On-demand Treatment Research Articles

Adenosine Triphosphate-Activated Cascade Reactor for On-Demand Antibacterial Treatment Through Controlled Hydroxyl Radical Generation.

Nanozymes have shown promise for antibacterial applications, but their effectiveness is often hindered by low catalytic performances in physiological conditions and uncontrolled production of hydroxyl radicals (·OH). To address these limitations, a comprehensive approach is presented through the development of an adenosine triphosphate (ATP)-activated cascade reactor (GGPcs). The GGPcs reactor synergistically combines the distinct properties of zeolitic imidazolate framework-8 (ZIF-8) and chitosan-integrated hydrogel microsphere. The ZIF-8 allows for the encapsulation of G-quadruplex/hemin DNAzyme to achieve ATP-responsive ·OH generation at neutral pH, while the hydrogel microsphere creates a confinement environment that facilitates glucose oxidation and provides a sufficient supply of H2O2. Importantly, the integrated chitosan in the hydrogel microsphere shields ZIF-8 from undesired disruption caused by gluconic acid, ensuring the responsive specificity of ZIF-8 toward ATP. By activating GGPcs with ATP secreted by bacteria, its effectiveness as an antibacterial agent is demonstrated for the on-demand treatment of bacterial infection with minimal side effects. This comprehensive approach has the potential to facilitate the design of advanced nanozyme systems and broaden their biological applications.

On-demand versus prophylactic therapy with factor VIII concentrate in patients with hemophilia A: Differences in efficacy and quality of life: A multicenter study

Abstract Background: Hemophilia A and B are inherited bleeding disorders in factors VIII and IX. Objectives: The study was to compare between on-demand and prophylactic treatment by factor VIII (FVIII) concentrate of hemophilic patients in Kirkuk, Sulaymaniyah, and Erbil hemophilia centers. Materials and Methods: The study included 45 patients with moderate and severe hemophilia treated with FVIII concentrate in three Iraqi centers (Kirkuk Oncology Center [n: 15], Hiwa Hospital in Sulaimaniya [n: 18], and Nanakali Hospital in Erbil city [n: 12]) and compared two different protocols in prophylactic therapy with FVIII concentrate in 2016 and on-demand treatment with FVIII concentrate in 2018 on the same patients. Comparisons included the number of vials used in two procedures and patient visits to our centers. Results: The survey found that hemophilia patients at Kirkuk Oncology Center are older than those in Sulaimaniya and Erbil. The average number of vials of FVIII concentrate used to treat hemophilia on prophylaxis was 73.58/year and 6.13/month, which was substantially less than in on demand (P < 0.001). The study found that the average number of FVIII concentrate vials used in on-demand hemophilia therapy at Hiwa Hospital was 79.4 vail/year and 6.62 vail/month, compared to 119.7 vail/year and 9.97 vail/month in prophylaxis (P < 0.001). The study also found that the average number of vials used in hemophilia therapy at Kirkuk Oncology Center and Nanakali Hospital in Erbil was lower than in other hospitals (P < 0.001). The study demonstrated that all patients in the on-demand hemophilia treatment program were dissatisfied, but their views improved after treatment with FVIII concentrate in prophylaxis protocol. Conclusions: We find that prophylactic administration of FVIII concentrate to hemophilia patients is superior than on-demand administration. We urge that future studies improve our results with larger patient groups and clinics in all governorates of Iraq.

Efficacy of Regular Prophylaxis with a Plasma-Derived Von Willebrand Factor/Factor VIII Concentrate in Reducing Heavy Menstrual Bleeding in Females with Von Willebrand Disease

Background: Heavy menstrual bleeding (HMB) is the dominant symptom affecting ~80-90% of women with VWD and is a common cause of outpatient visits and hospitalizations. Long-term prophylaxis with a von Willebrand factor (VWF) concentrate is recommended in von Willebrand disease (VWD) patients with a history of severe, frequent bleeds, and for women with VWD who experience HMB. A recent prospective study found that recombinant VWF was not superior to tranexamic acid at reducing HMB in women with VWD. The WIL-31 study demonstrated the efficacy of prophylaxis with a plasma-derived VWF/factor VIII (pdVWF/FVIII) concentrate containing VWF and FVIII in a 1:1 activity ratio (wilate ®) in adults and children with VWD of all types. The primary endpoint was met, showing a decrease of 84% in the mean total annualized bleeding rate (ABR) compared with prior on-demand treatment. The impact of pdVWF/FVIII prophylaxis on HMB was evaluated as a secondary endpoint of the WIL-31 study. Aims: To investigate the efficacy of regular prophylaxis with a pdVWF/FVIII concentrate in reducing the incidence of HMB in females with VWD who had previously been treated on demand. Methods: WIL-31 (NCT04052698) was a prospective, non-controlled, international, multicenter phase 3 trial that enrolled male/female patients, aged ≥6 years old with VWD type 1 (VWF:RCo <30 IU/dL), type 2 (except 2N) or type 3. Prior to entering the WIL-31 study, all patients had received on-demand treatment with a VWF-containing product during a 6-month, prospective, observational, run-in study (WIL-29). Patients in WIL-31 received regular pdVWF/FVIII prophylaxis 2-3 times per week at a dose of 20-40 IU/kg for 12 months. Exploratory analyses included comparison of heavy menstrual ABR (HMABR). HMB was defined as any menstrual bleed that impeded the ability to perform daily activities (such as work, housework, exercise, or social activities) during menstrual periods. Criteria for HMB included changing pads more frequently than hourly, menstrual bleeding lasting 7 or more days, or the presence of clots >1 cm combined with a history of flooding or a Pictorial Blood Assessment Chart (PBAC) score ≥185. PBAC scores were reviewed from patient diaries at each study visit. Results: Of the 33 patients included in the overall population, 14 (42%) were female and half (n=7; 13-43 years old) were of childbearing age. In these females, all VWD types were represented: type 1 (n=2), type 2 (n=1); and type 3 (n=4). Six (86%) females were on hormonal birth control during WIL-31. Prophylaxis with pdVWF/FVIII reduced the mean HMABR by 64% compared with on-demand treatment (3.0 vs 8.3 in WIL-31 and WIL-29, respectively). During on-demand treatment, 86% (6/7) of females experienced ≥1 HMB episode, which was reduced to 29% (2/7) during prophylaxis with four patients experiencing no HMB (Figure 1). During on-demand treatment, 6 females experienced 32 HMB episodes; of these, 7 (22%) required further treatment with pdVWF/FVIII and 2 (6%) required concomitant medication. Under prophylaxis, two patients (aged ≥17 years), experienced 12 HMBEs; of these, only one (8%) impeded daily activity and none required additional pdVWF/FVIII treatment, hospitalization, or concomitant medication. Mean (SD) intra-individual median PBAC scores (N=4) decreased by 43% from 227 (91.7) during on-demand treatment to 131 (59.9) with prophylaxis, a 96-point reduction. Conclusion: Prophylaxis with pdVWF/FVIII was efficacious in reducing HMB compared with on-demand treatment in 7 female patients with VWD. None of the cases of HMB during prophylaxis was severe enough to require additional treatment. Among women with VWD, HMB remains a major burden and further research is required.

