Obesity management for the hepatologist-What to do, how to do it and why?

Obesity is highly prevalent in hepatology clinics and has a significant impact on chronic liver disease and patient management. Hepatologists and gastroenterologists need to be actively engaged in the management of obesity. This review provides a detailed approach to this challenging comorbidity.

Objective monitoring tools for improved management of childhood asthma.

Asthma is a common chronic disease amongst children. Epidemiological studies showed that the mortality rate of asthma in children is still high worldwide. Asthma control is therefore essential to minimize asthma exacerbations, which can be fatal if the condition is poorly controlled. Frequent monitoring could help to detect asthma progression and ensure treatment effectiveness. Although subjective asthma monitoring tools are available, the results vary as they rely on patients' self-perception. Emerging evidence suggests several objective tools could have the potential for monitoring purposes. However, there is no consensus to standardise the use of objective monitoring tools. In this review, we start with the prevalence and severity of childhood asthma worldwide. Then, we detail the latest available objective monitoring tools, focusing on their effectiveness in paediatric asthma management. Publications of spirometry, fractional exhaled nitric oxide (FeNO), hyperresponsiveness tests and electronic monitoring devices (EMDs) between 2016 and 2023 were included. The potential advantages and limitations of each tool were also discussed. Overall, this review provides a summary for researchers dedicated to further improving objective paediatric asthma monitoring and provides insights for clinicians to incorporate different objective monitoring tools in clinical practices.

The Effects of the Dopamine Transporter Ligands JJC8-088 and JJC8-091 on Cocaine versus Food Choice in Rhesus Monkeys.

Although there are no Food and Drug Administration-approved treatments for cocaine use disorder, several modafinil analogs have demonstrated promise in reducing cocaine self-administration and reinstatement in rats. Furthermore, the range of dopamine transporter (DAT) compounds provides an opportunity to develop pharmacotherapeutics without abuse liability. This study extended the comparison of JJC8-088 and JJC8-091, the former compound having higher DAT affinity and predicted abuse liability, to rhesus monkeys using a concurrent cocaine versus food schedule of reinforcement. First, binding to striatal DAT was examined in cocaine-naïve monkey tissue. Next, intravenous pharmacokinetics of both JJC compounds were evaluated in cocaine-experienced male monkeys (n = 3/drug). In behavioral studies, acute and chronic administration of both compounds were evaluated in these same monkeys responding under a concurrent food versus cocaine (0 and 0.003-0.1 mg/kg per injection) schedule of reinforcement. In nonhuman primate striatum, JJC8-088 had higher DAT affinity compared with JJC8-091 (14.4 ± 9 versus 2730 ± 1270 nM, respectively). Both JJC compounds had favorable plasma pharmacokinetics for behavioral assessments, with half-lives of 1.1 hours and 3.5 hours for JJC8-088 (0.7 mg/kg, i.v.) and JJC8-091 (1.9 mg/kg, i.v.), respectively. Acute treatment with both compounds shifted the cocaine dose-response curve to the left. Chronic treatment with JJC8-088 decreased cocaine choice in two of the three monkeys, whereas JJC8-091 only modestly reduced cocaine allocation in one monkey. Differences in affinities of JJC8-091 DAT binding in monkeys compared with rats may account for the poor rodent-to-monkey translation. Future studies should evaluate atypical DAT blockers in combination with behavioral interventions that may further decrease cocaine choice. SIGNIFICANCE STATEMENT: Cocaine use disorder (CUD) remains a significant public health problem with no Food and Drug Administration-approved treatments. The ability of drugs that act in the brain in a similar manner to cocaine, but with lower abuse liability, has clinical implications for a treatment of CUD.

Co-Delivery of D-LAK Antimicrobial Peptide and Capreomycin as Inhaled Powder Formulation to Combat Drug-Resistant Tuberculosis.

