The use of predictive modelling to determine the likelihood of donor return during the COVID-19 pandemic.

Artificial intelligence (AI) uses sophisticated algorithms to "learn" from large volumes of data. This could be used to optimise recruitment of blood donors through predictive modelling of future blood supply, based on previous donation and transfusion demand. We sought to assess utilisation of predictive modelling and AI blood establishments (BE) and conducted predictive modelling to illustrate its use. A BE survey of data modelling and AI was disseminated to the International Society of Blood transfusion members. Additional anonymzed data were obtained from Italy, Singapore and the United States (US) to build predictive models for each region, using January 2018 through August 2019 data to determine likelihood of donation within a prescribed number of months. Donations were from March 2020 to June 2021. Ninety ISBT members responded to the survey. Predictive modelling was used by 33 (36.7%) respondents and 12 (13.3%) reported AI use. Forty-four (48.9%) indicated their institutions do not utilise predictive modelling nor AI to predict transfusion demand or optimise donor recruitment. In the predictive modelling case study involving three sites, the most important variable for predicting donor return was number of previous donations for Italy and the US, and donation frequency for Singapore. Donation rates declined in each region during COVID-19. Throughout the observation period the predictive model was able to consistently identify those individuals who were most likely to return to donate blood. The majority of BE do not use predictive modelling and AI. The effectiveness of predictive model in determining likelihood of donor return was validated; implementation of this method could prove useful for BE operations.

Association of Busulfan Exposure and Outcomes after HCT for Patients with an Inborn Error of Immunity.

Allogeneic HCT is a potentially curative treatment strategy for patients with inborn errors of immunities (IEIs). Objective of this study was to assess the optimal busulfan exposure prior to allogeneic HCT for patients with an IEI who received an intravenous busulfan-based conditioning regimen between 2000 and 2023. Patients from 17 international centers were included. Main outcome of interest was event-free survival (EFS). Patients were categorized into 4 IEI subgroups: combined-immunodeficiency (CID), severe combined immunodeficiency (SCID), neutrophil disorders and hemophagocytic lymphohistiocytosis (HLH)-related disorders. Busulfan exposure was calculated by individual centers (AUCCENTER) and was re-estimated using a validated model (AUCNONMEM). Overall, 562 patients were included: 173 (30.8%) CID, 154 (27.4%) SCID, 101 (18.0%) HLH-related disorders, and 134 (23.8%) neutrophil disorders. Median busulfan AUCNONMEM was 69.0 mg×h/L and correlated poorly with AUCCENTER (r2=0.54). Patients with SCID, HLH-related, and neutrophil disorders were analyzed together (n=389), because CID disease subtype was an effect modifier (p=0.03). Estimated 2-year EFS was 78.5%. In patients with the found optimal busulfan AUCNONMEM of 70-90 mg×h/L, 2-year EFS was superior to <70 mg×h/L (adj-HR 1.97, 95% CI 1.11-3.49, p=0.02), and >90 mg×h/L (adj-HR 5.05, 95% CI 2.43-10.49, p<0.0001). Full donor chimerism increased with higher busulfan AUCNONMEM, plateauing at 90 mg×h/L. For CID patients, optimal AUCNONMEM for donor chimerism was found to be >70 mg×h/L. Improved EFS and higher donor chimerism may be achieved by targeting a cumulative busulfan AUCNONMEM of 80 mg×h/L (range 70-90). Our study stresses the importance to uniformly using a validated population PK-model to estimate the AUCNONMEM.

Galectin-3 as a Prognostic Biomarker in Patients with First Acute Myocardial Infarction without Heart Failure.

