Association of BNT162b2 SARS-CoV-2 vaccination during pregnancy with postnatal outcomes in premature infants.

AIM: The effect of COVID-19 vaccine given during pregnancy on premature infants is unknown. This study aims to determine the association between maternal COVID-19 vaccine with postnatal outcome in premature infants. METHODS: This is a single-centre retrospective case-control study of infants born before 35 weeks gestation to mothers who received SARS-CoV-2 vaccine during pregnancy compared with infant born to non-vaccinated mothers. RESULTS: A total of 78 infants in each group were included. Infants in the vaccinated group had less respiratory distress syndrome (RDS) (p = 0.02) and less need for respiratory support (p = 0.002), and maternal vaccine had a protective effect on RDS [adjustable OR 0.38 (0.17-0.85)]. Vaccination during the first compared to the second trimester was associated with earlier gestational age (32.3 ± 2.1 vs. 33.3 ± 1.1 weeks, p = 0.03). CONCLUSION: We demonstrated that maternal SARS-CoV-2 vaccine is not associated with postnatal adverse effect in premature infants and potentially has a protective effect on RDS. Earlier gestational age among the infants born to mothers who received COVID-19 vaccine during the first trimester did not translate to higher rate of postnatal complications. These findings might suggest that COVID-19 vaccine is safe in high-risk pregnancies, but timing of administration should be considered. Further studies are needed to confirm our findings and the biological mechanism.

Achieving HIV Epidemic Control and Improving Maternal Healthcare Services with Community-Based HIV Service Delivery in Zambia: Mixed-Methods Assessment of the SMACHT Project.

Novel community-based approaches are needed to achieve and sustain HIV epidemic control in Zambia. Under the Stop Mother and Child HIV Transmission (SMACHT) project, the Community HIV Epidemic Control (CHEC) differentiated service delivery model used community health workers to support HIV testing, ART linkage, viral suppression, and prevention of mother-to-child transmission (MTCT). A multi-methods assessment included programmatic data analysis from April 2015 to September 2020, and qualitative interviews from February to March 2020. CHEC provided HIV testing services to 1,379,387 clients; 46,138 were newly identified as HIV-positive (3.3% yield), with 41,366 (90%) linked to ART. By 2020, 91% (60,694/66,841) of clients on ART were virally suppressed. Qualitatively, healthcare workers and clients benefitted from CHEC, with provision of confidential services, health facility decongestion, and increased HIV care uptake and retention. Community-based models can increase uptake of HIV testing and linkage to care, and help achieve epidemic control and elimination of MTCT.

Recommendations for procurement of starting materials by apheresis for advanced therapy medicinal products.

Activities involved in the production of certain advanced therapy medicinal products (ATMPs) require standardized approaches to mononuclear cell procurement to ensure the highest product quality, safety and process efficiency. These aims must be achieved while meeting regulatory and accreditation requirements for the procurement of mononuclear cells as starting materials. Mononuclear cells constitute the starting materials for many ATMPs, and this article sets out recommendations for procurement by clinical apheresis, addressing the variation among existing working practices and different manufacturers' requirements that currently poses a challenge when managing multiple different protocols.

Patient satisfaction and experience with intravenously administered C1-inhibitor concentrates in the United States.

BACKGROUND: Hereditary angioedema (HAE) is a rare genetic disorder with substantial morbidity and mortality. Despite expanded choices for effective acute treatment, prophylactic options are more limited. Intravenous C1 esterase inhibitor (C1-INH[IV]) is licensed and used to prevent HAE symptoms. OBJECTIVE: To better understand patient experiences with using C1-INH(IV), including level of satisfaction and types and frequency of complications. METHODS: Fifty adult members (≥18 years of age) of the US HAE Association who had HAE type I or II completed a self-administered internet survey. Eligible participants were experiencing at least 1 HAE attack per month and must have been receiving treatment with C1-INH(IV) as prophylaxis or acute therapy. RESULTS: Almost all respondents (n = 47; 94%) were using C1-INH(IV) for HAE prophylaxis. Most patients reported administration of C1-INH(IV) through a peripheral vein (n = 34) and 19 were currently (n = 17) or previously (n = 2) using a central venous port. Most respondents (62%) who used a peripheral vein to administer treatment reported having difficulty finding a usable vein or getting the infusion to work properly at least some of the time. Issues accessing veins, exhausted veins, and frequency of attacks were the main reasons physicians recommended ports to respondents. Although ports allow easier administration of therapy, 47% of respondents with ports experienced problems such as occlusion, thrombosis, and infection. Respondents using C1-INH prophylaxis reported a mean of 2.3 attacks per month during the previous 6 months. CONCLUSION: The survey results identified clinical challenges with IV HAE medication use, including venous access issues and ongoing monthly attack occurrence despite prophylactic C1-INH(IV) administration.