Efficacy of Regular Prophylaxis with a Plasma-Derived Von Willebrand Factor/Factor VIII Concentrate in Reducing Nose Bleeds in Children and Adults with Von Willebrand Disease

Background: The use of a von Willebrand factor (VWF) concentrate for long-term prophylaxis is recommended for individuals with von Willebrand disease (VWD) who have a history of frequent and severe bleeds, regardless of their age or the type of VWD. Bleeding from the nose (epistaxis) is one of the most common types of bleeding in VWD patients. The WIL-31 study demonstrated the efficacy of prophylaxis with a plasma-derived VWF/factor VIII (pdVWF/FVIII) concentrate containing VWF and FVIII in a 1:1 activity ratio (wilate ®) in adults and children with VWD of all types. The primary endpoint was met, showing a decrease of 84% in the mean total annualized bleeding rate (ABR) compared with prior on-demand treatment. Aims: To investigate the efficacy of regular prophylaxis with a pdVWF/FVIII concentrate in reducing nose bleeds in people with VWD, compared with previous on-demand treatment. Methods: WIL-31 (NCT04052698) was a prospective, non-controlled, international, multicenter phase 3 trial that enrolled male/female patients, aged ≥6 years with VWD type 1 (VWF:RCo <30 IU/dL), type 2 (except 2N) or type 3. Prior to entering the WIL-31 study, all patients had received on-demand treatment with a VWF-containing product during a 6-month, prospective, observational, run-in study (WIL-29); patients who experienced at least 6 bleeding episodes, excluding menstrual bleeds, of which ≥2 were treated with a VWF-containing product, were eligible to enter WIL-31. Patients in WIL-31 received regular prophylaxis with pdVWF/FVIII 2-3 times per week at a dose of 20-40 IU/kg for 12 months. In this post-hoc analysis, nose bleeds during WIL-29/-31 were described, and the mean ABRs were compared. Results: The study population included 33 patients with a median (range) age of 18 (7-61) years; 9 (27.3%) patients were 6-11 years old, 6 (18.2%) were 12-16 years old, and 18 (54.5%) were ≥17 years old. All VWD types were represented: type 1 (n=6), type 2 (n=5); and type 3 (n=22). There were 173 breakthrough bleeds in total during WIL-31, of which nose bleeds were the most common (89/173; 51.4%). Nose bleeds occurred in 16 of 33 patients during prophylaxis vs 26 of 33 during on-demand treatment. Of the 89 nose bleeds, 17 were traumatic, 69 spontaneous, and 3 due to allergic reaction (not product related). The mean number of spontaneous nose bleeds per patient during prophylaxis was 2.1, 2.3, 1.2, and 2.2, for the overall population, and the 6-11, 12-16, and ≥17 years age groups, respectively. Eight nose bleeds (9.0%) were major (all in the same patient). The mean nose ABR was reduced by 76% during prophylaxis vs on-demand treatment. The reduction was consistent across age groups (74-77%, Figure 1) but not across VWD types, with mean nose ABR reductions of 48, 89, and 80% for VWD type 1, type 2, and type 3 patients, respectively. During prophylaxis, a higher number of VWD type 3 patients, compared with type 1 and type 2 patients, experienced nose bleeds (12 vs 3 vs 1). The mean duration of nose bleeds decreased during prophylaxis vs on-demand for 12-17 years old, ≥17 years old, type 2 and type 3 VWD patients, but increased for 6-11 years old and severe type 1 patients. No relationship was observed between the number of nose bleeds and patient age (R 2=0.082). The majority (80.9%; 72/89) of nose bleeds were treated with pdVWF/FVIII with 86.1% (62/72) requiring only a single infusion; two required concomitant treatment with tranexamic acid. All treated nose bleeds were rated as “successfully treated”. Conclusion: The data indicate thatprophylaxis with pdVWF/FVIII was effective at reducing nose bleeds in patients with VWD type 2 and 3, and across all age groups.

Assessing Treatment Burden in Pediatric Hemophilia: Validation of the Observer-Reported Child Hemophilia Treatment Experience Measure (Child Hemo-TEM)

Background: Despite treatment safety and efficacy advancements for children with hemophilia (CwH), home treatment can be complicated and burdensome. Treatment burdens are major contributing factors to adherence issues. The Child Hemo-TEM is a patient-centric outcome measure developed following the United States (US) Food and Drug Administration guidance for patient-reported outcome measure development. Designed to assess the treatment burden for CwH, the measure is a caregiver observer-reported outcome (ObsRO) measure where questions are answered by the caregiver about the child's treatment experience based on what the caregiver has seen, heard, or been told by the child. Aim: The purpose of this study was to psychometrically validate the Child Hemo-TEM ObsRO. Methods: Data was collected through a cross-sectional, web survey from a population of caregivers of CwH aged 2 to < 12 years in the US. The survey consisted of the Child Hemo-TEM, sociodemographic items, child's hemophilia medical history, and supporting items/measures required to assess the measure's psychometric properties. The survey took up to 45 minutes to complete and was administered at a single time point. To be eligible for the study, caregivers needed to be: aged ≥ 18 years; a caregiver of a male child with a diagnosis of severe to moderate hemophilia A or B, with a factor level of < 2%, with or without an inhibitor, and currently receiving either prophylactic or on-demand treatment; and living in the same residence as the child over the past 2 weeks. Recruitment was conducted by a patient advocacy group and a professional market research firm. Recruitment quotas were targeted to ensure a diverse population and mix of frequency of prophylactic treatment(s) and treatment administration type. All psychometric analyses were conducted following an a-priori statistical analysis plan, which included examination of measurement characteristics, item reduction, factor analysis, measure scoring, internal consistency, reliability, and validity. Results: Caregivers ( n=187) of CwH completed the web survey. The respondents were, on average, 37.8 years of age, mothers (84.0%), and predominantly White/Caucasian (74.3%). Twelve items were dropped from the validation-ready, 19-item measure: 5 items due to high ceiling effects at baseline (>50%) mirrored by the Rasch results and 1 item as it was highly correlated with a retained item. Further, as there were only a small number of children who self-injected, 6 items designed to assess child self-injection were removed. The remaining items underwent further psychometric testing. An exploratory factor analysis generated a single, 7-item factor. The Child Hemo-TEM was found to be internally consistent with a Cronbach's α of 0.855. A-priori validity hypotheses were adapted to match the final factor structure. Hypothesized associations were predominantly confirmed with a few exceptions. For convergent validity (Pearson's r significance set at α = 0.05), a few of the associations, although significant, were below 0.30 (Table 1). The Child Hemo-TEM was able to discriminate between levels of self-complaining about their infusions (p < 0.001), psychological stress reported by parent (p < 0.001), and ease/difficulty of their medication in its current form, among other variables. Based on psychometric findings and taking into consideration learnings from the concept elicitation during measure development, the brief, 7-item Child Hemo-TEM was finalized with 1 domain capturing information from all the hypothesized concepts of treatment concerns (3 items), adherence (1 item), physical impact (1 item), and interference with daily life (2 items) (Figure 1). A five-point Likert response scale with ranges from “Never” to “Always”, or a “Don't know” option, is used. Conclusion: The Child Hemo-TEM ObsRO has been found to be conceptually sound with adequate evidence to support its reliability and validity. Incorporation of the measure into both clinical and research settings will help assess the pediatric patient's experience of living with hemophilia as well as aid clinicians in tailoring treatments to patient characteristics and situations. Future studies are needed to assess test-retest reproducibility, sensitivity to change, and meaningful change thresholds of this new measure.