BACKGROUND: Galectin-3 (Gal-3) is a biomarker involved in a wide range of diseases including cardiac remodeling following acute myocardial infarction (AMI). Identification of prognostic markers in patients with AMI can guide strategies towards improved survival and quality of life. METHODS: Our study included 59 patients with AMI and a preserved ejection fraction. We determined the Gal-3 plasma concentration within 24 h of chest pain onset from the aortic root, femoral/radial artery, coronary sinus and cubital vein. Major adverse cardiovascular events (MACEs) were evaluated at six months follow-up. RESULTS: MACE at six months post-AMI was recorded in 20 patients (34%). The Gal-3 plasma concentration from the aortic root and the femoral/radial artery were independent predictors of MACE at six months follow-up after the first AMI (OR 1.228; 95%CI: 1.011-1.491; p = 0.038; OR 3.438; 95%CI: 1.275-9.265; p = 0.015). ROC analysis identifies the Gal-3 plasma concentration from the aortic root as a better predictor of MACE or death (cut-off ≥ 10.86 ng/mL; AUC 0.858; 95%CI: 0.744-0.973; p < 0.001) than Gal-3 plasma concentration from the femoral/radial artery (cut-off ≥ 10.18 ng/mL; AUC 0.742; 95%CI: 0.596-0.888; p = 0.006). CONCLUSION: the Gal-3 plasma concentration in patients with AMI determined during coronary angiography, especially from the aortic root, within 24 h after chest pain onset is a valuable biomarker of prognosis at six months follow-up.

Combining pharmacometric models with predictive and prognostic biomarkers for precision therapy in Crohn's disease: A case study of brazikumab.

Pharmacometric models were used to investigate the utility of biomarkers in predicting the efficacy (Crohn's Disease Activity Index [CDAI]) of brazikumab and provide a data-driven framework for precision therapy for Crohn's disease (CD). In a phase IIa trial in patients with moderate to severe CD, treatment with brazikumab, an anti-interleukin 23 monoclonal antibody, was associated with clinical improvement. Brazikumab treatment effect was determined to be dependent on the baseline IL-22 (BIL22) or baseline C-reactive protein (BCRP; predictive biomarkers), and placebo effect was found to be correlated with the baseline CDAI (a prognostic biomarker). A maximal total inhibition on CDAI input function of 50.6% and 42.4% was predicted for patients with extremely high BIL22 or BCRP, compared to a maximal total inhibition of 20.9% and 17.8% for patients with extremely low BIL22 or BCRP, respectively, which were mainly due to the placebo effect. We demonstrated that model-derived baseline biomarker levels that achieve 50% of maximum unbound systemic concentration of 22.8 pg/mL and 8.03 mg/L for BIL22 and BCRP as the cutoffs to select subpopulations can effectively identify high-response subgroup patients with improved separation of responders when compared to using the median values as the cutoff. This work exemplifies the utility of pharmacometrics to quantify biomarker-driven responses in biologic therapies and distinguish between predictive and prognostic biomarkers, complementing clinical efforts of identifying subpopulations with higher likelihood of response to brazikumab.

Population Pharmacokinetics and Pharmacodynamics of Pegozafermin in Patients with Nonalcoholic Steatohepatitis.

Pegozafermin is a long-acting glycoPEGylated analog of fibroblast growth factor 21 (FGF21) in development for the treatment of nonalcoholic steatohepatitis (NASH) and severe hypertriglyceridemia. In a phase Ib/IIa placebo-controlled, double-blind, multiple ascending dose study in patients with NASH (NCT04048135), administration of pegozafermin resulted in clinically meaningful reductions in hepatic fat fraction (HFF), with a favorable safety and tolerability profile. We aimed to characterize the relationship between pegozafermin dosing, exposure and effects on HFF reduction. We used pharmacokinetic (PK) and pharmacodynamic (PD) modeling of data from the phase Ib/IIa study to identify model parameters and covariates affecting the exposure-response relationship. Clinical simulations were performed to help support dose selection for larger studies. Pegozafermin exposure was adequately described by a one compartment PK model, with one additional transit absorption compartment. PK/PD modeling demonstrated that HFF reduction was significantly related to pegozafermin exposure. HFF outcomes were correlated with average pegozafermin concentrations regardless of weekly dosing (q.w.) or dosing every 2 weeks (q2w). The significant PK/PD model covariates included baseline body weight, alanine aminotransferase level, and liver volume. Simulations showed that the 30 mg q.w. dose approximated the full PD effect; almost all patients would benefit from a greater than or equal to 30% HFF reduction, suggesting fibrosis regression. Furthermore, 44 mg q2w dosing (~22 mg q.w.) appeared to be an effective regimen for HFF reduction. Our modeling supports the feasibility of q.w. and q2w dosing for achieving favorable treatment outcomes in patients with NASH, and provides the rationale for dose selection for the phase IIb ENLIVEN study (NCT04929483).

