threshold of $150,000. Reimbursement of KRd for patients with RMM may represent an efficient allocation of the healthcare budget.

Benefits of belatacept-based immunosuppressive regimens in human immunodeficiency virus (HIV)-positive renal transplant recipients include avoidance of drug interactions between calcineurin inhibitors and highly active antiretroviral agents and decreased likelihood or severity of nonimmune toxicities such as new-onset diabetes after transplant, hyperlipidemia and hypertension. We report a successful case of de novo belatacept at >18 mo from transplant in an HIV-positive black man aged 50 years who received his first transplant from a living related kidney donor. To our knowledge, this case is the first reported of belatacept use in an HIV-positive renal transplant recipient., (© Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Objective: To evaluate the effectiveness of monetary reinforcement to increase the frequency of self-monitoring blood glucose (SMBG)., Research Design and Methods: Ten adolescents with poorly controlled diabetes enrolled in a 12-week program in which they earned monetary reinforcers based on SMBG frequency ($0.10 per test, with bonuses for ≥4 tests per day, and $251.40 maximum)., Results: SMBG increased from 1.8 ± 1.0 to 4.9 ± 1.0 tests per day (P < 0.001) with 90% completing four or more tests per day. Mean A1C fell from 9.3 ± 0.9% to 8.4 ± 1.5% (P = 0.05). Adolescents and parents reported high satisfaction with procedures., Conclusions: Reinforcing adolescents for SMBG may increase testing and improve A1C., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

In the Gram-negative enterobacterium Erwinia (Pectobacterium) and Serratia sp. ATCC 39006, intrinsic resistance to the carbapenem antibiotic 1-carbapen-2-em-3-carboxylic acid is mediated by the CarF and CarG proteins, by an unknown mechanism. Here, we report a high-resolution crystal structure for the Serratia sp. ATCC 39006 carbapenem resistance protein CarG. This structure of CarG is the first in the carbapenem intrinsic resistance (CIR) family of resistance proteins from carbapenem-producing bacteria. The crystal structure shows the protein to form a homodimer, in agreement with results from analytical gel filtration. The structure of CarG does not show homology with any known antibiotic resistance proteins nor does it belong to any well-characterised protein structural family. However, it is a close structural homologue of the bacterial inhibitor of invertebrate lysozyme, PliI-Ah, with some interesting structural variations, including the absence of the catalytic site responsible for lysozyme inhibition. Both proteins show a unique β-sandwich fold with short terminal α-helices. The core of the protein is formed by stacked anti-parallel sheets that are individually very similar in the two proteins but differ in their packing interface, causing the splaying of the two sheets in CarG. Furthermore, a conserved cation binding site identified in CarG is absent from the homologue., (Copyright © 2014. Published by Elsevier Ltd.)

Objective: An integrated sensor-augmented pump system has been introduced that interrupts basal insulin infusion for 2 h if patients fail to respond to low-glucose alarms. It has been suggested that such interruptions of basal insulin due to falsely low glucose levels detected by sensor could lead to diabetic ketoacidosis. We hypothesized that random suspension of basal insulin for 2 h in the overnight period would not lead to clinically important increases in blood β-hydroxybutyrate levels despite widely varying glucose values prior to the suspension., Research Design and Methods: Subjects measured blood glucose and blood β-hydroxybutyrate levels using a meter each night at 9:00 p.m., then fasted until the next morning. On control nights, the usual basal rates were continued; on experimental nights, the basal insulin infusion was reprogrammed for a 2-h zero basal rate at random times after 11:30 p.m., Results: In 17 type 1 diabetic subjects (mean age 24 ± 9 years, diabetes duration 14 ± 11 years, A1C level 7.3 ± 0.5% [56 mmol/mol]), blood glucose and blood β-hydroxybutyrate levels were similar at 9:00 p.m. on suspend nights (144 ± 63 mg/dL and 0.09 ± 0.07 mmol/L) and nonsuspend nights (151 ± 65 mg/dL and 0.08 ± 0.06 mmol/L) (P = 0.39 and P = 0.47, respectively). Fasting morning blood glucose levels increased after suspend nights compared with nonsuspend nights (191 ± 68 vs. 141 ± 75 mg/dL, P < 0.0001), and the frequency of fasting hypoglycemia decreased the morning following suspend nights (P < 0.0001). Morning blood β-hydroxybutyrate levels were slightly higher after suspension (0.13 ± 0.14 vs. 0.09 ± 0.11 mmol/L, P = 0.053), but the difference was not clinically important., Conclusions: Systems that suspend basal insulin for 2 h are safe and do not lead to clinically significant ketonemia even if the blood glucose level is elevated at the time of the suspension.