Nanoskiving core-shell nanowires: a new fabrication method for nano-optics.

This paper describes the fabrication of functional optical devices by sectioning quantum-dot-in-nanowires systems with predefined lengths and orientations. This fabrication process requires only two steps, embedding the nanowires in epoxy and using an ultramicrotome to section them across their axis ("nanoskiving"). This work demonstrates the combination of the following four capabilities: (i) the control of the length of the nanowire sections at the nanometer scale; (ii) the ability to process the nanowires after cutting using wet etching; (iii) the possibility of modifying the geometry of the wire by varying the sectioning angle; and (iv) the generation of as many as 120 consecutive slabs bearing nanowires that have uniform size and approximately reproducible lateral patterns and that can subsequently be transferred to different substrates. The quantum dots inside the nanowires are functional and of a high optical quality after the sectioning process and exhibit photoluminescent emission with wavelengths in the range of 650-710 nm.

Ten years of transfusion practitioners and better blood transfusion in Scotland.

After the Department of Health's Better Blood Transfusion recommendations ( DH 2002 ) ten years ago, a network of 18 transfusion practitioners supported by a central team in the Scottish National Blood Transfusion Service was established. This article discusses the impact that transfusion practitioners in Scotland have had in driving local transfusion teams to promote safe and effective transfusion practice across Scotland. They have done this through education, audit and raising awareness of current guidelines.

Restrictive versus liberal transfusion strategies for older mechanically ventilated critically ill patients: a randomized pilot trial.

OBJECTIVES: To compare hemoglobin concentration (Hb), RBC use, and patient outcomes when restrictive or liberal blood transfusion strategies are used to treat anemic (Hb≤90 g/L) critically ill patients of age≥55 years requiring≥4 days of mechanical ventilation in ICU. DESIGN: Parallel-group randomized multicenter pilot trial. SETTING: Six ICUs in the United Kingdom participated between August 2009 and December 2010. PATIENTS: One hundred patients (51 restrictive and 49 liberal groups). INTERVENTIONS: Patients were randomized to a restrictive (Hb trigger, 70 g/L; target, 71-90 g/L) or liberal (90 g/L; target, 91-110 g/L) transfusion strategy for 14 days or the remainder of ICU stay, whichever was longest. MEASUREMENTS AND MAIN RESULTS: Baseline comorbidity rates and illness severity were high, notably for ischemic heart disease (32%). The Hb difference among groups was 13.8 g/L (95% CI, 11.5-16.0 g/L); p<0.0001); mean Hb during intervention was 81.9 (SD, 5.1) versus 95.7 (6.3) g/L; 21.6% fewer patients in the restrictive group were transfused postrandomization (p<0.001) and received a median 1 (95% CI, 1-2; p=0.002) fewer RBC units. Protocol compliance was high. No major differences in organ dysfunction, duration of ventilation, infections, or cardiovascular complications were observed during intensive care and hospital follow-up. Mortality at 180 days postrandomization trended toward higher rates in the liberal group (55%) than in the restrictive group (37%); relative risk was 0.68 (95% CI, 0.44-1.05; p=0.073). This trend remained in a survival model adjusted for age, gender, ischemic heart disease, Acute Physiology and Chronic Health Evaluation II score, and total non-neurologic Sequential Organ Failure Assessment score at baseline (hazard ratio, 0.54 [95% CI, 0.28-1.03]; p=0.061). CONCLUSIONS: A large trial of transfusion strategies in older mechanically ventilated patients is feasible. This pilot trial found a nonsignificant trend toward lower mortality with restrictive transfusion practice.

Thrombocytopenia and platelet transfusion in UK critical care: a multicenter observational study.