Efficacy and safety of Aviron Rapid® in adolescents and children with viral acute upper respiratory tract infection: a multi-center, randomized, double blind, placebo-controlled clinical trial.

INTRODUCTION: Acute upper respiratory tract infections (AURTIs) are associated with a significant burden on society attributed to medical care and loss of productivity. Novel therapies that are able to shorten disease duration, while providing symptom relief and being well tolerated, are an unmet medical need.

QT Interval Prolongation with One or More QT-Prolonging Agents Used as Part of a Multidrug Regimen for Rifampicin-Resistant Tuberculosis Treatment: Findings from Two Pediatric Studies.

Rifampicin-resistant tuberculosis (RR-TB) involves treatment with many drugs that can prolong the QT interval; this risk may increase when multiple QT-prolonging drugs are used together. We assessed QT interval prolongation in children with RR-TB receiving one or more QT-prolonging drugs. Data were obtained from two prospective observational studies in Cape Town, South Africa. Electrocardiograms were performed before and after drug administration of clofazimine (CFZ), levofloxacin (LFX), moxifloxacin (MFX), bedaquiline (BDQ), and delamanid. The change in Fridericia-corrected QT (QTcF) was modeled. Drug and other covariate effects were quantified. A total of 88 children with a median (2.5th-to-97.5th range) age of 3.9 (0.5 to 15.7) years were included, of whom 55 (62.5%) were under 5 years of age. A QTcF interval of >450 ms was observed in 7 patient-visits: regimens were CFZ+MFX (n = 3), CFZ+BDQ+LFX (n = 2), CFZ alone (n = 1), and MFX alone (n = 1). There were no events with a QTcF interval of >500 ms. In a multivariate analysis, CFZ+MFX was associated with a 13.0-ms increase in change in QTcF (P < 0.001) and in maximum QTcF (P = 0.0166) compared to those when other MFX- or LFX-based regimens were used. In conclusion, we found a low risk of QTcF interval prolongation in children with RR-TB who received at least one QT-prolonging drug. Greater increases in maximum QTcF and ΔQTcF were observed when MFX and CFZ were used together. Future studies characterizing exposure-QTcF responses in children will be helpful to ensure safety with higher doses if required for effective treatment of RR-TB.

Translational predictions of phase 2a first-in-patient efficacy studies for antituberculosis drugs.

BACKGROUND: Phase 2a trials in tuberculosis typically use early bactericidal activity (EBA), the decline in sputum CFU over 14 days, as the primary end-point for testing the efficacy of drugs as monotherapy. However, the cost of phase 2a trials can range from USD 7 million to USD 19.6 million on average, while >30% of drugs fail to progress to phase 3. Better utilising pre-clinical data to predict and prioritise the most likely drugs to succeed will thus help to accelerate drug development and reduce costs. We aim to predict clinical EBA using pre-clinical in vivo pharmacokinetic (PK)-pharmacodynamic (PD) data and a model-based translational pharmacology approach. METHODS AND FINDINGS: First, mouse PK, PD and clinical PK models were compiled. Second, mouse PK-PD models were built to derive an exposure-response relationship. Third, translational prediction of clinical EBA studies was performed using mouse PK-PD relationships and informed by clinical PK models and species-specific protein binding. Presence or absence of clinical efficacy was accurately predicted from the mouse model. Predicted daily decreases of CFU in the first 2 days of treatment and between day 2 and day 14 were consistent with clinical observations. CONCLUSION: This platform provides an innovative solution to inform or even replace phase 2a EBA trials, to bridge the gap between mouse efficacy studies and phase 2b and phase 3 trials, and to substantially accelerate drug development.

