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Competing Interests: Conflicts of interest the authors declare no conflicts of interest.

Competing Interests: Conflicts of interest the authors declare they have no conflicts of interest.

Background: FLT180a (verbrinacogene setparvovec) is a liver-directed adeno-associated virus (AAV) gene therapy that uses a synthetic capsid and a gain-of-function protein to normalize factor IX levels in patients with hemophilia B., Methods: In this multicenter, open-label, phase 1-2 trial, we assessed the safety and efficacy of varying doses of FLT180a in patients with severe or moderately severe hemophilia B (factor IX level, ≤2% of normal value). All the patients received glucocorticoids with or without tacrolimus for immunosuppression to decrease the risk of vector-related immune responses. After 26 weeks, patients were enrolled in a long-term follow-up study. The primary end points were safety and efficacy, as assessed by factor IX levels at week 26., Results: Ten patients received one of four FLT180a doses of vector genomes (vg) per kilogram of body weight: 3.84×10 11 vg, 6.40×10 11 vg, 8.32×10 11 vg, or 1.28×10 12 vg. After receiving the infusion, all the patients had dose-dependent increases in factor IX levels. At a median follow-up of 27.2 months (range, 19.1 to 42.4), sustained factor IX activity was observed in all the patients except one, who resumed factor IX prophylaxis. As of the data-cutoff date (September 20, 2021), five patients had normal factor IX levels (range, 51 to 78%), three patients had levels from 23 to 43%, and one had a level of 260%. Of the reported adverse events, approximately 10% were related to FLT180a and 24% to immunosuppression. Increases in liver aminotransferase levels were the most common FLT180a-related adverse events. Late increases in aminotransferase levels occurred in patients who had received prolonged tacrolimus beyond the glucocorticoid taper. A serious adverse event of arteriovenous fistula thrombosis occurred in the patient with high factor IX levels., Conclusions: Sustained factor IX levels in the normal range were observed with low doses of FLT180a but necessitated immunosuppression with glucocorticoids with or without tacrolimus. (Funded by Freeline Therapeutics; ClinicalTrials.gov numbers, NCT03369444 and NCT03641703; EudraCT numbers, 2017-000852-24 and 2017-005080-40.)., (Copyright © 2022 Massachusetts Medical Society.)

Microfluidic concentration gradient generators ( µ -CGGs) have been utilized to identify optimal drug compositions through antimicrobial susceptibility testing (AST) for the treatment of antimicrobial-resistant (AMR) infections. Conventional µ -CGGs fabricated via photolithography-based micromachining processes, however, are fundamentally limited to two-dimensional fluidic routing, such that only two distinct antimicrobial drugs can be tested at once. This work addresses this limitation by employing Multijet-3D-printed microchannel networks capable of fluidic routing in three dimensions to generate symmetric multidrug concentration gradients. The three-fluid gradient generation characteristics of the fabricated 3D µ -CGG prototype were quantified through both theoretical simulations and experimental validations. Furthermore, the antimicrobial effects of three highly clinically relevant antibiotic drugs, tetracycline, ciprofloxacin, and amikacin, were evaluated via experimental single-antibiotic minimum inhibitory concentration (MIC) and pairwise and three-way antibiotic combination drug screening (CDS) studies against model antibiotic-resistant Escherichia coli bacteria. As such, this 3D µ -CGG platform has great potential to enable expedited combination AST screening for various biomedical and diagnostic applications., Competing Interests: Conflict of interestThe authors declare that they have no conflicts of interest., (© The Author(s) 2020.)

Etranacogene dezaparvovec (AMT-061) is a recombinant AAV5 vector including a gene cassette containing the factor IX (FIX) Padua variant under the control of a liver-specific promoter. A phase 2b study was conducted to confirm that a single dose of 2 × 1013 genome copies per kilogram of etranacogene dezaparvovec will result in FIX activity ≥5% 6 weeks after dosing. Secondary end points included FIX activity at other time points, bleed frequency, FIX replacement, and safety. Etranacogene dezaparvovec was administered as a single IV infusion to 3 adults with severe to moderately severe hemophilia B. Before treatment, participants had low levels of preexisting neutralizing antibodies to AAV5. This article reports a planned 26-week interim assessment. At week 6, mean FIX activity was 31% (23.9%-37.8%), increasing to 47% (33.2%-57.0%) at 26 weeks, with 2 subjects exhibiting sustained activity >40%. Consistent with the FIX activity, etranacogene dezaparvovec was associated with a complete bleed cessation with no need for FIX replacement therapy up to 26 weeks. Etranacogene dezaparvovec was generally well tolerated. No clinically significant elevations in levels of liver enzymes or inflammatory markers were observed, and no use of corticosteroids related to treatment was required. In individuals with severe to moderately severe hemophilia B, etranacogene dezaparvovec resulted in clinically relevant increases in FIX activity, cessation of bleeds, and abrogation of the need for FIX replacement, despite the presence of preexisting anti-AAV5 neutralizing antibodies detected by using a highly sensitive luciferase assay. Consistency of results in the 3 participants supported an expanded evaluation of the safety/efficacy of etranacogene dezaparvovec in the HOPE-B (Health Outcomes With Padua Gene; Evaluation in Hemophilia-B) phase 3 trial. The current trial was registered at www.clinicaltrials.gov as #NCT03489291., (© 2019 by The American Society of Hematology.)