INTRODUCTION: The emergence of multidrug-resistant (MDR) Mycobacterium tuberculosis (Mtb) posed a severe challenge to tuberculosis (TB) management. The treatment of MDR-TB involves second-line anti-TB agents, most of which are injectable and highly toxic. Previous metabolomics study of the Mtb membrane revealed that two antimicrobial peptides, D-LAK120-A and D-LAK120-HP13, can potentiate the efficacy of capreomycin against mycobacteria. AIMS: As both capreomycin and peptides are not orally available, this study aimed to formulate combined formulations of capreomycin and D-LAK peptides as inhalable dry powder by spray drying. METHODS AND RESULTS: A total of 16 formulations were prepared with different levels of drug content and capreomycin to peptide ratios. A good production yield of over 60% (w/w) was achieved in most formulations. The co-spray dried particles exhibited spherical shape with a smooth surface and contained low residual moisture of below 2%. Both capreomycin and D-LAK peptides were enriched at the surface of the particles. The aerosol performance of the formulations was evaluated with Next Generation Impactor (NGI) coupled with Breezhaler®. While no significant difference was observed in terms of emitted fraction (EF) and fine particle fraction (FPF) among the different formulations, lowering the flow rate from 90 L/min to 60 L/min could reduce the impaction at the throat and improve the FPF to over 50%. CONCLUSIONS: Overall, this study showed the feasibility of producing co-spray dried formulation of capreomycin and antimicrobial peptides for pulmonary delivery. Future study on their antibacterial effect is warranted.

Factors influencing participation in home, school, and community settings by children and adolescents with neuromuscular disorders: A qualitative descriptive study.

AIM: This study explored how children and adolescents with a neuromuscular disorder (NMD) and their parents experienced barriers and enablers to the child's participation. METHOD: This was a qualitative descriptive design. Fourteen semi-structured interviews were conducted (n = 13 mothers, n = 4 fathers, n = 8 children and adolescents) including one to three family members for each interview according to their preference. Data were analysed by content analysis, using the family of Participation-Related Constructs (fPRC), to characterize the components of participation. RESULTS: Meaningful participation was illustrated in the personal categories of the fPRC including the child's sense of self, preferences, and competence to perform activities. Enablers and barriers related to adaptive equipment and activity modification, social relationships, inclusion, accessibility to venues, social attitudes, and policies. INTERPRETATION: Personal motivators are critical to understanding what participation is meaningful to children and adolescents with NMDs. Social and physical supports within the child's immediate environment as well as accessibility and advocacy more widely in the community enable participation. The fPRC is a useful tool for understanding participation in these children; it informs how to support participation and suggests domains for evaluation in future intervention studies. Advocacy for participation should consider targets in the immediate and broader environments. WHAT THIS PAPER ADDS: The family of Participation-Related Constructs classified the components of participation for children and adolescents with neuromuscular disorders. Meaningful participation involved a complex interaction between personal and environmental factors. Barriers to participation included poor accessibility, lack of equipment, and social exclusion.

Spray-Dried and Spray-Freeze-Dried Powder Formulations of an Anti-Interleukin-4Rα Antibody for Pulmonary Delivery.

OBJECTIVE: The therapeutic options for severe asthma are limited, and the biological therapies are all parenterally administered. The purpose of this study was to formulate a monoclonal antibody that targets the receptor for IL-4, an interleukin implicated in the pathogenesis of severe asthma, into a dry powder intended for delivery via inhalation. METHODS: Dehydration was achieved using either spray drying or spray freeze drying, which exposes the thermolabile biomacromolecules to stresses such as shear and adverse temperatures. 2-hydroxypropyl-beta-cyclodextrin was incorporated into the formulation as protein stabiliser and aerosol performance enhancer. The powder formulations were characterised in terms of physical and aerodynamic properties, while the antibody was assessed with regard to its structural stability, antigen-binding ability, and in vitro biological activity after drying. RESULTS: The spray-freeze-dried formulations exhibited satisfactory aerosol performance, with emitted fraction exceeding 80% and fine particle fraction of around 50%. The aerosolisation of the spray-dried powders was hindered possibly by high residual moisture. Nevertheless, the antigen-binding ability and inhibitory potency were unaffected for the antibody in the selected spray-dried and spray-freeze-dried formulations, and the antibody was physically stable even after one-year storage at ambient conditions. CONCLUSIONS: The findings of this study establish the feasibility of developing an inhaled dry powder formulation of an anti-IL-4R antibody using spray drying and spray freeze drying techniques with potential for the treatment of severe asthma.