FK506-Binding Protein like (FKBPL) Has an Important Role in Heart Failure with Preserved Ejection Fraction Pathogenesis with Potential Diagnostic Utility.

Heart failure (HF) is the leading cause of hospitalisations worldwide, with only 35% of patients surviving the first 5 years after diagnosis. The pathogenesis of HF with preserved ejection fraction (HFpEF) is still unclear, impeding the implementation of effective treatments. FK506-binding protein like (FKBPL) and its therapeutic peptide mimetic, AD-01, are critical mediators of angiogenesis and inflammation. Thus, in this study, we investigated-for the first time-FKBPL's role in the pathogenesis and as a biomarker of HFpEF. In vitro models of cardiac hypertrophy following exposure to a hypertensive stimulus, angiotensin-II (Ang-II, 100 nM), and/or AD-01 (100 nM), for 24 and 48 h were employed as well as human plasma samples from people with different forms of HFpEF and controls. Whilst the FKBPL peptide mimetic, AD-01, induced cardiomyocyte hypertrophy in a similar manner to Ang-II (p < 0.0001), when AD-01 and Ang-II were combined together, this process was abrogated (p < 0.01-0.0001). This mechanism appears to involve a negative feedback loop related to FKBPL (p < 0.05). In human plasma samples, FKBPL concentration was increased in HFpEF compared to controls (p < 0.01); however, similar to NT-proBNP and Gal-3, it was unable to stratify between different forms of HFpEF: acute HFpEF, chronic HFpEF and hypertrophic cardiomyopathy (HCM). FKBPL may be explored for its biomarker and therapeutic target potential in HFpEF.

Analysis of Dynamic Efficacy Endpoints of the Nix-TB Trial.

BACKGROUND: Safer, better, and shorter treatments for multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) are an urgent global health need. The phase 3 clinical trial Nix-TB (NCT02333799) tested a 6-month treatment of MDR and XDR-TB consisting of high-dose linezolid, bedaquiline, and pretomanid (BPaL). In this study, we investigate the relationship between the pharmacokinetic characteristics of the drugs, patient characteristics and efficacy endpoints from Nix-TB. METHODS: Pharmacokinetic data were collected at weeks 2, 8, and 16. Efficacy endpoints including treatment outcomes, time to stable culture conversion, and longitudinal time to positivity in the mycobacterial growth indicator tube assay were each characterized using nonlinear mixed-effects modeling. Relationships between patient, treatment pharmacokinetics, and disease characteristics and efficacy endpoints were evaluated. RESULTS: Data from 93 (85% of the total) participants were analyzed. Higher body mass index was associated with a lower incidence of unfavorable treatment outcomes. Median time to stable culture conversion was 3 months in patients with lower baseline burden compared with 4.5 months in patients with high baseline burden. Participants with minimal disease had steeper time to positivity trajectories compared with participants with high-risk phenotypes. No relationship between any drugs' pharmacokinetics (drug concentration or exposure metrics) and any efficacy outcomes was observed. CONCLUSIONS: We have successfully described efficacy endpoints of a BPaL regimen from the Nix-TB trial. Participants with high-risk phenotypes significantly delayed time to culture conversion and bacterial clearance. The lack of a relationship between pharmacokinetic exposures and pharmacodynamic biomarkers opens the possibility to use lower, safer doses, particularly for toxicity-prone linezolid. CLINICAL TRIALS REGISTRATION: NCT02333799.