Experience with Accelerometer Physical Activity Tracking in Adults and Adolescents with Hemophilia A: Tool Validation Using Results from the XTEND-1 Efanesoctocog Alfa Phase 3 Trial

Introduction Wearable physical activity trackers have become increasingly common within clinical studies, patient monitoring, and health assessments. Physical activity is a key endpoint of interest when evaluating treatments for hemophilia. The objective of this analysis was to describe the psychometric properties of five outcome measures of physical activity from the accelerometer activity monitor used in the XTEND-1 study. Methods XTEND-1 (NCT04161495) was a Phase 3, open-label, multicenter study of the efficacy, safety, and pharmacokinetics of efanesoctocog alfa in previously treated adults and adolescents aged ≥12 years with severe hemophilia A. Patients receiving prior standard-of-care prophylaxis factor VIII (FVIII) received once-weekly (qw) prophylactic efanesoctocog alfa for 52 weeks (Arm A); patients on prior on-demand FVIII treatment received efanesoctocog alfa on-demand for 26 weeks, then prophylactic efanesoctocog alfa qw for 26 weeks (Arm B). Patients wore a triaxial medical grade accelerometer activity monitor device for continuous monitoring during pre-specified intervals 8 consecutive days after (or before) scheduled visits (to collect data for a full 7-day week + 1 additional day): after the screening, baseline, Week 4, 13, 26, 39 visits, and before the Week 52 visit. Compliance was assessed based on number of monitoring intervals and number of days wearing the device, and number of minutes spent wearing the device within those days. Five outcomes were assessed: light physical activity (LPA), moderate-to-vigorous activity, sedentary behavior (minutes/day spent in these individual outcomes out of total number minutes wearing device while awake), steps (number of steps taken per day), and metabolic equivalent of a task (MET; total estimated metabolic rate per day). Psychometric analyses of these outcomes using data from Arm A were conducted to evaluate test-retest reliability (TRTR), concurrent validity, known-groups validity, ability to detect change, and meaningful within-patient change (MWPC) of physical activity measurements ( Table 1). An analysis to detect potential influential outlier patients for each outcome that could potentially bias results, was conducted. Results In total, 132 out of 133 patients in Arm A and 26 out of 26 patients in Arm B, distributed in 19 countries, had accelerometer data. Compliance was defined post-hoc as ≥12 consecutive wear hours/day and results are presented for days achieving this threshold; no meaningful differences in results were found when incorporating number of monitoring intervals or number of days within the interval in the compliance definition. Most patients maintained or improved physical activity as measured by the activity monitors, with an overall increase in mean (SD) minutes during each monitoring period for LPA (baseline: 636 [234]; Week 52: 653 [237]), though there were variable changes throughout the study period. Measurements of LPA demonstrated acceptable TRTR, concurrent validity with three validation criteria, and ability to detect change with all or most of the anchor variables, while demonstrating good separation for improvement and deterioration thresholds to provide for MWPC ( Table 1). Two patients were identified as influential outliers for LPA. For moderate-to-vigorous activity, the concurrent validity showed that two validators met the criteria, and for steps, four validators met the criteria. Sedentary behavior and MET did not meet criterion with any of the validators ( Table 1). Out of the outcomes assessed, LPA showed the best psychometric properties within the study. Conclusion These analyses show how physical activity tracking through wearables was used to assess outcomes in patients with severe hemophilia A, who switched to a FVIII replacement therapy that provided normal to near-normal FVIII activity for most of the weekly dosing interval, resulting in reduced pain and improved physical functioning as assessed by patient-reported outcome measures. Analyses of these results revealed limitations in the psychometric properties of the assessed outcomes. To further understand the personal motivation and barriers for improving physical activity, addition of goal-setting could be considered in future clinical studies.

Understanding Treatment Burden in Pediatric Hemophilia: Development of the Child Hemophilia Treatment Experience Measure (Child Hemo-TEM)