Association of cash payment with intensity of opioid prescriptions.

BACKGROUND: It is difficult to track use and outcomes in patients who pay cash for their prescriptions at the pharmacy. In Texas, 14% of all opioid prescriptions are paid with cash, often by uninsured patients and pharmacy shoppers. OBJECTIVE: To evaluate the association of cash payment with intensity of opioid prescriptions. METHODS: Using a prescription drug monitoring program and the U.S. Census data for the 2019 calendar year, this cross-sectional descriptive study analyzed more than 4 million opioid prescriptions in Texas residents aged 18-64 years. The payment type was coded as insurance if the prescription was paid in whole or in part by a health plan and as cash otherwise. Daily morphine milligram equivalent (MME) dose was used to compare the intensity of opioid prescriptions. The association of uninsured rates with mean daily MME and the number of opioid prescriptions paid with cash per 100,000 persons were assessed at a county level. RESULTS: Cash payment was associated with 30% higher mean daily MME (59 vs. 45; P < 0.001) than insurance payment. This difference was driven by the prescriptions for patients aged 25-34 years and from the highest decile of prescribers based on the percentage of opioid prescriptions paid by cash. For instance, cash payment was associated with 82% higher mean daily MME (91 vs. 50; P < 0.001) when patients aged 25-34 years obtained their prescriptions from the highest decile of prescribers. At a county level, uninsured rates were not associated with mean daily MMEs or the number of opioid prescriptions paid with cash. CONCLUSION: Cash payment was associated with a higher intensity of opioid prescriptions, mirroring the rates of drug overdose deaths across the patient age groups. Further research and policy actions need to address unmet pain management needs in uninsured patients and potential pharmacy shopping with cash payment and fraudulent identifications.

Projecting the long-term societal value of a disease-modifying treatment for Alzheimer's disease in the United States.

INTRODUCTION: We estimate societal value of a disease-modifying Alzheimer's disease (AD) treatment that reduces progression by 30% in early stages. METHODS: Using the International Society for Pharmacoeconomics and Outcomes Research value flower as framework, we estimate gross societal value, that is, not including treatment cost, from avoided medical and social care costs, productivity and quality-adjusted life-years (QALY) gains for patients and caregivers, adjusting for severity of disease, value of financial insurance, and value of insurance for currently unafflicted adults with a Markov model. RESULTS: Predicted societal value from 2021 until 2041 is $2.62 trillion for the overall afflicted US population and $986 billion for the 2021 prevalent cohort or $134,418 per person, with valuation of patients' QALY gains (63%) and avoided nursing-home costs (20%) as largest components. Delays in access because of health system capacity constraints could reduce realized value between 52% and 69%. The value of insurance for the unafflicted is $4.52 trillion or $18,399 on average per person. DISCUSSION: With a total of $5.5 trillion, the projected gross societal value of a hypothetical AD treatment is substantial, which may help to put the cost of treatment into perspective.

Aberrant Transferrin and Ferritin Upregulation Elicits Iron Accumulation and Oxidative Inflammaging Causing Ferroptosis and Undermines Estradiol Biosynthesis in Aging Rat Ovaries by Upregulating NF-Κb-Activated Inducible Nitric Oxide Synthase: First Demonstration of an Intricate Mechanism.