Translational predictions of phase 2a first-in-patient efficacy studies for antituberculosis drugs.

Background: Phase 2a trials in tuberculosis typically use early bactericidal activity (EBA), the decline in sputum colony forming units (CFU) over 14 days, as the primary outcome for testing the efficacy of drugs as monotherapy. However, the cost of phase 2a trials can range from 7 to 19.6 million dollars on average, while more than 30% of drugs fail to progress to phase 3. Better utilizing preclinical data to predict and prioritize the most likely drugs to succeed will thus help accelerate drug development and reduce costs. We aim to predict clinical EBA using preclinical in vivo pharmacokinetic-pharmacodynamic (PKPD) data and a model-based translational pharmacology approach. Methods and Findings: First, mouse PK, PD and clinical PK models were compiled. Second, mouse PKPD models were built to derive an exposure response relationship. Third, translational prediction of clinical EBA studies was performed using mouse PKPD relationships and informed by clinical PK models and species-specific protein binding. Presence or absence of clinical efficacy was accurately predicted from the mouse model. Predicted daily decreases of CFU in the first 2 days of treatment and between day 2 and day 14 were consistent with clinical observations. Conclusion: This platform provides an innovative solution to inform or even replace phase 2a EBA trials, to bridge the gap between mouse efficacy studies and phase 2b and phase 3 trials, and to substantially accelerate drug development.

Rifapentine With and Without Moxifloxacin for Pulmonary Tuberculosis in People With Human Immunodeficiency Virus (S31/A5349).

BACKGROUND: Tuberculosis (TB) Trials Consortium Study 31/AIDS Clinical Trials Group A5349, an international randomized open-label phase 3 noninferiority trial showed that a 4-month daily regimen substituting rifapentine for rifampin and moxifloxacin for ethambutol had noninferior efficacy and was safe for the treatment of drug-susceptible pulmonary TB (DS-PTB) compared with the standard 6-month regimen. We explored results among the prespecified subgroup of people with human immunodeficiency virus (HIV) (PWH). METHODS: PWH and CD4+ counts ≥100 cells/µL were eligible if they were receiving or about to initiate efavirenz-based antiretroviral therapy (ART). Primary endpoints of TB disease-free survival 12 months after randomization (efficacy) and ≥ grade 3 adverse events (AEs) on treatment (safety) were compared, using a 6.6% noninferiority margin for efficacy. Randomization was stratified by site, pulmonary cavitation, and HIV status. PWH were enrolled in a staged fashion to support cautious evaluation of drug-drug interactions between rifapentine and efavirenz. RESULTS: A total of 2516 participants from 13 countries in sub-Saharan Africa, Asia, and the Americas were enrolled. Among 194 (8%) microbiologically eligible PWH, the median CD4+ count was 344 cells/µL (interquartile range: 223-455). The rifapentine-moxifloxacin regimen was noninferior to control (absolute difference in unfavorable outcomes -7.4%; 95% confidence interval [CI] -20.8% to 6.0%); the rifapentine regimen was not noninferior to control (+7.5% [95% CI, -7.3% to +22.4%]). Fewer AEs were reported in rifapentine-based regimens (15%) than the control regimen (21%). CONCLUSIONS: In people with HIV-associated DS-PTB with CD4+ counts ≥100 cells/µL on efavirenz-based ART, the 4-month daily rifapentine-moxifloxacin regimen was noninferior to the 6-month control regimen and was safe. CLINICAL TRIALS REGISTRATION: NCT02410772.

Management of blood transfusion services in low-resource countries.