Background: Currently available hemophilia treatments have resulted in significant improvements in quality of life. However, children with hemophilia (CwH) may still experience considerable treatment burden due to technical, physical, logistical, and emotional aspects of treatment administration. Aims: The objective of the current study was to examine the treatment experiences of CwH with the aim of developing a patient-centered measure of hemophilia to assess treatment burden in CwH, in accordance with the United States Food and Drug Administration guidelines for patient-reported outcome (PRO) measure development. Methods: Concept elicitation (CE) data included a review of the current hemophilia literature and 1-1.5-hour interviews with 4 clinical experts, 25 CwH, and 25 caregivers of CwH. A clinical expert was defined as a hematologist or nurse who currently had at least a 50% patient load in hemophilia and had been providing care to CwH for ≥ 5 years. CwH had to: be male; be between the ages of 8 to < 12 years; have a diagnosis of hemophilia A or B, with or without an inhibitor, and a factor level of < 2%; and currently be receiving, by caregiver administering or self-administering (with or without assistance), either on-demand or prophylactic treatment for hemophilia via factor replacement therapy or a bypassing agent. For caregivers to be eligible, their CwH had similar eligibility criteria except that they had to be < 12 years of age. The child, caregiver, and clinician CE interview transcripts were analyzed using Dedoose software. The information was synthesized and coded based on grounded theory principles. Based on this analysis, a theoretical model of the treatment experiences of CwH was developed and items reflecting the major and minor aspects of, distal consequences, and modifiers to the experience were included. Items reflecting the major concepts were generated and cognitive debriefing (CD) was conducted with 12 children and 15 caregivers. Results: For the CE, the average age of the child participants was 9.6 years (median 10, range 8-11). Sixty-four percent ( n=16) of the sample was White/Caucasian, all had severe hemophilia, the majority ( n=23, 92%) had hemophilia A, and had been treated with factor for an average of 8.9 years (median 9, range 7-11). The average age of caregivers' CwH was 6.3 years (median 6, range 2-11). Forty-four percent of children ( n=11) were White/Caucasian, all had severe hemophilia, the majority ( n=22, 88%) had hemophilia A, and had been receiving treatment for an average of 6.0 years (median 5.5, range 2-11.5). The treatment experience issues most frequently reported by 50% or more by either or both child participants or caregivers of CwH were: Ease of Use: inserting the needle; Adherence: missing or delaying treatments and difficulty keeping track of schedule/remembering to do treatment; Emotional Impacts and Treatment Concerns: feeling nervous, anxious or scared; proud/good about oneself; emotionally resolved/used to treatment; and stress; Physical Impacts: pain and scarring/scar tissue; and Interference with Daily Life: needing to stop activities to do treatment (see Table 1 for list of issues reported by ≥ 10% of either one or both child or caregiver and percent endorsements). Based on the theoretical model (see Figure 1), a preliminary measure was generated, and the CD was completed. As a result of the CD, a decision was made to develop only a caregiver observer-reported outcome (ObsRO) measure to capture the experiences of children aged < 12 years. The decision to not develop a PRO was based on the interviews with children aged 10 to < 12 years, which resulted in 10 out of the 12 respondents using an incorrect timeframe when answering one or more items, about one-third answered one or more items related to the impact of a bleed and not their treatment, and over half of the children had issues with comprehension with one or more items and/or trouble navigating layout/skip pattern. Following CD, the validation-ready version of the measure, the Child Hemo-TEM, was finalized. Conclusion: This study has identified key aspects of the treatment experience of CwH, which support thecontent validity of the Child Hemo-TEM ObsRO. Compared to generic measures, condition- and age-specific instruments, should have greater face validity, be more responsive to change over time, and may be more useful to both clinicians and researchers to assess the hemophilia treatment burden of CwH.

Efficacy and Safety of Prophylaxis with a Plasma-Derived Von Willebrand Factor/Factor VIII Concentrate in Children and Adolescents with Von Willebrand Disease - a Sub-Analysis of Data from the Wil-31 Study

Background: Prophylaxis with von Willebrand factor (VWF) concentrate is recommended for individuals with von Willebrand disease (VWD) who have a history of frequent and severe bleeds, regardless of their age. The WIL-31 study demonstrated the efficacy of prophylaxis with a plasma-derived VWF/factor VIII (pdVWF/FVIII) concentrate containing VWF and FVIII in a 1:1 activity ratio (wilate ®) in adults and children with VWD of all types. Here we specifically report on the results in children and adolescents. Aims: To investigate the efficacy and safety of regular prophylaxis with a pdVWF/FVIII concentrate in children and adolescents with VWD, compared with prior on-demand treatment. Methods: WIL-31 (NCT04052698) was a prospective, non-controlled, international, multicenter phase 3 trial that enrolled male/female patients aged ≥6 years with VWD type 1 (VWF:RCo <30 IU/dL), type 2 (except 2N) or type 3. Prior to entering the WIL-31 study, all patients had received on-demand treatment with a pdVWF/FVIII concentrate during a 6-month, prospective, observational, run-in study (WIL-29); patients who experienced at least 6 BEs, excluding menstrual bleeds, with at least 2 of these BEs treated with a VWF-containing product, were eligible to enter WIL-31. Patients in WIL-31 received regular pdVWF/FVIII prophylaxis 2-3 times per week at a dose of 20-40 IU/kg for 12 months. In this post-hoc analysis patients were grouped by age: children (6-11 years old), adolescents (12-16 years old), and adults (≥17 years old). Mean total and spontaneous ABR were compared, and the number and site of breakthrough bleeds were described. Safety and tolerability were assessed throughout the study. Results: The study population included 33 patients, with a median (range) age of 18 (7-61) years. Nine (27.3%) patients were children, 6 (18.2%) were adolescents, and 18 (54.5%) were adults. During 12 months of prophylaxis, 67% (6/9) of children and 83% (5/6) of adolescents experienced 34 (all minor) and 26 bleeds (20 minor; 6 major), respectively. Among children and adolescents, 82% (28/34) and 77% (20/26) of bleeds required treatment, with “excellent/good” efficacy achieved in 100% and 95% of treated bleeds, respectively. The mean total ABRs during on-demand vs prophylaxis were 32.5 vs 3.7 in children and 28.9 vs 4.3 in adolescents, representing 88.6% and 85.1% reductions during prophylaxis compared with on-demand treatment. Of these bleeds, the most common sites were nose (74%; 25/34) and oral cavity (9%; 3/34) for children, and nose (46%; 12/26), ankle (23%; 6/26) and elbow (19%; 5/26) joints for adolescents. During prophylaxis children experienced no joint bleeds; the mean knee, ankle, and elbow joint ABRs in adolescents were 0.2, 1.0, and 0.8, respectively. The mean spontaneous ABRs during on-demand treatment vs prophylaxis were 22.8 vs 2.5 (88.9% reduction) and 21.7 vs 1.5 (93.2% reduction) (Figure 1). Forty-four percent of children, and 33% of adolescents had zero spontaneous bleeding events during 12 months of prophylaxis. No serious adverse events related to study treatment and no thrombotic events were observed, and no safety concerns were raised by clinical laboratory, vital sign, and physical examination findings. There were no cases of parvovirus B19 seroconversion or inhibitor development judged to be related to study treatment. Conclusion: Prophylaxis with pdVWF/FVIII was efficacious and well tolerated in children and adolescents with all types of VWD.