We report herein a novel mechanism, unraveled by proteomics and validated by in vitro and in vivo studies, of the aberrant aging-associated upregulation of ovarian transferrin and ferritin in rat ovaries. The ovarian mass and serum estradiol titer plummeted while the ovarian labile ferrous iron and total iron levels escalated with age in rats. Oxidative stress markers, such as nitrite/nitrate, 3-nitrotyrosine, and 4-hydroxy-2-nonenal, accumulated in the aging ovaries due to an aberrant upregulation of the ovarian transferrin, ferritin light/heavy chains, and iron regulatory protein 2(IRP2)-mediated transferrin receptor 1 (TfR1). Ferritin inhibited estradiol biosynthesis in ovarian granulosa cells in vitro via the upregulation of a nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and p65/p50-induced oxidative and inflammatory factor inducible nitric oxide synthase (iNOS). An in vivo study demonstrated how the age-associated activation of NF-κB induced the upregulation of iNOS and the tumor necrosis factor α (TNFα). The downregulation of the keap1-mediated nuclear factor erythroid 2-related factor 2 (Nrf2), that induced a decrease in glutathione peroxidase 4 (GPX4), was observed. The aberrant transferrin and ferritin upregulation triggered an iron accumulation via the upregulation of an IRP2-induced TfR1. This culminates in NF-κB-iNOS-mediated ovarian oxi-inflamm-aging and serum estradiol decrement in naturally aging rats. The iron accumulation and the effect on ferroptosis-related proteins including the GPX4, TfR1, Nrf2, Keap1, and ferritin heavy chain, as in testicular ferroptosis, indicated the triggering of ferroptosis. In young rats, an intraovarian injection of an adenovirus, which expressed iron regulatory proteins, upregulated the ovarian NF-κB/iNOS and downregulated the GPX4. These novel findings have contributed to a prompt translational research on the ovarian aging-associated iron metabolism and aging-associated ovarian diseases.

Optimization of PEGylated KL4 Peptide for siRNA Delivery with Improved Pulmonary Tolerance.

Pulmonary delivery of small interfering RNA (siRNA) is a promising therapeutic strategy for treating various respiratory diseases but an effective carrier for the delivery of siRNA into the cells of the lungs and a robust gene-silencing effect is still lacking. Previously, we reported that the KL4 peptide, a synthetic cationic peptide with a repeating KLLLL sequence, can mediate effective siRNA transfection in lung epithelial cells but its high hydrophobic leucine content, and hence poor water solubility, limits its application as a delivery vector. Here, we show that the covalent attachment of monodisperse poly(ethylene glycol) (PEG) improves the solubility of KL4 and the uptake of its complex with siRNA into lung epithelial cells, such that very robust silencing is produced. All PEGylated KL4 peptides, with PEG length varying between 6 and 24 monomers, could bind and form nanosized complexes with siRNA, but the interaction between siRNA and peptides became weaker as the PEG chain length increased. All PEGylated KL4 peptides exhibited satisfactory siRNA transfection efficiency on three human lung epithelial cell lines, including A549 cells, Calu-3 cells, and BEAS-2B cells. The PEG12KL4 peptide, which contains 12 monomers of PEG, was optimal for siRNA delivery and also demonstrated a low risk of inflammatory response and toxicity in vivo following pulmonary administration.

Impact of diabetes and chronic dialysis on post-transplant survival in combined heart-kidney transplant recipients.

Growing research supports an increased survival benefit of combined heart and kidney transplantation in patients with both heart and renal failure. As a result, the frequency of these combined transplants continues to increase. Despite this trend, little has been done to quantify the impact of chronic illness in this population. We identified adult recipients of combined heart-kidney transplant from the Scientific Registry of Transplant Recipients (SRTR) database between 2005 and 2018. We focused on renal disease secondary to diabetes and duration of dialysis as markers of chronic illness. The primary outcome was post-transplant mortality. Our final multivariable Cox proportional hazard model found that diabetes-associated renal disease (HR 1.57, 95% CI 1.14-2.15, p = .01) and dialysis duration (HR 1.08, 95% CI 1.01-1.15, p = .02) were significant predictors of post-transplant mortality. Given the significant impact of dialysis duration and renal disease secondary to diabetes mellitus, these chronically ill patients should be closely examined for conditions such as peripheral vascular disease and frailty, which have been shown to affect mortality in heart transplant recipients and are prevalent in the chronic dialysis population.

Model studies towards prodrugs of the glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON) containing a diazo precursor.