Purpose: To evaluate the effects of metreleptin in patients with partial lipodystrophy (PL)., Methods: Patients aged ≥ 6 months with PL, circulating leptin < 12.0 ng/mL, and diabetes mellitus, insulin resistance, or hypertriglyceridemia received metreleptin doses (once or twice daily) titrated to a mean of 0.124 mg/kg/day. Changes from baseline to month 12 in glycated hemoglobin (HbA1c) and fasting serum triglycerides (TGs; co-primary endpoints), fasting plasma glucose (FPG), and liver volume were evaluated. Additional assessments included the proportions of patients achieving target decreases in HbA1c or fasting TGs at month 12, long-term treatment effects, and treatment-emergent adverse events (TEAEs)., Results: Significant (p < 0.05) reductions in HbA1c (-0.6%), fasting TGs (-20.8%), FPG (-1.2 mmol/L), and liver volume (-13.4%) were observed in the overall PL population at month 12. In a subgroup of patients with baseline HbA1c ≥ 6.5% or TGs ≥ 5.65 mmol/L, significant (p < 0.05) reductions were seen in HbA1c (-0.9%), fasting TGs (-37.4%), FPG (-1.9 mmol/L), and liver volume (-12.4%). In this subgroup, 67.9% of patients had a ≥ 1% decrease in HbA1c or ≥ 30% decrease in fasting TGs, and 42.9% had a ≥ 2% decrease in HbA1c or ≥ 40% decrease in fasting TGs. Long-term treatment in this subgroup led to significant (p < 0.05) reductions at months 12, 24, and 36 in HbA1c, fasting TGs, and FPG. Metreleptin was well tolerated with no unexpected safety signals. The most common TEAEs were abdominal pain, hypoglycemia, and nausea., Conclusions: In patients with PL, treatment with metreleptin was well tolerated and resulted in improvements in glycemic control, hypertriglyceridemia, and liver volume.

Purpose: The purpose of this study is to summarize the effectiveness and safety of metreleptin in patients with congenital or acquired generalized lipodystrophy., Methods: Patients (n = 66) aged ≥6 months had lipodystrophy, low circulating leptin, and ≥1 metabolic abnormality (diabetes mellitus, insulin resistance, or hypertriglyceridemia). Metreleptin dose (once or twice daily) was titrated to a mean dose of 0.10 mg/kg/day with a maximum of 0.24 mg/kg/day. Means and changes from baseline to month 12 were assessed for glycated hemoglobin (HbA1c), fasting triglycerides (TGs), and fasting plasma glucose (FPG). Additional assessments included the proportions of patients achieving target decreases in HbA1c or fasting TGs at months 4, 12, and 36, medication changes, and estimates of liver size. Treatment-emergent adverse events (TEAEs) were recorded., Results: Significant mean reductions from baseline were seen at month 12 for HbA1c (-2.2%, n = 59) and FPG (-3.0 mmol/L, n = 59) and mean percent change in fasting TGs (-32.1%, n = 57) (all p ≤ 0.001). Reductions from baseline over time in these parameters were also significant at month 36 (all p < 0.001, n = 14). At month 4, 34.8% of patients had a ≥1% reduction in HbA1c and 62.5% had a ≥30% reduction in fasting TGs; at month 12, 80% of patients had a ≥1% decrease in HbA1c or ≥30% decrease in TGs, and 66% had a decrease of ≥2% in HbA1c or ≥40% decrease in TGs. Of those on medications, 41%, 22%, and 24% discontinued insulin, oral antidiabetic medications, or lipid-lowering medications, respectively. Mean decrease in liver volume at month 12 was 33.8% (p < 0.001, n = 12). Most TEAEs were of mild/moderate severity., Conclusions: In patients with generalized lipodystrophy, long-term treatment with metreleptin was well tolerated and resulted in sustained improvements in hypertriglyceridemia, glycemic control, and liver volume.