Immunogenicity of a Plasma-Derived Von Willebrand Factor/Factor VIII Concentrate during the Wil-31 Prophylaxis Study in Patients with Von Willebrand Disease

Background: Long-term prophylaxis with a von Willebrand factor (VWF) concentrate is recommended in people with von Willebrand disease (VWD) with a history of frequent and severe bleeds. The WIL-31 study demonstrated the efficacy of prophylaxis with a plasma-derived VWF/factor VIII (pdVWF/FVIII) concentrate containing VWF and FVIII in a 1:1 activity ratio (wilate ®) in adults and children with VWD of all types. The primary endpoint was met, showing a decrease in mean total annualized bleeding rate (ABR) of 84% compared with prior on-demand treatment. Aim: To assess the immunogenicity of pdVWF/FVIII when used during the WIL-31 study in children and adults with VWD of all types. Methods: WIL-31 (NCT04052698) was a prospective, non-controlled, international, multicenter phase 3 trial that enrolled male/female patients aged ≥6 years with VWD type 1 (VWF: RCo <30 IU/dL), type 2 (except 2N) or type 3. Prior to entering the WIL-31 study, all patients had received on-demand treatment with a VWF-containing product during a 6-month, prospective, observational, run-in study (WIL-29); patients who experienced at least 6 bleeding episodes (BEs), excluding menstrual bleeds, of which ≥2 were treated with a VWF-containing product, were eligible to enter WIL-31. During WIL-31, patients received regular pdVWF/FVIII (containing VWF and FVIII in a 1:1 activity ratio) prophylaxis 2-3 times per week at a dose of 20-40 IU/kg for 12 months. FVIII (chromogenic and one-stage assays) and VWF (VWF:RCo assay) activities were assessed at baseline and throughout the study. Retention samples were collected at screening and baseline visits for possible later inhibitor testing (to be performed at a central laboratory using the Nijmegen-Bethesda assay for FVIII inhibitors and the mixing study based on VWF:RCo for VWF inhibitors). Inhibitor testing was also performed if inhibitor development was suspected. Results: Inhibitor testing was performed in 2 of 33 patients because of unusual pharmacokinetic results at the 6-month visits, even though neither patient had any clinical signs of an inhibitor. The VWF inhibitors were detected in samples from two brothers taken at their 6-month visits. However, when retained blood samples from the screening visits of both boys were tested, both samples tested inhibitor-positive, demonstrating that both boys had developed the inhibitors prior to starting prophylaxis during WIL-31. During and before the WIL-29 run-in study, both boys had been treated on demand with another pdVWF/FVIII concentrate. The boys had both been diagnosed with VWD shortly after birth, and it was suspected that they had type 2A based on family history and were 15 (patient A) and 11 years old (patient B) at the start of WIL-31. They had a family history of VWD (both parents were diagnosed with VWD), but no family history of inhibitors. After the completion of WIL-31, both patients were reclassified to type 3 VWD following further investigation including next-generation sequencing. Baseline VWF activity indicated low VWF:RCo levels (Patient A: 0.092 IU/mL and Patient B: 0.65 IU/mL; Figure 1). The boys received 38 (patient A) and 34 IU/kg (patient B) pdVWF/FVIII respectively, twice weekly during WIL-31, and their mean total ABRs decreased by 85% and 91%, respectively, during WIL-31 compared with WIL-29. All bleeding episodes during WIL-31 were spontaneous nose bleeds. Both boys continued the same prophylactic regimen until the end of WIL-31. In one patient the inhibitor titer was negative by the end of the study. Conclusion: VWF inhibitors were detected in 2 of the 33 patients on prophylaxis with pdVWF/FVIII in the WIL-31 study and subsequent investigation revealed that both patients were already positive for VWF inhibitors prior to the study start. In one of the patients, the inhibitor resolved during continued prophylaxis. Despite the inhibitors, prophylaxis was effective in both patients with an ≥85% reduction in ABR compared to on demand treatment.

Recombinant ADAMTS13 for the Treatment of Acute TTP Events in Patients with Congenital Thrombotic Thrombocytopenic Purpura: Results from the Phase 3 Randomized, Controlled, Crossover Study and the Phase 3b Continuation Study

Background Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultra-rare, life-threatening thrombotic microangiopathy caused by an inherited deficiency of the enzyme ADAMTS13. An ongoing phase 3 study (NCT03393975) and phase 3b continuation study (NCT04683003) are investigating the safety and efficacy of recombinant ADAMTS13 (rADAMTS13; TAK-755; Takeda Development Center Americas, Inc., Lexington, MA, USA) for prophylaxis and on-demand treatment of acute events in patients with cTTP. Aims To assess the efficacy and safety of rADAMTS13 for the treatment of acute TTP events and long-term prophylaxis in patients with severe cTTP. Methods The phase 3 prospective, randomized, controlled, open-label, multicenter, crossover study (NCT03393975) is open to enroll patients 0-70 years old with severe cTTP (ADAMTS13 activity <10%). Upon completion of the phase 3 study, patients could enroll into the phase 3b prospective, open-label, multicenter, single treatment arm continuation study (NCT04683003). In the phase 3 study, patients were randomized 1:1 at enrollment to receive prophylaxis with either rADAMTS13 or standard of care (SoC). SoC was determined by the treating physician and could include fresh frozen plasma, pooled solvent/detergent-treated plasma, or factor VIII/von Willebrand factor concentrates. Patients in the phase 3b continuation study received open-label rADAMTS13 treatment. In both studies, patients could be enrolled and receive treatment on demand for acute TTP events. Per protocol, rADAMTS13 was to be administered at 40 IU/kg on Day 1, 20 IU/kg on Day 2 and 15 IU/kg daily from Day 3 onwards until 2 days after resolution of the acute event (defined as platelet count either ≥150,000/μL or within 25% of baseline; and elevation of LDH levels ≤1.5× of baseline or ≤1.5× the upper limit of normal). Data are presented from a pre-planned interim analysis (data cutoff: August 12, 2022) and focus on the treatment of acute TTP events in both studies. Results At the time of the data cutoff, 8 acute TTP events were reported in 7 patients ( Table), all of whom were ≥18 years old. None of the events occurred while the patient was receiving rADAMTS13 prophylaxis. Six events occurred in 5 patients (median age: 20.0 years; sex: 3 male, 2 female) who received on-demand treatment in the phase 3 study; 2 of these patients were randomized to receive rADAMTS13 and 3 to receive SoC. One event also occurred in the phase 3 study while the patient was receiving prophylaxis with SoC. One event occurred in the screening period prior to the patient starting rADAMTS13 prophylaxis in the phase 3b continuation study; this event was treated with rADAMTS13. Platelet counts observed during the first 3 days of treatment for all 8 acute TTP events are shown in the Figure. Prior to study treatment, on Day 0, the mean platelet counts were similar between the rADAMTS13 and SoC cohorts. Over the first 3 treatment days, the mean platelet count increased more than ~5-fold with rADAMTS13, and ~3-fold with SoC. All three acute TTP events treated with rADAMTS13 resolved without requiring the administration of any other treatment containing ADAMTS13. Based on pharmacokinetics (PK) data available in 5 patients (3 received treatment with rADAMTS13 and 2 with SoC), the post-infusion ADAMTS13 activity levels ~1 hour after administration were between 80% to 270% of normal with rADAMTS13 and between 10% to 48% with SoC. These observed ADAMTS13 activity levels were as expected based on the linear PK observed following single dose PK assessments in the phase 3 study. Of the 4 patients who received SoC for the treatment of an acute TTP event, 2 experienced a mild treatment-emergent adverse event (TEAE) that was considered related to the SoC (nausea and pruritis). Of the 3 patients who received rADAMTS13, 1 patient experienced 3 mild TEAEs (feeling hot, nausea, and thrombocytosis) that were considered related to rADAMTS13. No serious TEAEs related to rADAMTS13 were reported and no neutralizing antibodies against ADAMTS13 were observed. Conclusions The resolution of acute TTP events and an improvement in platelet count in patients with cTTP following treatment with rADAMTS13 was closely related to higher ADAMTS13 activity exposure. No serious TEAEs related to rADAMTS13 were reported.