Two distinct diazo precursors, imidazotetrazine and nitrous amide, were explored as promoieties in designing prodrugs of 6-diazo-5-oxo-l-norleucine (DON), a glutamine antagonist. As a model for an imidazotetrazine-based prodrug, we synthesized (S)-2-acetamido-6-(8-carbamoyl-4-oxoimidazo[5,1-d][1,2,3,5]tetrazin-3(4H)-yl)-5-oxohexanoic acid (4) containing the entire scaffold of temozolomide, a precursor of the DNA-methylating agent clinically approved for the treatment of glioblastoma multiforme. For a nitrous amide-based prodrug, we synthesized 2-acetamido-6-(((benzyloxy)carbonyl)(nitroso)amino)-5-oxohexanoic acid (5) containing a N-nitrosocarbamate group, which can be converted to a diazo moiety via a mechanism similar to that of streptozotocin, a clinically approved diazomethane-releasing drug containing an N-nitrosourea group. Preliminary characterization confirmed formation of N-acetyl DON (6), also known as duazomycin A, from compound 4 in a pH-dependent manner while compound 5 did not exhibit sufficient stability to allow further characterization. Taken together, our model studies suggest that further improvements are needed to translate this prodrug approach into glutamine antagonist-based therapy.

Treatment patterns in patients with metastatic non-small-cell lung cancer in the era of immunotherapy.

Background: Chemotherapy (CT) alone was previously standard first-line (1L) therapy for metastatic non-small-cell lung cancer (NSCLC) but alternative treatments, including immunotherapy (I-O), are now available. Patients & methods: In this retrospective study, adults with stage IV NSCLC who initiated 1L treatment between 1 August 2018 and 31 December 2019 and had ≥2 visits were identified in the Flatiron database. Patients were followed up until 30 June 2020. Baseline characteristics and treatment patterns were described by treatment group: CT, I-O + CT, I-O monotherapy and other. Results: Approximately 20% of patients received 1L CT in the 2018-2019 timeframe studied; these patients tended to have squamous histology and low (≤49%) programmed death ligand-1 expression. Conclusion: A proportion of patients with metastatic NSCLC still receive 1L CT despite the availability and widespread use of I-O therapies.

It's not always too late: a case for minimally invasive salvage esophagectomy.

INTRODUCTION: Standard of care for locally advanced esophageal carcinoma is neoadjuvant chemoradiation (nCRT) and surgical resection 4-8 weeks after completion of nCRT. It is recommended that the CRT to surgery interval not exceed 90 days. Many patients do not undergo surgery within this timeframe due to patient/physician preference, complete clinical response, or poor performance status. Select patients are offered salvage esophagectomy (SE), defined in two ways: resection for recurrent/persistent disease after complete response to definitive CRT (dCRT) or esophagectomy performed > 90 days after completion of nCRT. Salvage esophagectomy reportedly has higher postoperative morbidity and poor survival outcomes. In this study, we assessed outcomes, overall, and disease-free survival of patients undergoing salvage esophagectomy by both definitions (recurrent/persistent disease after dCRT and/or > 90 days), compared to planned (resection after nCRT/within 90 days) esophagectomy (PE). MATERIALS AND METHODS: Retrospective review of a prospectively maintained database identified patients who underwent minimally invasive esophagectomy at a single institution from 2009 to 2019. Esophagectomy for benign disease and patients who did not receive nCRT were excluded. Outcomes included postoperative complications, length of stay (LOS), disease-free survival, and overall survival. RESULTS: 97 patients underwent minimally invasive esophageal resection for esophageal carcinoma. 89.7% of patients were male. Mean age was 64.9 years (range 36-85 years). 94.8% of patients had adenocarcinoma, with 16 transthoracic and 81 transhiatal approaches. On comparing planned esophagectomy (n = 87) to esophagectomy after dCRT failure (n = 10), no significant differences were identified in overall survival (p = 0.73), disease-free survival (p = 0.32), 30-day or major complication rate, anastomotic leak, or LOS. Similarly, when comparing esophagectomy < 90 days after CRT (n = 62) to > 90 days after CRT completion (n = 35), no significant differences were identified in overall survival (p = 0.39), disease-free survival (p = 0.71), 30-day or major complication rate, LOS, or anastomotic leak rate between groups. In this comparison, local recurrence was noted to be elevated with SE as compared to PE (64.3% vs. 25.0%, p = 0.04). CONCLUSION: Overall survival and disease-free survival were equivalent between SE and PE. Local recurrence was noted to be increased with SE, though this did not appear to affect survival. Although planned esophagectomy remains the standard of care, salvage esophagectomy has comparable outcomes and is appropriate for selected patients.

