Introduction This study examined changes in biomarkers of exposure (BoE) after 5 days of nicotine-salt pod system (NSPS) use, compared with continuation of usual-cigarette smoking and cigarette abstinence, among adult combustible cigarette smokers. Aims and Methods A randomized, open-label, parallel-cohort, confinement study of healthy adult smokers, naive to NSPS use, was conducted. Participants (N = 90) were randomized to six cohorts (n = 15 each): exclusive ad libitum use of NSPS (four flavors: Virginia Tobacco, Mint, Mango, Creme), continuation of usual-brand cigarette smoking, or cigarette abstinence. Total nicotine equivalents and BoE (NNN, NNAL, 3-HPMA, MHBMA, S-PMA, HMPMA, CEMA, 1-OHP, and COHb) were measured. Results Eight non-nicotine BoEs, measured in urine, were reduced by an aggregate of 85.0% in the pooled NSPS cohort; increased by 14.4% in the cigarette cohort (p < .001 for pooled NSPS vs. cigarette); and reduced by 85.3% in the abstinence cohort (p > .05; 99.6% relative reduction between pooled NSPS vs. abstinence). Similar changes in individual BoEs were also observed (p < .001 for each BoE between pooled NSPS vs. cigarettes; and abstinence vs. pooled NSPS; p > .05 for each BoE between pooled NSPS vs. abstinence). Blood COHb decreased by 71.8% in the pooled NSPS cohort and 69.1% in the abstinence cohort (p > .05) and increased by 13.3% in the cigarette cohort (p < .001). Mean total urine nicotine equivalents increased in the pooled NSPS and cigarette cohorts by 9% and 26%, respectively, and did not significantly differ (p > .05). Conclusion Complete switching from cigarettes to NSPS produced significant reductions in key non-nicotine BoEs associated with cigarette smoking. Implications The results of this study concorded with evidence that complete switching from combustible cigarettes to tobacco and nontobacco-flavored vapor products may reduce exposure to key carcinogens and other toxicants known to be associated with tobacco-related diseases. Future research is needed to assess the long-term health effects of NSPS use. These results should not be interpreted to mean that the use of NSPS is without any risk, particularly for nonusers of tobacco products.

BACKGROUND Nucleic acid–targeted pathogen inactivation technology using amustaline (S‐303) and glutathione (GSH) was developed to reduce the risk of transfusion‐transmitted infectious disease and transfusion‐associated graft‐versus‐host disease with red blood cell (RBC) transfusion. STUDY DESIGN AND METHODS A randomized, double‐blind, controlled study was performed to assess the in vitro characteristics of amustaline‐treated RBCs (test) compared with conventional (control) RBCs and to evaluate safety and efficacy of transfusion during and after cardiac surgery. The primary device efficacy endpoint was the postproduction hemoglobin (Hb) content of RBCs. Exploratory clinical outcomes included renal and hepatic failure, the 6‐minute walk test (a surrogate for cardiopulmonary function), adverse events (AEs), and the immune response to amustaline‐treated RBCs. RESULTS A total of 774 RBC unis were produced. Mean treatment difference in Hb content was –2.27 g/unit (95% confidence interval, –2.61 to –1.92 g/unit), within the prespecified equivalence margins (±5 g/unit) to declare noninferiority. Amustaline‐treated RBCs met European guidelines for Hb content, hematocrit, and hemolysis. Fifty‐one (25 test and 26 control) patients received study RBCs. There were no significant differences in RBC usage or other clinical outcomes. Observed AEs were within the spectrum expected for patients of similar age undergoing cardiovascular surgery requiring RBCs transfusion. No patients exhibited an immune response specific to amustaline‐treated RBCs. CONCLUSION Amustaline‐treated RBCs demonstrated equivalence to control RBCs for Hb content, have appropriate characteristics for transfusion, and were well tolerated when transfused in support of acute anemia. Renal impairment was characterized as a potential efficacy endpoint for pivotal studies of RBC transfusion in cardiac surgery.

Background and Objectives Pathogen reduction technology using amustaline (S-303) was developed to reduce the risk of transfusion-transmitted infection and adverse effects of residual leucocytes. In this study, the viability of red blood cells (RBCs) prepared with a second-generation process and stored for 35 days was evaluated in two different blood centres. Materials and MethodsIn a single-blind, randomized, controlled, two-period crossover study (n = 42 healthy subjects), amustaline-treated (Test) or Control RBCs were prepared in random sequence and stored for 35 days. On day 35, an aliquot of 51 Cr/ 99m Tc radiolabeled RBCs was transfused. In a subgroup of 26 evaluable subjects, 24-h RBC post-transfusion recovery, mean life span, median life span (T 50 ) and life span area under the curve (AUC) were analysed.Results The mean 24-h post-transfusion recovery of Test and Control RBCs was comparable (83Á2 -5Á2 and 84Á9 -5Á9%, respectively; P = 0Á06) and consistent with the US Food and Drug Administration (FDA) criteria for acceptable RBC viability. There were differences in the T 50 between Test and Control RBCs (33Á5 and 39Á7 days, respectively; P < 0Á001), however, these were within published reference ranges of 28-35 days. The AUC (per cent surviving 9 days) for Test and Control RBCs was similar (22Á6 and 23Á1 per cent surviving cells 9 days, respectively; P > 0Á05). Following infusion of Test RBCs, there were no clinically relevant abnormal laboratory values or adverse events.Conclusion RBCs prepared using amustaline pathogen reduction meet the FDA criteria for post-transfusion recovery and are metabolically and physiologically appropriate for transfusion following 35 days of storage.