Background: Screening and brief intervention for substance use in health care systems is recommended to identify and intervene with patients who abuse alcohol and other substances. However, there is limited research on the utility of short, single-item questions to identify illicit substance users., Objective: Pilot validation of two single-item screening questions to detect illicit substance use, one for marijuana and one for other illicit drugs. The goal was to identify sensitive, time-efficient screening questions that can be easily integrated into busy health care settings., Methods: A cross-sectional design was used. At intake, along with questions for tobacco and alcohol, nurses administered two brief screen questions to adult patients seen in designated areas in a large urban medical center. After patients were triaged to rooms, health educators (blind to brief screen responses) administered the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) as the reference standard., Results: On the ASSIST, 14% and 9% of participants reported risky marijuana and illicit (nonmarijuana) drug use, respectively. Sensitivity values for the marijuana and street drug questions were 72% (95% confidence interval [CI] 67% to 78%) and 40% (95% CI 32% to 48%), respectively. Specificity values for the marijuana and street drug questions were 96% (95% CI 95% to 97%) and 99% (95% CI 98% to 99%), respectively. Values differed minimally as a function of patient characteristics., Conclusions: It is important to use validated questions to identify substance misuse so that individuals are not missed in the screening process. It is the possible that administration protocols play a role in detection rates. Future research is needed to identify easy-to-administer drug use screening questions., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Heparan sulfate proteoglycans (HSPGs) play a key role in shaping the tumor microenvironment by presenting growth factors, cytokines, and other soluble factors that are critical for host cell recruitment and activation, as well as promoting tumor progression, metastasis, and survival. M402 is a rationally engineered, non-cytotoxic heparan sulfate (HS) mimetic, designed to inhibit multiple factors implicated in tumor-host cell interactions, including VEGF, FGF2, SDF-1α, P-selectin, and heparanase. A single s.c. dose of M402 effectively inhibited seeding of B16F10 murine melanoma cells to the lung in an experimental metastasis model. Fluorescent-labeled M402 demonstrated selective accumulation in the primary tumor. Immunohistological analyses of the primary tumor revealed a decrease in microvessel density in M402 treated animals, suggesting anti-angiogenesis to be one of the mechanisms involved in-vivo. M402 treatment also normalized circulating levels of myeloid derived suppressor cells in tumor bearing mice. Chronic administration of M402, alone or in combination with cisplatin or docetaxel, inhibited spontaneous metastasis and prolonged survival in an orthotopic 4T1 murine mammary carcinoma model. These data demonstrate that modulating HSPG biology represents a novel approach to target multiple factors involved in tumor progression and metastasis.

The initial choice of anticoagulant therapy administered in emergency departments for acute coronary syndromes (ACS) has important consequences for subsequent patient care, as neither unfractionated heparin (UFH) nor low-molecular-weight heparin (LMWH) are ideally suited for all potential clinical treatment pathways. UFH remains widely used for surgical interventions because of the ability to rapidly reverse its anticoagulant activity. However, the unpredictable pharmacokinetic profile of UFH presents safety issues, and the low subcutaneous bioavailability limits the utility of UFH for patients who are medically managed. LMWH has superior pharmacokinetic properties, but its anticoagulant activity cannot be effectively monitored or reversed during surgery. There is an unmet medical need for a baseline anticoagulant therapy that addresses these shortcomings while retaining the beneficial properties of both UFH and LMWH. We describe here M118, a novel LMWH designed specifically for use in the treatment of ACS. M118 shows broad anticoagulant activity, including potent activity against both factor Xa (~240 IU/mg) and thrombin (factor IIa; ~170 IU/mg), low polydispersity, high (78%) subcutaneous bioavailability in rabbits, and predictable subcutaneous and intravenous pharmacokinetics. Additionally, the anticoagulant activity of M118 is monitorable by standard coagulation assays and is reversible with protamine. M118 demonstrates superior activity to conventional LMWH in a rabbit model of abdominal arterial thrombosis without increasing bleeding risk, and is currently being evaluated in a phase II clinical trial evaluating efficacy and safety in patients undergoing percutaneous coronary intervention.