BACKGROUND AND OBJECTIVES: Enabling universal access to safe blood components should be a key component of every country's national healthcare strategy. This study aimed to assess the current status of infrastructure and resources of blood transfusion services (BTS) in low- and middle-income countries. MATERIALS AND METHODS: A cross-sectional survey was designed to gather information on blood donations, components, redistribution, testing resources and quality management systems (QMSs). The survey was distributed to the International Society of Blood Transfusion members between October 2021 and November 2021. RESULTS: A total of 54 respondents from 20 countries responded to the survey. This included hospital-based BTS/blood centres (46%), national blood centres (11%)and national and regional blood services (11%). Voluntary non-remunerated, replacement and paid donors accounted for 94.2%, 84.6% and 21.1% of donations, respectively. Apheresis donation was available in 59.6% of institutions. National/regional criteria for redistribution of blood components were reported by 75.9% of respondents. Blood components incurred payment charges in 81.5% of respondents' institutions, and payments were borne by patients in 50% of them. Testing methods, such as manual (83%), semi-automated (68%) or fully automated (36.2%), were used either alone or in combination. QMSs were reported in 17 institutions, while accreditation and haemovigilance were reported in 12 and 8 countries, respectively. CONCLUSION: QMS was implemented in most of the countries despite the common use of paid donations and the lack of advanced testing. Efforts to overcome persistent challenges and wider implementation of patient blood management programmes are required.

Efficacy and Safety of COVID-19 Convalescent Plasma in Hospitalized Patients-An Open-Label Phase II Clinical Trial.

Background: COVID-19 convalescent plasma (CCP) is an important antiviral option for selected patients with COVID-19. Materials and Methods: In this open-label, phase 2, clinical trial conducted from 30 April 2020 till 10 May 2021 in the Republic of North Macedonia, we evaluated the efficacy and safety of CCP in hospitalized patients. Treatment was with a single unit of CCP having an anti-RBD IgG concentration higher than 5 AU/mL. Results: There were 189 patients that completed the study, of which 65 (34.4%) had WHO 8-point clinical progression scale score of 3 (requiring hospital care but not oxygen support), 65 (34.4%) had a score of 4 (hospitalized and requiring supplemental oxygen by mask or nasal prongs), and 59 (31.2%) had a score of 5 (hospitalized and requiring supplemental oxygen by non-invasive ventilation or high-flow oxygen). Mean age was 57 years (range 22−94), 78.5% were males, 80.4% had elevated body mass index, and 70.9% had comorbidity. Following CCP transfusion, we observed clinical improvement with increase rates in oxygenation-free days of 32.3% and 58.5% at 24 h and seven days after CCP transfusion, a decline in WHO scores, and reduced progression to severe disease (only one patient was admitted to ICU after CCP transfusion). Mortality in the entire cohort was 11.6% (22/189). We recorded 0% mortality in WHO score 3 (0/65) and in patients that received CCP transfusion in the first seven days of disease, 4.6% mortality in WHO score 4 (3/65), and 30.5% mortality in WHO score 5 (18/59). Mortality correlated with WHO score (Chi-square 19.3, p < 0.001) and with stay in the ICU (Chi-square 55.526, p ≤ 0.001). No severe adverse events were reported. Conclusions: This study showed that early administration of CCP to patients with moderate disease was a safe and potentially effective treatment for hospitalized COVID-19 patients. The trial was registered at clinicaltrials.gov (NCT04397523).

Systemic Biomarkers and Unique Pathways in Different Phenotypes of Heart Failure with Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) accounts for around 50% of all heart failure cases. It is a heterogeneous condition with poorly understood pathogenesis. Here, we aimed to identify unique pathogenic mechanisms in acute and chronic HFpEF and hypertrophic cardiomyopathy (HCM). We performed unbiased, comprehensive proteomic analyses of plasma samples from gender- and BMI-matched patients with acute HFpEF (n = 8), chronic HFpEF (n = 9) and HCM (n = 14) using liquid chromatography-mass spectrometry. Distinct molecular signatures were observed in different HFpEF forms. Clusters of biomarkers differentially abundant between HFpEF forms were predominantly associated with microvascular inflammation. New candidate protein markers were also identified, including leucine-rich alpha-2-glycoprotein 1 (LRG1), serum amyloid A1 (SAA1) and inter-alpha-trypsin inhibitor heavy chain 3 (ITIH3). Our study is the first to apply systematic, quantitative proteomic screening of plasma samples from patients with different subtypes of HFpEF and identify candidate biomarkers for improved management of acute and chronic HFpEF and HCM.