Transcriptomic Profiling to Understand Inhibitor Development in Previously Untreated Patients with Severe Hemophilia a

Background: When starting treatment with factor VIII (FVIII) concentrate in individuals with severe hemophilia A, minimizing the risk of FVIII inhibitor development is an important concern for clinicians, patients and their families. Despite increased understanding of some of the genetic and environmental risk factors for inhibitor formation from epidemiological studies, identification of previously untreated patients (PUPs) at risk of developing inhibitors remains a challenge. Prediction of inhibitor development may help optimize care in PUPs with hemophilia A. RNA sequencing (RNA-Seq) with next-generation sequencing (NGS) could be used to investigate the underlying mechanisms of inhibitor development. Aims: Toevaluate peripheral blood transcriptomic profiles prior to and during early FVIII treatment in severe hemophilia A patients who did or did not develop inhibitors to simoctocog alfain the prospective NuProtect study. Methods: The NuProtect study (NCT01712438; EudraCT 2012-002554-23) was a multicenter, multinational, open-label, non-controlled, phase III study that enrolled male PUPs with severe hemophilia A (FVIII:C <1%) of any age and ethnicity. Patients received simoctocog alfa for prophylaxis or on-demand treatment, as well as for surgical prophylaxis. RNA-Seq was performed on blood samples collected from baseline and every 3-4 exposure days (ED) up to 20 EDs or until inhibitor development to assess messenger RNA (mRNA) expression profiles. Bioinformatics analyses were performed for the following timepoints: baseline, early treatment and a later timepoint on treatment. Principal component analysis (PCA) was performed to identify differences in global mRNA expression profiles between inhibitor and non-inhibitor patients. Gene ontology (GO) analyses were performed to detect differences in GO clusters between inhibitor and non-inhibitor patients. Results: Within this first analysis of the full dataset, transcriptomic profiles from 78 of 108 severe hemophilia A PUPs were analyzed (inhibitors n=22, non-inhibitors n=56). Median (range) age at ED1 was 13 (0.5-146) months; 44.9% of patients had the intron 22 inversion F8 gene mutation. Although the PCA indicated no strong global signal for differential expression profiles between non-inhibitor and inhibitor patients, GO analyses demonstrated differences between these patient groups. Inhibitor patients demonstrated increased gene expression of metabolic processes (GO:0008152) and cellular processes (GO:0009987) at baseline. Upregulation of immune system processes (GO:0002376) was seen in inhibitor patients at the early timepoint compared with non-inhibitor patients. Expression of ribosomal proteins, including RPL17 and RPS8 were significantly upregulated at baseline in inhibitor patients (p<0.05). Inhibitor patients further demonstrated upregulation of proteins involved in adaptive immune responses: IGHV1-69-2 at all timepoints (p<0.01) and IGHV2-70D at baseline and the early timepoint (p<0.01) compared with non-inhibitor patients. Upregulation of the B-cell related factors DPP4 at baseline and the early timepoint (p<0.05) and CD20 at the late timepoint (p<0.05) was observed in inhibitor patients compared with non-inhibitor patients. Conclusion: Differential transcriptomic profiles were seen in severe hemophilia A patients who developed inhibitors compared with those who do not, even before commencing FVIII treatment. Inhibitor patients demonstrated alterations in ribosomal protein expression that could disrupt protein synthesis efficiency, protein folding and quality control processes, and trigger cellular stress responses. Inhibitor patients also showed an upregulation of B-cell mediated factors involved in adaptive immune mechanisms. Additional analyses are ongoing to evaluate dynamic changes in gene expression during commencement of FVIII replacement to further identify patients at risk of inhibitor development.

Universal Access to On-Demand Treatment of Patients with Hereditary Angioedema, the Chilean Experience.

Background: In Chile, patients with hereditary angioedema (HAE) type I and type II are protected under Ley Ricarte Soto (LRS), which guarantees access to on demand plasma-derived C1-INH (pdC1-INH) since 2018. We aimed to analyze the first 3 years of LRS. Methods: Review of the LRS database between 2018 and 2021. Results: During the study period, 154 patients were covered by LRS, with an estimated prevalence of HAE in Chile at 0.8:100,000 inhabitants. A delay in diagnosis of 22 years was noted, 50 patients received epinephrine during an attack before the diagnosis of HAE. Mean number of attacks per year was 8, with 50% of adults and 42% of children experiencing more than 1 attack per month. Conclusion: Disease awareness must improve to reduce the diagnostic delay of HAE. Long-term prophylactic medications should be included in LRS to treat patients with high attack rates and control the costs of frequent on-demand treatment with pdC1-INH.