General surgery training in the era of robotic surgery: a qualitative analysis of perceptions from resident and attending surgeons.

BACKGROUND: The use of the surgical robot has increased annually since its introduction, especially in general surgery. Despite the tremendous increase in utilization, there are currently no validated curricula to train residents in robotic surgery, and the effects of robotic surgery on general surgery residency training are not well defined. In this study, we aim to explore the perceptions of resident and attending surgeons toward robotic surgery education in general surgery residency training. METHODS: We performed a qualitative thematic analysis of in-person, one-on-one, semi-structured interviews with general surgery residents and attending surgeons at a large academic health system. Convenient and purposeful sampling was performed in order to ensure diverse demographics, experiences, and opinions were represented. Data were analyzed continuously, and interviews were conducted until thematic saturation was reached, which occurred after 20 residents and seven attendings. RESULTS: All interviewees agreed that dual consoles are necessary to maximize the teaching potential of the robotic platform, and the importance of simulation and simulators in robotic surgery education is paramount. However, further work to ensure proper access to simulation resources for residents is necessary. While most recognize that bedside-assist skills are essential, most think its educational value plateaus quickly. Lastly, residents believe that earlier exposure to robotic surgery is necessary and that almost every case has a portion that is level-appropriate for residents to perform on the robot. CONCLUSIONS: As robotic surgery transitions from novelty to ubiquity, the importance of effective general surgery robotic surgery training during residency is paramount. Through in-depth interviews, this study provides examples of effective educational tools and techniques, highlights the importance of simulation, and explores opinions regarding the role of the resident in robotic surgery education. We hope the insights gained from this study can be used to develop and/or refine robotic surgery curricula.

Paraesophageal hernia repair: a curative consideration for chronic anemia?

INTRODUCTION: Chronic anemia is a common, coinciding or presenting diagnosis in patients with paraesophageal hernia (PEH). Presence of endoscopically identified ulcerations frequently prompts surgical consultation in the otherwise asymptomatic patient with anemia. Rates of anemia resolution following paraesophageal hernia repair (PEHR) often exceed the prevalence of such lesions in the study population. A defined algorithm remains elusive. This study aims to characterize resolution of anemia after PEHR with respect to endoscopic diagnosis. MATERIALS AND METHODS: Retrospective review of a prospectively maintained database of patients with PEH and anemia undergoing PEHR from 2007 to 2018 was performed. Anemia was determined by preoperative labs: Hgb < 12 mg/dl in females, Hgb < 13 mg/dl in males, or patients with ongoing iron supplementation. Improvement of post-operative anemia was assessed by post-operative hemoglobin values and continued necessity of iron supplementation. RESULTS: Among 56 identified patients, 45 were female (80.4%). Forty patients (71.4%) were anemic by hemoglobin value, 16 patients (28.6%) required iron supplementation. Mean age was 65.1 years, with mean BMI of 27.7 kg/m2. One case was a Type IV PEH and the rest Type III. 32 (64.0%) had potential source of anemia: 16 (32.0%) Cameron lesions, 6 (12.0%) gastric ulcers, 12 (24.0%) gastritis. 10 (20.0%) had esophagitis and 4 (8%) Barrett's esophagus. 18 (36%) PEH patients had normal preoperative EGD. Median follow-up was 160 days. Anemia resolution occurred in 46.4% of patients. Of the 16 patients with pre-procedure Cameron lesions, 10 (63%) had resolution of anemia. Patients with esophagitis did not achieve resolution. 72.2% (13/18) of patients with no lesions on EGD had anemia resolution (p = 0.03). CONCLUSION: Patients with PEH and identifiable ulcerations showed 50% resolution of anemia after hernia repair. Patients without identifiable lesions on endoscopy demonstrated statistically significant resolution of anemia in 72.2% of cases. Anemia associated with PEH adds an indication for surgical repair with curative intent.

Enhanced Oral Bioavailability of 2-(Phosphonomethyl)-pentanedioic Acid (2-PMPA) from its (5-Methyl-2-oxo-1,3-dioxol-4-yl)methyl (ODOL)-Based Prodrugs.

