Recombinant factor VIII Fc fusion protein for first-time immune tolerance induction: final results of the verITI-8 study.

Inhibitor development remains a major challenge in factor VIII (FVIII) replacement therapy. verITI-8 is the first prospective study of a recombinant FVIII Fc fusion protein (rFVIIIFc; efmoroctocog alfa) for first-time immune tolerance induction (ITI) in males with severe hemophilia A and high-titer inhibitors (historical peak ≥5 Bethesda units [BU]/mL). In this single-arm, open-label, multicenter study, screening was followed by ITI (rFVIIIFc 200 IU/kg per day until tolerization or maximum of 48 weeks). Those who achieved ITI success entered a tapering period, returning to standard prophylaxis, and then entered follow-up. Primary end point was time to tolerization with rFVIIIFc defined by inhibitor titer <0.6 BU/mL, incremental recovery (IR) ≥66% of expected IR (IR ≥1.32 IU/dL per IU/kg), and half-life (t½) ≥7 hours within 48 weeks. Sixteen patients received ≥1 rFVIIIFc dose. Twelve (75%), 11 (69%), and 10 patients (63%), respectively, achieved negative inhibitor titers, an IR ≥66%, and a t½ ≥7 hours (ie, tolerance) within 48 weeks. Median times in weeks to achieve these markers of success were 7.4 (interquartile range [IQR], 2.2-17.8), 6.8 (IQR, 5.4-22.4), and 11.7 (IQR, 9.8-26.2), respectively. All patients experienced ≥1 treatment-emergent adverse event (TEAE), and 1 reported ≥1 related TEAE (injection site pain). Nine patients experienced ≥1 treatment-emergent serious AE. No thrombotic events, discontinuations because of AEs, or deaths were reported during the study. As the first extended half-life rFVIII with prospective data in ITI, rFVIIIFc offered short time to tolerization with durable responses in almost two-thirds of patients and was well tolerated. This trial was registered at www.clinicaltrials.gov as #NCT03093480.

Recombinant porcine factor VIII in patients with congenital haemophilia A with inhibitors undergoing surgery: Phase 3, single-arm, open-label study.

INTRODUCTION: Recombinant porcine factor VIII (rpFVIII; susoctocog alfa) is predicted to provide functional FVIII activity in patients with congenital haemophilia A with inhibitors (CHAWI). AIMS: To evaluate the efficacy and safety of rpFVIII in patients with CHAWI undergoing invasive procedures. METHODS: This phase 3, multicentre, single-arm, open-label study (NCT02895945) enrolled males aged 12-75 years with severe/moderately severe CHAWI who required surgical/invasive procedures. Patients received a loading dose of rpFVIII 1-2 h before surgery. The primary outcome was the proportion of all procedures with a 'good' or 'excellent' response (treatment success) on the global haemostatic efficacy assessment score. RESULTS: Of the eight dosed patients, five completed the study. Six of seven surgeries (85.7%; 95% confidence interval, 42.1-99.6) achieved treatment success; five were rated 'excellent', one was rated 'good'. Seven surgery-related bleeding episodes occurred in three patients during the study, with none requiring additional surgical intervention. Overall, six of eight patients experienced 17 treatment-emergent adverse events. Three patients developed de novo inhibitors to rpFVIII. Five patients reported anamnestic reactions, three to both human (h) FVIII (i.e., alloantibodies to exogenous FVIII detected with anti-hFVIII assays) and rpFVIII, and two to hFVIII only. Four serious adverse events were considered related to rpFVIII (three anti-rpFVIII antibody positive; one anamnestic reaction to hFVIII and rpFVIII). CONCLUSION: Good haemostasis was achieved with rpFVIII during the immediate perioperative period. The study was terminated early because the study sponsor and health authorities determined that the risk of anamnestic reactions outweighs the benefits in this study population.

A Naked Eye and Fluorescence Turn-on Sensor for Smartphone Assisted Solid and Solution Phase Sensing of Highly Toxic Triphosgene.

A naked eye and fluorescence turn-on 1,8-naphtahlimide based chemosensor,1, possessing Schiff base linkage was utilized for the rapid detection of highly toxic triphosgene. The proposed sensor selectively detected triphosgene over various other competitive analytes including phosgene with the detection limit of 6.15 and 1.15 µM measured using UV-vis and fluorescence spectrophotometric techniques, respectively. Colorimetric changes observed in solution phase were processed by image analysis using smartphone leading to on-site and inexpensive determination of triphosgene. Further, solid phase sensing of triphosgene was carried out by 1 loaded PEG membranes and silica gel.

Rapid sequence tandem intubation to navigate a subglottic obstruction.