Summary Transfusion‐dependent thalassaemia (TDT) requires red blood cell concentrates (RBCC) to prevent complications of anaemia, but carries risk of infection. Pathogen reduction of RBCC offers potential to reduce infectious risk. We evaluated the efficacy and safety of pathogen‐reduced (PR) Amustaline‐Glutathione (A‐GSH) RBCC for TDT. Patients were randomized to a blinded 2‐period crossover treatment sequence for six transfusions over 8–10 months with Control and A‐GSH‐RBCC. The efficacy outcome utilized non‐inferiority analysis with 90% power to detect a 15% difference in transfused haemoglobin (Hb), and the safety outcome was the incidence of antibodies to A‐GSH‐PR‐RBCC. By intent to treat (80 patients), 12·5 ± 1·9 RBCC were transfused in each period. Storage durations of A‐GSH and C‐RBCC were similar (8·9 days). Mean A‐GSH‐RBCC transfused Hb (g/kg/day) was not inferior to Control (0·113 ± 0·04 vs. 0·111 ± 0·04, P = 0·373, paired t‐test). The upper bound of the one‐sided 95% confidence interval for the treatment difference from the mixed effects model was 0·005 g/kg/day, within a non‐inferiority margin of 0·017 g/kg/day. A‐GSH‐RBCC mean pre‐transfusion Hb levels declined by 6·0 g/l. No antibodies to A‐GSH‐RBCC were detected, and there were no differences in adverse events. A‐GSH‐RBCCs offer potential to reduce infectious risk in TDT with a tolerable safety profile.

BACKGROUND Liver transplant may require large‐volume plasma transfusion with increased risk of transfusion‐transmitted infection (TTI). Pathogen inactivation of plasma with amotosalen‐UVA offers the potential to mitigate TTI risk. STUDY DESIGN AND METHODS A retrospective cohort design was used to compare the therapeutic efficacy and key safety outcomes for liver transplants supported with quarantine plasma (Q‐FFP [reference]) or amotosalen‐UVA plasma (IBS plasma [test]). The outcomes evaluated were volume of plasma, the numbers of red blood cell (RBC) components, and the total dose of platelets (PLTs) transfused during and 7 days after transplant. The safety outcomes were acute hepatic artery thrombosis (HAT) and mortality. RESULTS Transplantation and transfusion records for 212 Q‐FFP transplants and 215 IBS plasma transplants were reviewed. Not all transplants required plasma; 161 received Q‐FFP and 174 received IBS plasma. Among the transplants that required plasma, there were significant differences in median values between cohorts for delay to transplantation (p = 0.002), model end‐stage liver disease score (p < 0.001), pretransplant hematocrit (p = 0.006), and graft cold perfusion time (p = 0.033). The median volumes of plasma transfused were not different for test and reference (2.160 L vs. 1.969 L, p = 0.292). Transplants in the test cohort required a mean of 3.7% more RBC components (p = 0.767) and on average a 16.5% increase in total PLT dose (p = 0.518). No significant differences were observed for the frequency of acute HAT or mortality. CONCLUSION In this retrospective study, IBS plasma provided therapeutic support of liver transplant not different from Q‐FFP.

Dravet syndrome (DS) is an intractable developmental and epileptic encephalopathy significantly impacting affected children and their families. A novel, one-time, adeno-associated virus (AAV)-mediated gene regulation therapy was designed to treat the underlying cause of DS, potentially improving the full spectrum of DS manifestations. To ensure the first-in-human clinical trial addresses meaningful outcomes for patients and families, we examined their perspectives, priorities, goals, and desired outcomes in the design phase through a mixed methods approach (quantitative and qualitative). We conducted a non-identifiable parent caregiver survey, shared through a patient advocacy organization (n = 36 parents; children age 6 years). Parents were also engaged via three group discussions (n = 10; children age 2-20 years) and optional follow-up in-depth individual interviews (n = 6). Qualitative data analysis followed an inductive interpretive process, and qualitative researchers conducted a thematic analysis with a narrative approach. Survey results revealed most children (94%) were diagnosed by age 1, with onset of seizures at mean age 6.2 months and other DS manifestations before 2 years. The most desired disease aspects to address with potential new disease-modifying therapies were severe seizures (ranked by 92% of caregivers) and communication issues (development, expressive, receptive; 72-83%). Qualitative results showed the need for trial outcomes that recognize the impact of DS on the whole family. Parents eventually hope for trials including children of all ages and were both excited about the potential positive impact of a one-time disease-modifying therapy and mindful of potential long-term implications. Participants reflected on the details and risks of a clinical trial design (e.g., sham procedures) and described the different factors that relate to their decision to participate in a trial. Their main aspirations were to stop neurodevelopmental stagnation, to reduce seizures, and to reduce the impact on their families' wellbeing. To our knowledge, this is the first study within a patient-oriented research framework that specifically explored parents' needs and perceptions regarding clinical trials of a potential disease-modifying therapy for children with a severe, developmental disease, such as DS.