2-(Phosphonomethyl)-pentanedioic acid (2-PMPA) is a potent (IC50 = 300 pM) and selective inhibitor of glutamate carboxypeptidase II (GCPII) with efficacy in multiple neurological and psychiatric disease preclinical models and more recently in models of inflammatory bowel disease (IBD) and cancer. 2-PMPA (1), however, has not been clinically developed due to its poor oral bioavailability (<1%) imparted by its four acidic functionalities (c Log P = -1.14). In an attempt to improve the oral bioavailability of 2-PMPA, we explored a prodrug approach using (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (ODOL), an FDA-approved promoiety, and systematically masked two (2), three (3), or all four (4) of its acidic groups. The prodrugs were evaluated for in vitro stability and in vivo pharmacokinetics in mice and dog. Prodrugs 2, 3, and 4 were found to be moderately stable at pH 7.4 in phosphate-buffered saline (57, 63, and 54% remaining at 1 h, respectively), but rapidly hydrolyzed in plasma and liver microsomes, across species. In vivo, in a single time-point screening study in mice, 10 mg/kg 2-PMPA equivalent doses of 2, 3, and 4 delivered significantly higher 2-PMPA plasma concentrations (3.65 ± 0.37, 3.56 ± 0.46, and 17.3 ± 5.03 nmol/mL, respectively) versus 2-PMPA (0.25 ± 0.02 nmol/mL). Given that prodrug 4 delivered the highest 2-PMPA levels, we next evaluated it in an extended time-course pharmacokinetic study in mice. 4 demonstrated an 80-fold enhancement in exposure versus oral 2-PMPA (AUC0-t: 52.1 ± 5.9 versus 0.65 ± 0.13 h*nmol/mL) with a calculated absolute oral bioavailability of 50%. In mouse brain, 4 showed similar exposures to that achieved with the IV route (1.2 ± 0.2 versus 1.6 ± 0.2 h*nmol/g). Further, in dogs, relative to orally administered 2-PMPA, 4 delivered a 44-fold enhanced 2-PMPA plasma exposure (AUC0-t for 4: 62.6 h*nmol/mL versus AUC0-t for 2-PMPA: 1.44 h*nmol/mL). These results suggest that ODOL promoieties can serve as a promising strategy for enhancing the oral bioavailability of multiply charged compounds, such as 2-PMPA, and enable its clinical translation.

A cost-effectiveness analysis of reslizumab in the treatment of poorly controlled eosinophilic asthma.

Introduction: Poorly controlled severe eosinophilic asthma is difficult and costly to manage. Reslizumab, an add-on treatment for adults with severe eosinophilic asthma, reduces the number of exacerbations and improves the quality of life (QoL). The objective of this study was to evaluate the cost-effectiveness of reslizumab. Methods: A Markov model was used to compare the cost-effectiveness of add-on reslizumab with the standard-of-care (SOC) from the US societal perspective over a five-year time horizon. Efficacy and safety inputs for the model were based on data from two clinical trials (NCT01287039 and NCT01285323). Other model inputs, including mortality rates, costs, and utility, were estimated from literature, the Centers for Disease Control and Prevention (CDC), the US Department of Veterans Affairs (VA) and the Centers for Medicare and Medicaid Services (CMS). One-way, threshold, and probabilistic sensitivity analyses (PSA) were performed. Adherence, treatment response, and the placebo effect were evaluated in separate scenario analyses. Results: The base case incremental cost-effectiveness ratio (ICER) was $697 403 (2017 USD) per quality-adjusted life-years (QALYs). In the PSA, reslizumab becomes cost-effective in 50% of the iterations at a willingness-to-pay (WTP) threshold of $689 000. The model is most sensitive to the QoL improvement with reslizumab treatment in the one-way and threshold analyses. The response and adherence models had lower ICERs than the base model but still above $500 000. The ICER of the placebo effect model was $29 820. Conclusions: The improvement in QoL and exacerbation rates with reslizumab are associated with high costs, making reslizumab unlikely to be cost-effective at the $200 000 WTP threshold.