Emergency airway management requires matching the appropriate intubation tools to anticipated obstacles. Video laryngoscopy and flexible endoscopy are often used for difficult airways. Here we describe a case where neither method alone was anticipated to be sufficient. A 53-year-old female with an obstructing lung mass required intubation for a mixed type 1 and 2 respiratory failure. Chest x-ray revealed a tortuous subglottic obstruction. The patient could not be temporized on maximized non-invasive airway support. These factors made tandem intubation, sequentially using video laryngoscopy and flexible endoscopic intubation, an appropriate intubation strategy. In this case report we describe the rationale and technique for a rapid sequence tandem intubation.

Women and girls with haemophilia and bleeding tendencies: Outcomes related to menstruation, pregnancy, surgery and other bleeding episodes from a retrospective chart review.

INTRODUCTION: Women or girls with haemophilia (WGH) represent a group of female symptomatic carriers who experience bleeding events more frequently than non-carriers. Bleeding events include spontaneous/traumatic bleeds and prolonged bleeding related to surgery, menstruation and pregnancy. Challenges for the treatment of WGH include lack of screening, diagnosis and treatment guidelines. AIM: Evaluate clinical characteristics, haemostasis management and clinical outcomes regarding menstruation, childbirth, dental procedures, surgeries and other bleeding events in WGH. METHODS: A retrospective, non-interventional review of medical records from WGH among three haemophilia treatment centres (HTCs) was conducted in the United States (2012-2018). Patients with ≥2 visits to the HTC and who had undergone intervention for haemostasis management with the outcome documented were included. Descriptive statistics were used. RESULTS: Of 47 women and girls included in the chart review (37 with factor VIII deficiency, 10 with factor IX deficiency), median age at diagnosis was 22.6 years. Approximately 79% (n = 37) were diagnosed with mild haemophilia. Events of interest were primarily managed by factor concentrates or antifibrinolytics. Most treatment approaches were successful across clinical scenarios, except for heavy menstrual bleeding being insufficiently controlled in 8 (57%) of the 14 patients who experienced it. CONCLUSIONS: Bleeding events in WGH, such as excessive and prolonged bleeding during menstruation, demonstrate a unique burden and require specific medical intervention. These results highlight the importance of assessing the need for haemostasis management in WGH and may contribute to future prospective study designs.

Real-world data demonstrate improved bleed control and extended dosing intervals for patients with haemophilia B after switching to recombinant factor IX Fc fusion protein (rFIXFc) for up to 5 years.

INTRODUCTION: In clinical trials, recombinant factor IX fusion protein (rFIXFc) has demonstrated safety, efficacy and prolonged activity with extended dosing intervals for treatment of haemophilia B. AIM: To assess the real-world clinical utility of rFIXFc in a variable patient population and routine clinical practice. METHODS: A multicentre, retrospective chart review was conducted of patients with haemophilia B who had received rFIXFc prophylaxis or on-demand treatment for ≥6 months across six sites in the United States. RESULTS: Sixty-four eligible patients were identified who had a median (range) duration on rFIXFc of 2.7 (0.5-5.0) years. Of 32 patients on rFIXFc prophylaxis who switched from prophylaxis with another factor treatment (ie pre-rFIXFc) and had a known pre-rFIXFc dosing interval, the initial dosing interval was lengthened for 26 (81%) patients and maintained for the remaining 6 (19%) patients. Most (n = 48 [91%]) patients who received rFIXFc prophylaxis from the beginning to the end of the chart review period (n = 53) maintained or lengthened the dosing interval from first through last dose of rFIXFc. For patients receiving rFIXFc prophylaxis, there was an approximate 50% reduction in weekly factor consumption compared with pre-rFIXFc prophylaxis. Overall annualized bleed rates, annualized spontaneous bleed rates and annualized joint bleed rates decreased after switching to rFIXFc prophylaxis (n = 24 with bleed data). Compliance to recommended treatment improved or remained stable in most patients with available data (30/31). CONCLUSION: Recombinant factor IX fusion protein prophylaxis improved bleed control, reduced overall consumption, reduced frequency of infusion and improved compliance for patients with haemophilia B in a real-world setting.

Patient and caregiver preferences for haemophilia A treatments: A discrete choice experiment.

