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Study sponsors and market authorization holders are required by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) to enroll patients administered a gene therapy product, whether in a trial setting or post‐licensure, in a long term follow‐up safety study to continue the safety assessments of their product. These follow‐up studies range between 5 and 15 years after dosing. This unprecedented duration of engagement with patients and caregivers raises logistical challenges that will require innovation and collaboration across sponsors and regulators. In this paper we delineate some of the key considerations for designing long term follow‐up protocols in the gene therapy setting, with an eye toward platform and master protocol approaches, and offer guidance for innovative operational and statistical methods that can help assess the safety profile and durability of response for these novel therapeutics. [ABSTRACT FROM AUTHOR]

Addition of an excess of ZnMe2 to a mixture of [Ru(PPh3)3HCl] and IMes (IMes=1,3‐bis(2,4,6‐trimethylphenyl)imidazolin‐2‐ylidene) yields the bis‐cyclometallated complex, [Ru(IMes)"(PPh3)2] 2, together with the mono‐cyclometallated, Ru−Zn heterobimetallic complex [Ru(IMes)′(PPh3)2(ZnMe)] 3. Treatment of 2 with H2, PhSiH3 or pinacolborane yields the previously reported complex, [Ru(IMes)′(PPh3)2H] 1, the synthesis of which has been reinvestigated. Further studies of small molecule reactivity show that 1 adds H2 to give [Ru(IMes)(PPh3)2H4] 4, whilst 2 reacts with catecholborane to give [Ru(IMes‐Bcat)′(PPh3)2H] 5, in which (IMes‐Bcat)′ signifies a borylated NHC ligand that is singly‐metallated onto Ru. Treatment of 2 with CO gives the 18‐electron dicarbonyl product [Ru(IMes)"(PPh3)(CO)2] 6. Compounds 1–3, 5 and 6 have been structurally characterised. [ABSTRACT FROM AUTHOR]

Addition of an excess of ZnMe2 to a mixture of [Ru(PPh3)3HCl] and IMes (IMes=1,3‐bis(2,4,6‐trimethylphenyl)imidazolin‐2‐ylidene) yields the bis‐cyclometallated complex, [Ru(IMes)"(PPh3)2] 2, together with the mono‐cyclometallated, Ru−Zn heterobimetallic complex [Ru(IMes)′(PPh3)2(ZnMe)] 3. Treatment of 2 with H2, PhSiH3 or pinacolborane yields the previously reported complex, [Ru(IMes)′(PPh3)2H] 1, the synthesis of which has been reinvestigated. Further studies of small molecule reactivity show that 1 adds H2 to give [Ru(IMes)(PPh3)2H4] 4, whilst 2 reacts with catecholborane to give [Ru(IMes‐Bcat)′(PPh3)2H] 5, in which (IMes‐Bcat)′ signifies a borylated NHC ligand that is singly‐metallated onto Ru. Treatment of 2 with CO gives the 18‐electron dicarbonyl product [Ru(IMes)"(PPh3)(CO)2] 6. Compounds 1–3, 5 and 6 have been structurally characterised. [ABSTRACT FROM AUTHOR]

Introduction: Hospital‐acquired central line‐associated bloodstream infections (CLABSI) are "never events" in U.S. healthcare. National efforts to improve CLABSI rates are ongoing. Efforts are important for all patients with a central venous catheter (CVC) and critical to children with intestinal failure (IF) who depend on long‐term, daily use of a CVC and undergo extended hospitalizations. We describe outcomes of a multidisciplinary CLABSI elimination effort on a 24‐bed medical‐surgical unit caring for children with IF. Methods: Unit CLABSI events from 1/9/2012 to 4/16/2020 were evaluated with multiple improvement interventions. We leveraged prospectively maintained clinical registries and National Healthcare Safety Network (NHSN) reporting data to extract patient and unit demographics, ethanol lock utilization, and unit CVC days. Interventions were developed utilizing expert consensus and CDC guidelines with active frontline staff engagement. Descriptive statistics and tests of non‐parametric data were employed for analysis. Results: Ninety‐five patients with IF and 862 non‐IF patients experienced a total of 1,629 admissions with 20,372 CVC days. Twelve hospital‐acquired CLABSI events occurred during the study period, including 7 following NHSN definition change on 1/1/2015 (0.56 per 1,000 CVC days). After the last unit CLABSI on 12/5/2016, there were 7,117 CVC days through study conclusion. Conclusions: Described interventions with an enhanced culture of collaborative care profoundly improved hospital‐acquired CLABSI occurrence. Success in a specific population translated to all other unit patients with a CVC. Findings suggest elimination is not the result of a single new product or practice, but also includes support and empowerment of those caring for the patient and their CVC. [ABSTRACT FROM AUTHOR]