Effect of Factor VIII and Von Willebrand Factor Activities on Number of Bleeding Events in Previously Treated Patients with Von Willebrand Disease on Regular Prophylaxis with a Plasma-Derived Von Willebrand Factor/Factor VIII Concentrate

Background: von Willebrand disease (VWD) is characterized by a deficiency or reduction of activity in von Willebrand factor (VWF). As VWF has a role in stabilizing coagulation factor VIII (FVIII), VWD patients often suffer from secondary FVIII deficiency. Current guidelines recommend that VWD patients with a history of severe and frequent bleeds should use long-term prophylaxis with factor replacement therapy. The WIL-31 study demonstrated the efficacy of prophylaxis with a plasma-derived VWF/factor VIII concentrate containing VWF and FVIII in a 1:1 activity ratio (pdVWF/FVIII; wilate ®) in adults and children with VWD. The primary endpoint was met, showing a decrease of 84% in the mean total annualized bleeding rate (ABR). As elevated levels of FVIII are associated with an increased risk for thrombosis, it is important to determine whether repeated dosing with pdVWF/FVIII leads to accumulation of FVIII over time. Aims: To investigate the activity levels of VWF and FVIII in patients with VWD receiving regular prophylaxis with pdVWF/FVIII. Methods: WIL-31 (NCT04052698) was a prospective, non-controlled, international, multicenter phase 3 trial that enrolled male/female patients, aged ≥6 years old with VWD type 1 (VWF:RCo <30 IU/dL), type 2 (except 2N) or type 3. Prior to entering the WIL-31 study, all patients had received on-demand treatment with a pdVWF/FVIII concentrate during a 6-month, prospective, observational, run-in study (WIL-29). Patients in WIL-31 received regular pdVWF/FVIII prophylaxis 2-3 times per week at a dose of 20-40 IU/kg for 12 months. VWF activity (VWF:RCo) and FVIII activity (measured by the chromogenic [Chr] and one-stage [OS] assays) were performed at baseline and throughout the study. Full pharmacokinetic (PK) analyses were performed in all patients aged 6-16 years, a single dose of 60 ± 10 IU/kg pdVWF/FVIII was administered. Samples were collected at up to 1 hour prior to injection and then at multiple time points post-injection (1-72 hours). Safety, including the occurrence of thrombotic events, was monitored throughout the study. Results: The overall study population included 33 patients, with a median age of 18 years consisting of 9 (27.3%) patients aged 6-11 years, 6 (18.2%) patients aged 12-16 years, and 18 (54.5%) patients aged ≥17 years. Six (18.2%) patients had severe type 1 VWD, 5 (15.2%) patients had type 2, and 22 (66.7%) patients had type 3. Baseline FVIII and VWF activities in WIL-31 were similar regardless of age group, and as expected were lower in patients with type 3 VWD compared with severe type 1 and type 2 (Figure 1). There was a negative correlation of baseline FVIII and VWF activity with the number of spontaneous bleeding episodes (BEs) during prophylaxis. Patients who had no spontaneous BEs during prophylaxis had higher baseline FVIII and VWF levels compared with those who had spontaneous BEs. Mean peak and trough FVIII and VWF activity levels remained consistent during the study and there was no accumulation of either factor over the 12-month prophylaxis period (Figure 2). Full PK assessments were performed according to protocol in 13 patients aged 6-16 years. The mean ± standard deviation in vivo half-life was 16.1±6.7, 16.2±7.7, and 9.8±7.7 hours, for FVIII Chr, FVIII OS, and VWF:RCo, respectively. No thrombotic events were observed. Conclusion: No accumulation of FVIII or VWF in the plasma was reported in 33 patients who received regular prophylaxis with pdVWF/FVIII for 12 months, regardless of VWD type and age.

On-demand Versus Continuous Maintenance Treatment With a Proton Pump Inhibitor for Mild Gastroesophageal Reflux Disease: A Prospective Randomized Multicenter Study.

It remains unclear which maintenance treatment modality is most appropriate for mild gastroesophageal reflux disease (GERD). We aimed to compare on-demand treatment with continuous treatment using a proton pump inhibitor (PPI) in the maintenance treatment for patients with non-erosive GERD or mild erosive esophagitis. Patients whose GERD symptoms improved after 4 weeks of standard dose PPI treatment were prospectively enrolled at 25 hospitals. Subsequently, the enrolled patients were randomly assigned to either an on-demand or a continuous maintenance treatment group, and followed in an 8-week interval for up to 24 weeks. A total of 304 patients were randomized to maintenance treatment (continuous, n = 151 vs on-demand, n = 153). The primary outcome, the overall proportion of unwillingness to continue the assigned maintenance treatment modality, failed to confirm the non-inferiority of on-demand treatment (45.9%) compared to continuous treatment (36.1%). Compared with the on-demand group, the GERD symptom and health-related quality of life scores significantly more improved and the overall satisfaction score was significantly higher in the continuous treatment group, particularly at week 8 and week 16 of maintenance treatment. Work impairment scores were not different in the 2 groups, but the prescription cost was less in the on-demand group. Serum gastrin levels significantly elevated in the continuous treatment group, but not in the on-demand group. Continuous treatment seems to be more appropriate for the initial maintenance treatment of non-erosive GERD or mild erosive esophagitis than on-demand treatment. Stepping down to on-demand treatment needs to be considered after a sufficient period of continuous treatment.

Plasma-derived human factor X concentrate for the treatment of patients with hereditary factor X deficiency.

Hereditary factor X (FX) deficiency (HFXD) is an autosomal recessive rare bleeding disorder that leads to defects in the FX protein. Depending on the degree of deficiency, patients may be at risk of life-threatening bleeding episodes. Historical treatments for FX deficiency include prothrombin complex concentrates, which can increase the risk of thrombosis, and fresh frozen plasma, which can cause volume overload and transfusion reactions. Plasma-derived FX (pdFX), a single-factor, high-purity, high-potency human FX treatment, was approved in 2015 in the United States and in 2016 in Europe for on-demand treatment and prophylaxis of bleeding episodes and perioperative management of patients with HFXD. Five studies that examined the use of pdFX in patients with mild (plasma FX activity [FX:C] ≥5IU/dL), moderate (FX:C ≥1 and<5IU/dL), or severe (FX:C<1IU/dL) HFXD were reviewed: TEN01, TEN02 and TEN03 were prospective, open-label, multicentre, nonrandomised studies, and TEN05 and TEN06 were multicentre retrospective studies. When used as an on-demand treatment, pdFX was judged by investigators to be successful in treating 41/42 (97.6%), 2/3 (66.6%) and 79/79 (100%) bleeds in TEN01, TEN02 and TEN05, respectively. When used prophylactically, pdFX was judged 'excellent' for the prevention of bleeds in nine (100%) and eight (100%) patients in TEN02 and TEN05, respectively. Perioperative treatment and pharmacokinetics were also assessed. pdFX was safe and well tolerated. Together, these studies support the use of pdFX for on-demand treatment of bleeding, routine prophylaxis, and perioperative management of bleeding in patients with HFXD.

Hydrogel-Based Biosensors for Bacterial Infections.