INTRODUCTION: Long-acting products are changing the haemophilia A treatment landscape by giving patients and caregivers treatment options with varying product attributes. AIM: A discrete choice experiment (DCE) was used to elicit treatment attribute preferences among patients with haemophilia A and caregivers of children with haemophilia A. MATERIALS & METHODS: A survey of sociodemographics and preferences was completed by an online panel of adult patients with haemophilia A and caregivers of children (<18 years) with haemophilia A. The DCE included a series of questions in which respondents chose their preferred option from pairs of hypothetical treatment profiles with systematic variation in the levels of six attributes (safety concerns with too much clotting, bleed protection, dosing frequency, length of time the product has been approved for use, product type and joint health studies). Preference weights and relative attribute importance scores were estimated using random parameters logit models. RESULTS: One hundred and thirteen patients (mean age: 35.5 years) and 96 caregivers (mean age of child: 10.3 years) were included. For patients with haemophilia A, the top three attributes ranked from the most to least important were: (a) dosing frequency; (b) bleed protection; and (c) safety concerns with too much clotting. For caregivers of children with haemophilia A, the ranking was as follows: (a) safety concerns; (b) bleed protection; and (c) dosing. CONCLUSIONS: Patients with haemophilia A viewed dosing as the most important driver of treatment decision-making whereas caregivers of children with haemophilia A valued safety the most.

Descriptive evaluation of cigarettes and other tobacco products act in a North Indian city.

BACKGROUND: India is a signatory to Framework Convention on Tobacco Control and also enacted cigarettes and other tobacco products Act (COTPA) in 2003. OBJECTIVES: To undertake a comprehensive assessment (Section 4, 5, 6, 7, 8, and 9 under COTPA) of legislation against tobacco products in a North Indian city. METHODS: An observational, cross-sectional study was conducted at 108 public places which included educational institutions, offices, health institutes, transit sites, and hotels/restaurants. Structured checklists with compliance indicators for various sections under COTPA were used. Different brands of tobacco products were observed for pictorial warnings. RESULTS: No active smoking was observed at 80.5% public places, while 54.6% places had displayed "No smoking" signage. About 68.5% public places were found free of evidence of smell/ashes of recent smoking, and 86.1% places had no smoking aids. Merely, one-third public places (36.1%) were complying with all Section 4 indicators. Around 42.3% point of sale had advertisements of tobacco products, and 73.1% had a display of tobacco products visible to minors. Around 60% educational institutions displayed signages as per Section 6b of COTPA, and 32.5% had tobacco shops being run within 100 yards of institution's radius. There was minimal smoking activity within the campus. Health warnings were present in 80.8% of tobacco products, more with Indian brands as compared to foreign brands. CONCLUSION: The city of Chandigarh, which was declared the first smoke-free city of India, showed poor compliance with COTPA.

Anaesthetic concerns of a child with symptomatic vitamin D deficiency rickets with secondary hyperparathyroidism: A case report.

Rickets is a paediatric bone disorder characterised by defective mineralisation of bony matrix due to abnormalities in calcium and phosphate metabolism. Despite being a common disease globally, literature on the anaesthetic concerns in rickets are scant. Herein, we describe the management of a 12-year-old child with symptomatic vitamin D deficiency rickets with secondary hyperparathyroidism, undergoing general anaesthesia for an urgent orthopaedic procedure. There are numerous risks involved in such a case, such as hypocalcemia, hypophosphatemia, chest and vertebral deformities, restrictive lung disease, difficult intubation and weaning, difficult regional anaesthesia, chronic bone pain, infectious complications and postoperative decreased renal function, all of which require careful preoperative assessment and risk stratification. In elective surgeries, it is important to optimise the metabolic parameters before taking up the case. However, in urgent and emergent procedures like ours, it is imperative to take up the case after informing the parents of the risks involved.

Anesthetic Management of a Broken Tracheostomy Tube Stem as a Foreign Body in the Trachea: A Case Report.

Tracheostomy is commonly performed in patients to secure the airway. There are known early and late complications related to tracheostomy. Few case reports have described the rupture of the stem of the tracheostomy tube and its migration into the tracheobronchial tree. Here we describe a pediatric case with a broken stem of the tracheostomy tube in the trachea, acting as a foreign body and causing mild respiratory distress. The patient was successfully managed with neck exploration under general anesthesia using a supraglottic airway device in low-resource settings. In addition, we have described the potential problems that may be faced while managing the airway of such patients and how to deal with these complications.

Diplopia with a Cavernous Sinus Metastasis of a Remote Endometrial Stromal Tumour.

Structural lesions involving the visual pathways often require tissue diagnosis to guide therapy. However, pathology is not always definitive, and a biopsy showing poorly differentiated cells poses significant difficulty in identifying the primary tumour. We report a case of metastatic disease causing cavernous sinus syndrome, in which biopsy revealed poorly differentiated tissue. The patient reported a history of a resected uterine tumour, and it was only after obtaining slides from 7 years prior that the diagnosis was made.