Background and Objective: Subcutaneously injected rapid-acting insulin analogs do not replicate physiologic insulin action due to delays in their onset and peak action resulting in postprandial glucose excursions. The InsuPatch (IP) is a novel insulin infusion site warming device developed to accelerate insulin action by increasing blood flow to the area of insulin absorption. Thirteen adolescents with type 1 diabetes (T1D, mean age 14 ± 4 yr) were enrolled in this study to investigate the effect of the IP on the pharmacodynamics and pharmacokinetics of a 0.2 unit/kg bolus dose of aspart insulin using the euglycemic clamp technique., Research Design and Methods: Each subject underwent two euglycemic clamp procedures on separate occasions: one with IP and one without IP activation in random order., Results: When the insulin bolus was given with IP activation as compared to without IP activation, time to reach maximum insulin action (T(GIRmax)) and to reach 50% maximum action (T(50%GIRmax)) were 35 and 18 min earlier (125 ± 8 min vs. 90 ± 6 min, p = 0.002 and 58 ± 5 min. vs. 40 ± 3 min, p = 0.01, respectively), and the area under curve, AUC(GIR 0-90 min), reflecting early glucodynamic action, was significantly greater (p = 0.001). IP activation also accelerated the rise in plasma insulin levels after the bolus (p = 0.03) and resulted in a higher peak (p = 0.04) and greater overall increase (p = 0.02) in plasma insulin levels., Conclusions: Our results show that insulin infusion site warming with IP activation accelerates the time action profile of aspart insulin which may be of benefit to current open-loop and future closed-loop insulin delivery in patients with T1D., (© 2012 John Wiley & Sons A/S.)

Inducible expression is a valuable approach for the elucidation of gene functions. Here, we present new configurations of the tetracycline-dependent gene regulation (tet) system for Staphylococcus aureus. To provide improved and expanded modes of control, strains and plasmids were constructed for the constitutive expression of tetR or a variant allele, rev-tetR(r2). The encoded regulators respond differently to the effector anhydrotetracycline (ATc), which causes target gene expression to be induced with TetR or repressed with rev-TetR. To quantify and compare regulation mediated by episomal or chromosomal (rev-)tetR constructs, expression from a chromosomal P(xyl/tet)-gfpmut2 fusion was measured. Chromosomally encoded TetR showed tight repression and allowed high levels of dose-dependent gene expression in response to ATc. Regulatory abilities were further verified using a strain in which a native S. aureus gene (zwf) was put under tet control in its native chromosomal location. Tight repression was reflected by transcript amounts, which were barely detectable under repressed conditions and high in ATc-treated cells. In reporter gene assays, this type of control, termed Tet-on, was more efficient than Tet-off regulation, in which addition of ATc causes downregulation of a target gene. The latter was achieved and quantified by direct rev-TetR control of P(xyl/tet)-gfpmut2. Additionally, TetR was used in trans to control the expression of antisense RNA for posttranscriptional gene silencing. Induction of antisense RNA expression of the fabI gene caused pronounced growth retardation lasting several hours. These results demonstrate the efficiency of the new tet systems and their flexible use for different purposes.

Allelic variants of CHEK2 contribute to an elevated risk for human breast cancer and possibly other cancer types. In particular, the CHEK2*1100delC polymorphic variant has been identified as a low-penetrance breast cancer susceptibility allele in breast cancer families with wild type BRCA1 and BRCA2. To better understand the molecular basis by which this allele increases risk for disease, we have generated a mouse in which the wild type CHEK2 (Chk2 in mouse) allele has been replaced with the 1100delC variant. Mouse embryo fibroblasts (MEFs) derived from these mice have an altered cell cycle profile in which a far greater proportion of cells are in S-phase and in G2 (4N) compared with wild type cells. The mutant cells show signs of spontaneous genomic instability as indicated by polyploidy and an increase in DNA double strand breaks.

Epidermolysis bullosa simplex with mottled pigmentation (EBS-MP), characterized by trauma-induced blisters, distinct pigmentary changes of the trunk and extremities, and acral hyperkeratotic papules, is almost exclusively caused by a common KRT5 missense mutation affecting the V1 region of keratin 5. We studied the first Hispanic family, the largest single generation of affected family members in which 5 out of 10 siblings inherited EBS-MP from their affected father, as well a second large pedigree, the first reported of Finnish ancestry. In both families, the heterozygous transition mutation 74C-->T of the keratin 5 gene, which results in amino acid substitution P25L, completely co-segregated with the EBS-MP phenotype.