Selective inhibition of tyrosine kinase 2 (TYK2) may offer therapeutic promise in inflammatory conditions, with its role in downstream pro‐inflammatory cytokine signaling. In this first‐in‐human study, we evaluated the safety, tolerability, and pharmacokinetics (PK) of a novel TYK2 inhibitor, PF‐06826647, in healthy participants. This phase I, randomized, double‐blind, placebo‐controlled, parallel‐group study included two treatment periods (single ascending dose (SAD) and multiple ascending dose (MAD)) in healthy participants and a cohort of healthy Japanese participants receiving 400 mg q.d. or placebo in the MAD period (NCT03210961). Participants were randomly assigned to PF‐06826647 or placebo (3:1). Participants received a single oral study drug dose of 3, 10, 30, 100, 200, 400, or 1,600 mg (SAD period), then 30, 100, 400, or 1,200 mg q.d. or 200 mg b.i.d. for 10 days (MAD period). Safety (adverse events (AEs), vital signs, and clinical laboratory parameters), tolerability, and PK were assessed. Overall, 69 participants were randomized to treatment, including six Japanese participants. No deaths, serious AEs, severe AEs, or AEs leading to dose reduction or temporary/permanent discontinuation were observed. All AEs were mild in severity. No clinically relevant laboratory abnormalities or changes in vital signs were detected. PF‐06826647 was rapidly absorbed with a median time to maximum plasma concentration of 2 hours in a fasted state, with modest accumulation (< 1.5‐fold) after multiple dosing and low urinary recovery. PF‐06826647 was well‐tolerated, with an acceptable safety profile for doses up to 1,200 mg q.d. for 10 days, supporting further testing in patients. [ABSTRACT FROM AUTHOR]

Selective inhibition of tyrosine kinase 2 (TYK2) may offer therapeutic promise in inflammatory conditions, with its role in downstream pro-inflammatory cytokine signaling. In this first-in-human study, we evaluated the safety, tolerability, and pharmacokinetics (PK) of a novel TYK2 inhibitor, PF-06826647, in healthy participants. This phase I, randomized, double-blind, placebo-controlled, parallel-group study included two treatment periods (single ascending dose (SAD) and multiple ascending dose (MAD)) in healthy participants and a cohort of healthy Japanese participants receiving 400 mg q.d. or placebo in the MAD period (NCT03210961). Participants were randomly assigned to PF-06826647 or placebo (3:1). Participants received a single oral study drug dose of 3, 10, 30, 100, 200, 400, or 1,600 mg (SAD period), then 30, 100, 400, or 1,200 mg q.d. or 200 mg b.i.d. for 10 days (MAD period). Safety (adverse events (AEs), vital signs, and clinical laboratory parameters), tolerability, and PK were assessed. Overall, 69 participants were randomized to treatment, including six Japanese participants. No deaths, serious AEs, severe AEs, or AEs leading to dose reduction or temporary/permanent discontinuation were observed. All AEs were mild in severity. No clinically relevant laboratory abnormalities or changes in vital signs were detected. PF-06826647 was rapidly absorbed with a median time to maximum plasma concentration of 2 hours in a fasted state, with modest accumulation (< 1.5-fold) after multiple dosing and low urinary recovery. PF-06826647 was well-tolerated, with an acceptable safety profile for doses up to 1,200 mg q.d. for 10 days, supporting further testing in patients., (© 2020 Pfizer Inc. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)