Secondary Stroke Risk Reduction in Black Adults: a Systematic Review.

OBJECTIVE: To address the fact that Black adults (BAs) experience significantly greater stroke burden than the general population, we conducted a systematic literature review which described evidence-based interventions targeting secondary stroke risk reduction in BAs. DATA SOURCE: Publications were selected from PubMed, Ovid, Cochrane, and Web of Science databases. We included peer-reviewed, longitudinal, English-language studies performed in the USA which reported results for BAs separately and had adult participants who had experienced stroke-related events. RESULTS: Six of the 7 studies employed behavioral interventions which promoted education on stroke risk factors, problem-solving skills, and healthy-coping strategies. These studies demonstrated improvements in one or more biologic outcomes including cholesterol control and systolic blood pressure. CONCLUSIONS: Existing interventions on secondary stroke risk reduction approaches are effective in reducing secondary stroke risk among BAs, especially in individuals with poorly controlled blood pressure at baseline. However, additional research is needed because the current approaches may limit generalizability.

Persistent Brain Connectivity Changes in Healthy Volunteers Following Nitrous Oxide Inhalation.

Background: Nitrous oxide holds promise in the treatment of major depressive disorder. Its psychotropic effects and NMDA receptor antagonism have led to comparisons with ketamine. Despite longstanding use, persistent effects of nitrous oxide on the brain have not been characterized. Methods: Sixteen healthy volunteers were recruited in a double-blind crossover study. In randomized order, individuals underwent a 1-hour inhalation of either 50% nitrous oxide/oxygen or air/oxygen mixtures. At least two 7.5-minute echo-planar resting-state functional magnetic resonance imaging scans were obtained before and at 2 and 24 hours after each inhalation (average 130 min/participant). Using the time series of preprocessed, motion artifact-scrubbed, and nuisance covariate-regressed imaging data, interregional signal correlations were measured and converted to T scores. Hierarchical clustering and linear mixed-effects models were employed. Results: Nitrous oxide inhalation produced changes in global brain connectivity that persisted in the occipital cortex at 2 and 24 hours postinhalation (p < .05, false discovery rate-corrected). Analysis of resting-state networks demonstrated robust strengthening of connectivity between regions of the visual network and those of the dorsal attention network, across 2 and 24 hours after inhalation (p < .05, false discovery rate-corrected). Weaker changes in connectivity were found between the visual cortex and regions of the frontoparietal and default mode networks. Parallel analyses following air/oxygen inhalation yielded no significant changes in functional connectivity. Conclusions: Nitrous oxide inhalation in healthy volunteers revealed persistent increases in global connectivity between regions of primary visual cortex and dorsal attention network. These findings suggest that nitrous oxide inhalation induces neurophysiological cortical changes that persist for at least 24 hours.

Post hoc longitudinal assessment of the efficacy and safety of recombinant factor IX Fc fusion protein in hemophilia B.

Long-term efficacy and safety of the extended half-life recombinant factor IX Fc fusion protein (rFIXFc) has been established among previously treated patients with severe hemophilia B in 2 phase 3 trials (B-LONG [#NCT01027364] and Kids B-LONG [#NCT01440946]) and a long-term extension study (B-YOND [#NCT01425723]). In this study, we report post hoc analyses of pooled longitudinal data for up to 6.5 years for rFIXFc prophylaxis. In the B-LONG study, subjects ≥12 years received weekly dose-adjusted prophylaxis (WP; starting dose, 50 IU/kg), individualized interval-adjusted prophylaxis (IP; initially, 100 IU/kg every 10 days), or on-demand dosing. In the Kids B-LONG study, subjects <12 years received 50 to 60 IU/kg every 7 days, adjusted as needed. In the B-YOND study, subjects received WP (20-100 IU/kg every 7 days), IP (100 IU/kg every 8-16 days), modified prophylaxis, or on-demand dosing; switching between treatment groups was permitted. A total of 123 subjects from B-LONG and 30 from Kids B-LONG study were included, of whom 93 and 27, respectively, enrolled in the B-YOND study. The median cumulative duration of treatment was 3.63 years (range, 0.003-6.48 years) in B-LONG/B-YOND and 2.88 years (range, 0.30-4.80 years) in Kids B-LONG/B-YOND group. Annualized bleed rates (ABRs) remained low, annualized factor consumption remained stable, and adherence remained high throughout treatment. Low ABRs were also maintained in subjects with dosing intervals ≥14 days or with target joints at baseline. Complete resolution of evaluable target joints and no recurrence in 90.2% of baseline target joints during follow-up were observed. rFIXFc prophylaxis was associated with sustained clinical benefits, including long-term bleed prevention and target joint resolution, for severe hemophilia B.