Early and out-of-hospital use of COVID-19 convalescent plasma: An international assessment of utilization and feasibility.

BACKGROUND AND OBJECTIVES: The use of coronavirus disease 2019 (COVID-19) convalescent plasma (CCP) in the treatment of patients with severe acute respiratory syndrome-2 infection has been controversial. Early administration of CCP before hospital admission offers a potential advantage. This manuscript summarizes current trials of early use of CCP and explores the feasibility of this approach in different countries. MATERIALS AND METHODS: A questionnaire was distributed to the International Society of Blood Transfusion (ISBT) CCP working group. We recorded respondents' input on existing trials on early/outpatient CCP and out-of-hospital (OOH)/home transfusion (HT) practices in their countries and feedback on challenges in initiating home CCP infusion programmes. In addition, details of existing trials registered on clinicaltrials.gov were summarized. RESULTS: A total of 31 country representatives participated. Early/OOH CCP transfusion studies were reported in the United States, the Netherlands, Spain and Brazil. There were a total of six published and five ongoing trials on the prophylactic and therapeutic early use of CCP. HT was practised in Australia, the UK, Belgium, France, Japan, Nigeria, the Netherlands, Spain, Italy, Norway, the United States and some provinces in Canada. Thirty-four representatives indicated a lack of OOH CCP or HT in their institutions and countries. Barriers to implementation of OOH/HT included existing legislation, lack of policies pertaining to outpatient transfusion, and associated logistical challenges, including lack of staffing and resources. CONCLUSION: Early administration of CCP remains a potential option in COVID-19 management in countries with existing OOH/HT programmes. Legislation and regulatory bodies should consider OOH/HT practice for transfusion in future pandemics.

Production and Quality Assurance of Human Polyclonal Hyperimmune Immunoglobulins Against SARS-CoV-2.

The coronavirus disease 2019 (COVID-19) pandemic has highlighted the potential therapeutic value of early passive polyclonal immunotherapy using high-titer convalescent plasma (CCP). Human polyclonal hyperimmune immunoglobulin (HIG) has several advantages over CCP. Unlike CCP, HIG can provide standardized and controlled antibody content. It is also subjected to robust pathogen reduction rendering it virally safe and is purified by technologies demonstrated to preserve immunoglobulin neutralization capacity and Fc fragment integrity. This document provides an overview of current practices and guidance for the collection and testing of plasma rich in antibodies against Severe Acute Respiratory Coronavirus 2 (SARS-CoV-2) and its industrial fractionation for the manufacture of quality-assured and safe HIG. Considerations are also given to the production of HIG preparations in low- and middle-income countries.

Combination of Mycobacterium tuberculosis RS Ratio and CFU Improves the Ability of Murine Efficacy Experiments to Distinguish between Drug Treatments.

Murine tuberculosis drug efficacy studies have historically monitored bacterial burden based on CFU of Mycobacterium tuberculosis in lung homogenate. In an alternative approach, a recently described molecular pharmacodynamic marker called the RS ratio quantifies drug effect on a fundamental cellular process, ongoing rRNA synthesis. Here, we evaluated the ability of different pharmacodynamic markers to distinguish between treatments in three BALB/c mouse experiments at two institutions. We confirmed that different pharmacodynamic markers measure distinct biological responses. We found that a combination of pharmacodynamic markers distinguishes between treatments better than any single marker. The combination of the RS ratio with CFU showed the greatest ability to recapitulate the rank order of regimen treatment-shortening activity, providing proof of concept that simultaneous assessment of pharmacodynamic markers measuring different properties will enhance insight gained from animal models and accelerate development of new combination regimens. These results suggest potential for a new era in which antimicrobial therapies are evaluated not only on culture-based measures of bacterial burden but also on molecular assays that indicate how drugs impact the physiological state of the pathogen.