BACKGROUNDLeukoreduction (LR) of platelet concentrate (PC) has evolved as the standard to mitigate risks of alloimmunization, clinical refractoriness, acute transfusion reactions (ATRs), and cytomegalovirus infection, but does not prevent transfusion‐associated graft‐versus‐host disease (TA‐GVHD). Amotosalen–ultraviolet A pathogen reduction (A‐PR) of PC reduces risk of transfusion‐transmitted infection and TA‐GVHD. In vitro data indicate that A‐PR effectively inactivates WBCs and infectious pathogens.STUDY DESIGN AND METHODSA sequential cohort study evaluated A‐PR without LR, gamma irradiation, and bacterial screening in hematopoietic stem cell transplant (HSCT) recipients. The first cohort received conventional PC (control) processed without LR, but with gamma irradiation and bacterial screening. The second cohort received A‐PR PC (test) processed without: LR, bacterial screening, or gamma irradiation. The primary efficacy outcome was the 1‐hour corrected count increment. The primary safety outcome was treatment‐emergent ATR. Secondary outcomes included clinical refractoriness, and 100‐day status for engraftment, TA‐GVHD, HSCT‐GVHD, infections, and mortality.RESULTSMean corrected count increment (× 103) of 33 test PC recipients was similar (18.9 ± 8.8 vs. 16.6 ± 8.4; p = 0.296) to that of 31 control PC recipients. Test recipients had a reduced, but nonsignificant, incidence of ATR (test = 9.1%, Control = 19.4%; p = 0.296). The frequencies of clinical refractoriness (0 of 33 vs. 4 of 31 patients) and refractory transfusions (6.6% vs. 19.3%) were lower in the test cohort (p = 0.05 and 0.02), respectively. No patient in either cohort had TA‐GVHD. Day 100 engraftment, HSCT‐GVHD, mortality, and infectious disease complications were similar between cohorts.CONCLUSIONSThis study indicated that A‐PR PC without LR, gamma irradiation, or bacterial screening is feasible for support of HSCT.

BACKGROUND Plasma thawed and stored at 1 to 6°C for up to 5 days (thawed plasma [TP]) provides rapid availability in emergencies and reduces plasma waste, but it carries risks of coagulation factor loss or activation, bacterial outgrowth, and viral contamination. We characterized changes in amotosalen/ultraviolet A (UVA) light pathogen‐reduced, fresh‐frozen plasma (FFP) and plasma frozen within 24 hours (PF24) with post‐thaw storage. STUDY DESIGN AND METHODS Amotosalen/UVA light‐treated FFP and PF24 were thawed after approximately 3 to more than 12 months of frozen storage and held at 1 to 6°C for 5 days. Global assessments of coagulation and hemostatic, antithrombotic, and activation markers indicative of function were assessed. RESULTS Day 5, thawed amotosalen/UVA light‐treated FFP and PF24 contained levels of Factors II, V, VIII, IX, X, von Willebrand factor ristocetin cofactor (vWF:RCo), fibrinogen, antithrombin III (ATIII), protein C, and protein S similar to the levels measured in Day 5 TP, as described in the Circular of Information. Thrombin generation was robust on Day 5 (amotosalen/UVA: FFP = 1866 ± 402 nM/minute; PF24 = 1800 ± 277 nM/minute). Most factor activities on Day 5, including von Willebrand factor‐cleaving protease (ADAMTS‐13), were more than 90% of Day 0 values, except for known labile Factors V and VIII and protein S. All units contained greater than 0.4 IU/mL protein S and α2 plasmin inhibitor on Day 5. Global functional indices, including thrombin‐antithrombin complexes, nonactivated thromboplastin time, and thrombin‐generation peak height, did not indicate activation of the coagulation cascade, although isolated units showed raised levels of Factor VIIa and Complement 3a. CONCLUSION Amotosalen/UVA light‐treated FFP and PF24 demonstrated retention of procoagulant and antithrombotic activity after 5 days post‐thaw storage at 1 to 6°C.