Plasma derivatives: new products and new approaches.

The infusion of plasma-derived or recombinant factors to treat bleeding disorders such as hemophilia A and B is a success story in the management of a chronic disease. The effectiveness of this approach is however limited by challenges with adverse effects of treatment. The most notable of these are the development of inhibitory antibodies that target the protein therapeutic. The current standard of care for management of hemophiliacs is prophylactic treatment that includes frequent infusions of a Factor VIII product. Failure to comply with the prophylactic regimen is a major hurdle in the management of these patients. We discuss here more recent findings that argue for a pharmacogenetic approach to understanding (and eventually circumventing) immunogenicity. We also review strategies used to bioengineer coagulation factors to extend the half-lives of coagulation proteins. The rapid progress in the last few years to bioengineer coagulation factors in different ways to attain this goal is described. Finally, novel technologies and potential products are emerging that utilize synthetic molecules in lieu of replacement proteins obviating the limitations associated with replacement therapies.

Systematic Literature Review of Text Messaging Interventions to Promote Medication Adherence Among People With Serious Mental Illness.

OBJECTIVE: Mobile health tools are feasible options to encourage behavior change among patients with serious mental illness. Mobile health tools vary widely, both in platforms used and content delivered. This literature review assessed the use of text messaging interventions to promote medication adherence among patients with serious mental illness. METHODS: A systematic literature review using PRISMA guidelines examined short message service (SMS) text messaging interventions promoting medication adherence to people with a serious mental illness diagnosis. Databases included PubMed, Cochrane, CINAHL, and PsycINFO. Data extraction included demographic information, participant diagnoses, intervention components, medication class, adherence measures, research design, and study outcomes. Study quality was also assessed. RESULTS: Of 114 full-text articles screened, 10 articles were selected from nine unique interventions (N=937 people with serious mental illness). Study durations ranged from 30 days to 18 months, with frequency of SMS ranging from twice weekly to 12 times daily. Of the nine unique trials, most reported using an automated server to deliver SMS messages (N=7), two-way SMS capabilities (N=6), customized message content or timing (N=7), and additional components (e.g., provider contact, educational content, and monetary rewards) (N=7). Seven of the 10 articles reported statistically significant improvement in medication adherence and in at least one clinical outcome. CONCLUSIONS: Evidence to date indicates that text messaging interventions are feasible and appear to improve medication adherence and clinical outcomes among patients with serious mental illness. Future research should assess implementation approaches and how to scale up efforts in nonresearch settings.

Recent advances in therapeutic options for rare hemostatic disorders: selected poster extracts of recent research in hemophilia A, congenital hemophilia with inhibitors, von Willebrand disease, and thrombotic thrombocytopenic purpura presented at the 29th congress of the International Society on Thrombosis and Haemostasis (ISTH 2021, Jul 17-21; virtual congress).

Hemophilia, von Willebrand disease (VWD), and thrombotic thrombocytopenic purpura (TTP) are rare diseases affecting normal hemostasis. Although they differ in their pathogenesis and clinical manifestation, if left undiagnosed and untreated, all these conditions can result in severe long-term consequences and can be potentially life-threatening. This article summarizes a poster series funded by Takeda and presented virtually at the 29th annual congress of the International Society on Thrombosis and Haemostasis (ISTH) in 2021: Data from real-world evidence highlight the importance of joint health and personalized prophylaxis to prevent bleeding for patients with hemophilia, the need to further raise disease awareness in support of timely diagnosis and access to treatment in general practice settings for patients with VWD, and describe the clinical burden for patients with TTP and the importance to advance treatment options for these patients.

Novel Derivatives of Nicotinic Acid as Promising Anticancer Agents.

BACKGROUND: Cancer has become the second leading cause of death worldwide. Despite of the availability of significant number of anticancer agents, cancer is still incurable especially at the last stages. Remarkable targets for anticancer research and drug discovery are heterocyclic compounds, and among them, superior effect has been shown by the nitrogen containing compounds than non-nitrogen containing compounds. Nicotinic acid, a nitrogen containing moiety and its derivatives have gained an immense importance in the development of anticancer drugs owing to the wide variety of biological properties displayed by them. OBJECTIVE: The objective of this review is to provide researchers the information about various synthetic approaches used for the synthesis of anticancer drugs of nicotinic acid from 2001 onwards and to reveal their application and importance in the treatment of this dreadful disease. CONCLUSION: As indicated by this review, considerable work has been done in terms of synthesis and investigation of anticancer potential of nicotinamide derivatives. The information provided in this article may be of great value for the researchers seeking to develop efficient anticancer drugs.