International Society of Blood Transfusion survey of experiences of blood banks and transfusion services during the COVID-19 pandemic.

BACKGROUND AND OBJECTIVES: The coronavirus disease 2019 (COVID-19) pandemic has impacted blood systems worldwide. Challenges included maintaining blood supplies and initiating the collection and use of COVID-19 convalescent plasma (CCP). Sharing information on the challenges can help improve blood collection and utilization. MATERIALS AND METHODS: A survey questionnaire was distributed to International Society of Blood Transfusion members in 95 countries. We recorded respondents' demographic information, impacts on the blood supply, CCP collection and use, transfusion demands and operational challenges. RESULTS: Eighty-two responses from 42 countries, including 24 low- and middle-income countries, were analysed. Participants worked in national (26.8%) and regional (26.8%) blood establishments and hospital-based (42.7%) institutions. CCP collection and transfusion were reported by 63% and 36.6% of respondents, respectively. Decreases in blood donations occurred in 70.6% of collecting facilities. Despite safety measures and recruitment strategies, donor fear and refusal of institutions to host blood drives were major contributing factors. Almost half of respondents working at transfusion medicine services were from large hospitals with over 10,000 red cell transfusions per year, and 76.8% of those hospitals experienced blood shortages. Practices varied in accepting donors for blood or CCP donations after a history of COVID-19 infection, CCP transfusion, or vaccination. Operational challenges included loss of staff, increased workloads and delays in reagent supplies. Almost half of the institutions modified their disaster plans during the pandemic. CONCLUSION: The challenges faced by blood systems during the COVID-19 pandemic highlight the need for guidance, harmonization, and strengthening of the preparedness and the capacity of blood systems against future infectious threats.

Trend of Galectin-3 Levels in Patients with Non-ST-Elevation and ST-Elevation Myocardial Infarction.

Background and Objectives: Given the fact that galectin-3 has a predictive significance on the development of myocardial dysfunction after acute myocardial infarction, the aim of our study was to examine potential factors that could be important for the dynamics of the concentration of this biomarker in the early postinfarction period. Materials and Methods: This study included 89 patients with a diagnosis of stable angina pectoris (SAP) or the first non-ST elevation (NSTEMI) or ST-elevation (STEMI) myocardial infarction, who underwent percutaneous coronary intervention (PCI). The study group included 23 patients with the first NSTEMI and 42 patients with STEMI, while the control group consisted of 24 patients with SAP hospitalized for elective PCI without a previous MI. All patients had preserved left ventricular ejection fraction. Galectin-3 levels were determined on days 1, 5, and 30 after PCI. The significance of various independent variables as predictors of galectin-3 concentration was analyzed after a series of univariate linear regression modeling in a multivariate linear regression model. Results: The average patients' age was 63.99 ± 9.13 years. Statistically significantly higher values of C-reactive protein were established in STEMI compared to SAP (p < 0.01) or NSTEMI (p < 0.001), whereas WBC count was significantly lower in SAP than in STEMI (p < 0.001) and NSTEMI (p < 0.01) group. Although there were no statistically significant differences in measured galectin-3 concentrations between the examined groups on days 1, 5, and 30 after PCI, HTA, triglyceride level, LA size, treatment with trimetazidine and long-acting nitrates, as well as percentage of LM stenosis and E/A ratio were identified as independent predictors of galectin-3 concentration. Conclusions: In the post-MI period, very early values of galectin-3 correlate mostly with atherosclerosis factors, while on day 30 this biomarker correlates with diastolic dysfunction and "announces" left ventricular remodeling.