An ERAS protocol for bariatric surgery: is it safe to discharge on post-operative day 1?

BACKGROUND: Laparoscopic sleeve gastrectomy is the most commonly performed bariatric surgery in the world. Enhanced recovery after surgery (ERAS) protocols have been shown to reduce complications and decrease length of stay for various types of surgeries. In this study, we propose an ERAS protocol for laparoscopic sleeve gastrectomy and compare the clinical outcomes with patients who received standard care. METHODS: We performed a single-institution retrospective analysis in patients who underwent laparoscopic sleeve gastrectomy from February 2015 to December 2017. Patients were stratified into standard care and ERAS protocol groups. The ERAS protocol consisted of goal-directed patient education, specific pre- and post-op multi-modal medication regimen, early ambulation, and early oral intake. Patients were discharged on their first post-operative day if they met appropriate post-surgical milestones. The primary outcomes were length of stay, 7- and 30-day readmission rates, and complication rates. Secondary outcomes included anti-emetic and pain medication utilization, post-operative emesis episodes per day, post-operative pain scores, and mortality. RESULTS: We included 214 consecutive patients who underwent sleeve gastrectomy, 130 were in the ERAS group and 84 were in the standard care group. Median hospital stay was significantly shorter in the ERAS group compared to the standard care group (1 vs. 2 days; p < 0.001). There were no differences in 7- or 30-day readmission rates (1.5 vs. 1.2%; p = 0.838, 2.3 vs. 2.4%; p = 0.966) or post-operative complications (6.2 vs. 3.6%; p = 0.410). The ERAS group also had decreased median intra-operative opioid consumption and self-reported pain scores on post-operative day 1 (27.5 MME vs. 27.4 MME; p = 0.044, 3.3 vs. 3.9; p = 0.046). Mortality rate was 0% overall. CONCLUSION: A cost-effective ERAS protocol for laparoscopic sleeve gastrectomy results in shorter length of stay, without increase in peri-operative morbidity or readmission rates.

Systematic review of ultrasound visual biofeedback in intervention for speech sound disorders.

BACKGROUND: As cost and access barriers to ultrasound technology have decreased, interest in using ultrasound visual biofeedback (U-VBF) as a tool for remediating speech sound disorders (SSD) has increased. A growing body of research has investigated U-VBF in intervention for developmental SSD; however, diversity in study design, participant characteristics, clinical methods and outcomes complicate the interpretation of this literature. Thus, there is a need for a synthesis and review of the evidence base for using U-VBF in intervention for SSD. AIMS: To synthesise and evaluate the research evidence for U-VBF in intervention for developmental SSD. METHODS: A systematic review was conducted. Eight electronic databases were searched for peer-reviewed articles published before 2018. Details about study design, participants, intervention procedures, service delivery, intervention intensity and outcomes were extracted from each study that met the inclusion criteria. The included studies were rated using both a critical appraisal tool and for their reporting of intervention detail. MAIN CONTRIBUTIONS: Twenty-eight papers, comprising 29 studies, met the inclusion criteria. The most common research design was single-case experimental design (44.8% of studies). The studies included between one and 13 participants (mean = 4.1) who had a mean age of approximately 11 years (range = 4;0-27 years). Within the research evidence, U-VBF intervention was typically provided as part of, or as an adjunct to, other articulatory-based therapy approaches. A range of lingual sounds were targeted in intervention, with 80.6% of participants across all reviewed studies receiving intervention targeting rhotics. Outcomes following therapy were generally positive with the majority of studies reporting that U-VBF facilitated acquisition of targets, with effect sizes ranging from no effect to a large effect. Difficulties with generalisation were observed for some participants. Most studies (79.3%) were categorised as efficacy rather than effectiveness studies and represented lower levels of evidence. Overall, the reviewed studies scored more highly on measures of external validity than internal validity. CONCLUSIONS: The evidence base for U-VBF is developing; however, most studies used small sample sizes and lower strength designs. Current evidence indicates that U-VBF may be an effective adjunct to intervention for some individuals whose speech errors persist despite previous intervention. The results of this systematic review underscore the need for more high-quality and large-scale research exploring the use of this intervention in both controlled and community contexts.