Hydrogels are known to have the advantages such as good biodegradability, biocompatibility, and easy functionalization, making them ideal candidates for biosensors. Hydrogel-based biosensors that respond to bacteria-induced microenvironmental changes such as pH, enzymes, antigens, etc., or directly interact with bacterial surface receptors, can be applied for early diagnosis of bacterial infections, providing information for timely treatment while avoiding antibiotic abuse. Furthermore, hydrogel biosensors capable of both bacteria diagnosis and treatment will greatly facilitate the development of point-of-care monitoring of bacterial infections. In this review, the recent advancement of hydrogel-based biosensors for bacterial infection is summarized and discussed. First, the biosensors based on pH-sensitive hydrogels, bacterial-specific secretions-sensitive hydrogels, and hydrogels directly in contact with bacterial surfaces are presented. Next, hydrogel biosensors capable of detecting bacterial infection in the early stage followed by immediate on-demand treatment are discussed. Finally, the challenges and future development of hydrogel biosensors for bacterial infections are proposed.

Neurological Complications Associated with Hereditary Bleeding Disorders.

Hereditary bleeding disorders may have a wide variety of clinical presentations ranging from mild mucosal and joint bleeding to severe central nervous system (CNS) bleeding, of which intracranial hemorrhage (ICH) is the most dreaded complication. In this review, we will discuss the pathophysiology of specific hereditary bleeding disorders, namely, hemophilia A, hemophilia B, and von Willebrand disease (vWD); their clinical manifestations with a particular emphasis on neurological complications; a brief overview of management strategies pertaining to neurological complications; and a review of literature guiding treatment strategies. ICH is the most significant cause of morbidity and mortality in patients with hemophilia. Adequate control of bleeding with the administration of specific factors or blood products, identification of risk factors for bleeding, and maintaining optimal coagulant activity are essential for appropriately managing CNS bleeding complications in these patients. The administration of specific recombinant factors is tailored to a patient's pharmacokinetics and steady-state levels. During acute bleeding episodes, initial factor activity should be maintained between 80 and 100%. Availability of monoclonal antibody Emicizumab has revolutionized prophylactic therapies in patients with hemophilia. Management of ICH in patients with vWD involves using plasma-derived factor concentrates, recombinant von Willebrand factor, and supportive antifibrinolytic agents individualized to the type and severity of vWD. Hemophilia and vWD are the most common hereditary bleeding disorders that can predispose patients to life-threatening CNS complications-intracranial bleeds, intraspinal bleeding, and peripheral nerve syndromes. Early care coordination with a hematologist can help develop an effective prophylactic regimen to avoid life-threatening bleeding complications in these patients. Further research is needed to evaluate using emicizumab as an on-demand treatment option for acute bleeding episodes in patients with hemophilia.

Wireless and Closed-Loop Smart Dressing for Exudate Management and On-Demand Treatment of Chronic Wounds.

Chronic wounds have become a significant threat to people's physical and mental health and have increased the burden of social medical care. Intelligent wound dressing (IWD) with wound condition monitoring and closed-loop on-demand drug therapy can shorten the healing process and alleviate patient suffering. However, single-function wound dressings cannot meet the current needs of chronic wound treatment. Here, a wearable IWD consisting of wound exudate management, sensor monitoring, closed-loop therapy, and flexible circuit modules is reported, which can achieve effective synergy between wound exudate management and on-demand wound therapy. The dressing is attached to the wound site, and the wound exudate is spontaneously pumped into the microfluidic channel for storage. Meanwhile, the IWD can detect the state of the wound through the temperature and humidity sensor, and use this as feedback to control the liquid metal (LM) heater through a smartphone, thereby realizing the on-demand drug release from the hydrogel. In a mouse model of infected wounds, IWD accelerates wound healing by reducing inflammatory responses, promoting angiogenesis and collagen deposition.

Lysozyme-based nanozyme encapsulated in double-network hydrogel for monitoring and repair of MRSA infected wounds

The presence of bacterial infection at the wound site poses a huge socioeconomic burden to public health as it adversely affects the tissue regeneration and thereby prolongs the wound healing process. To overcome the “black-box” status of healing process, the effective monitoring and treatment of infected wound is imperative in clinical practice, which has urged continuous exploration of wound dressings with integrated abilities of antibacterial effect, timely diagnosis and therapy. In this study, a dual-functional hydrogel of antimicrobial and the ability to monitor wound infections was prepared. In the gel, antibacterial protein of lysozyme was used for the sufficient loading of hemin molecules. The obtained lysozyme@Hemin nanopaticles (Ly@He NPs) was co-encapsulated with AgNO3 in the double-network hydrogel composed of gelatin and polyvinyl alcohol, which endows the obtained hydrogel not only desirable mechanical characteristics but dual capabilities of bactericidal effect and bacterial infection monitoring around the wound site. In addition to the sustained bactericidal effects by the silver leveraging from the hydrogel, the generation of abundant reactive hydroxyl radicals induced by the nanozyme of Ly@He NPs contributed significantly to the improved antibacterial activity of hydrogel. Moreover, based on the peroxidase (POD)-like activity, the prepared hydrogel was capable of monitoring the wound infection status by the colorimetric detection of glutathione, a biomarker of bacterial infection. Finally, both in vivo and in vitro experimental results pointed to the satisfying efficacy of the hydrogel to eliminate and monitor bacterial infection. Therefore, the proposed system holds enormous potentials in the development of integrated nanoplatforms for the diagnosis and on-demand treatment of bacteria-infected wounds.

Evolution of Guidelines for the Management of Hereditary Angioedema due to C1 Inhibitor Deficiency.

Hereditary angioedema (HAE) is a severe and disabling condition characterized by recurrent episodes of subcutaneous or mucosal swelling in the skin and respiratory and gastrointestinal tracts. HAE due to C1-esterase inhibitor deficiency (C1-INH-HAE) is the most prevalent subtype. The present Iberian study compared C1-INH-HAE treatment guidelines published between 2010 and 2022 to identify the main differences in therapeutic approaches for on-demand treatment and short- and long-term prophylaxis (LTP). HAE guidelines evolved with the availability of new treatments and with a change in the management paradigm towards an individualized, patient-centered approach, where quality of life (QOL) is central. A parallel trend was observed towards increasingly frequent home-based treatment, which potentially facilitates timely interventions, provides greater flexibility and convenience, and is associated with increased QOL, enabling patients to lead more normal lives. Most innovations over the years were made for LTP, together with the advent of new therapies and awareness of patients' needs. Several prophylactic therapies with a high level of evidence became available, although formal head-to-head comparisons are lacking. The treatment goals became more ambitious, ranging from a reduction in the frequency, severity, and duration of attacks to achieving total disease control and normalization of patients' lives. The document also addresses relevant items such as changes in terminology (eg, the introduction of designations as "first-line") and the introduction of patient-reported outcome measures to assess patients' perceptions of their self-experienced QOL and well-being. Unmet needs in the management of C1-INH-HAE are identified.