BACKGROUND: Platelet (PLT) transfusions are widely used, but few studies have described patterns of use in critical care. STUDY DESIGN AND METHODS: As part of a prospective multicenter observational study of all sequentially admitted patients to UK general intensive care units (ICUs) over 8 weeks, daily data were collected throughout admission on frequency of thrombocytopenia and use of PLT transfusions, in addition to clinical outcomes, including bleeding. RESULTS: There were 1923 admissions recruited across 29 ICUs for analysis (96.6% of all eligible admissions). The period prevalences of severe thrombocytopenia (<50 × 10(9) /L) for the entire ICU stay were 12.4% (234/1881) and 13.7% (263/1914) when the 24 hours before admission was also included. A total of 35.4% of patients who experienced severe thrombocytopenia died in the ICU. A total of 169 patients (9% of study population) received 534 units of transfused PLTs (median number of units per patient admission was 2; interquartile range, 1-3; maximum, 38). Pretransfusion PLT counts were more than 50 × 10(9) for 40% of PLT transfusions overall, and even when no clinically significant bleeding was recorded on the day of transfusion, the lowest recorded PLT count was more than 50 × 10(9) for 34% of transfusions. There was evidence of only modest increments in PLT count. CONCLUSION: Thrombocytopenia is common in critical care, but there is wide variation in PLT transfusion use. Patients commonly received PLT transfusions on days without clinically significant hemorrhage. The high prevalence of thrombocytopenia in the critically ill population and inconsistent patterns of PLT transfusions indicate the importance of improving the evidence base for PLT use.

Prolyl endopeptidase activity in bronchoalveolar lavage fluid: a novel diagnostic biomarker in a guinea pig model of invasive pulmonary aspergillosis.

Improved diagnostics are needed to detect invasive pulmonary aspergillosis, a life-threatening infection caused by the pathogenic fungus Aspergillus fumigatus. We are investigating secreted fungal proteases as novel biomarkers for the diagnosis of this disease. Although the A. fumigatus genome encodes a multitude of secreted proteases, few have been experimentally characterized. Here, we employed an unbiased combinatorial library of internally quenched fluorogenic probes to detect infection-associated proteolysis in the lungs of guinea pigs experimentally infected with A. fumigatus. Comparative protease activity profiling revealed a prolyl endopeptidase activity that is reproducibly induced during infection but is not observed in healthy animals. This proteolytic activity was found in four independent animal experiments involving two A. fumigatus isolates. We synthesized a small, focused fluorogenic probe library to define the substrate specificity of the prolyl endopeptidase substrate motif and to identify optimal Probe sequences. These efforts resulted in the identification of a panel of six individual substrate-based fluorescent probes capable of detecting infection in guinea pigs with high statistical significance (P<0.005 in most cases). Receiver operating characteristic analyses demonstrated that this fluorogenic assay could detect A. fumigatus infection-associated proteolysis with comparable sensitivity and specificity as existing diagnostic procedures, suggesting that further optimization of the methodology may lead to improved diagnostics options for invasive pulmonary aspergillosis.

Thiyl radical induced cis/trans isomerism in double bond containing elastomers.

This report presents an evaluation of thiyl radical-induced cis/trans isomerism in double bond-containing elastomers, such as natural, polychloroprene, and polybutadiene rubbers. The study aims to extensively investigate structural changes in polymers after functionalisation using thiol-ene chemistry, a useful click reaction for modifying polymers and developing materials with new functionalities. The paper reports on the use of different thiols, and cis/trans isomerism was detected through 1H NMR analysis, even at very low alkene/thiol mole ratios. The study finds that the configurational arrangements between non-functionalised elastomer units and thiolated units followed a trans-functionalised-cis units arrangement up to an alkene/thiol mole feed ratio of 0.3, while from 0.4 onward, a combination of trans-functionalised-cis and cis-functionalised-trans configurations are found. Additionally, it is observed that by increasing the level of functionalisation, the glass transition temperature of the resulting modified elastomer also increases. Overall, this study provides valuable insights into the effects of thiol-ene chemistry on the structure and properties of elastomers and could have important implications for the development of new materials with enhanced functionality.

SARS-CoV-2 Infection of Young Infants during the Omicron Wave: A Case Series.

We describe the clinical course of 4 infants infected with severe acute respiratory syndrome coronavirus 2. All were admitted to our tertiary care neonatal intensive care unit during the Omicron variant wave in our region. All 4 infants, who were less than 3 months of age, including three born prematurely, presented with critical illness. However, their clinical presentation varied considerably. Of them, two infants presented with apnea, one with respiratory distress, and one with gastrointestinal manifestation. Our experience with these four infants provides evidence for a severe form of disease and varied clinical presentation in neonates and young infants speculated to be infected with Omicron variant.

An algorithm to identify medical practices common to both the General Practice Research Database and The Health Improvement Network database.

PURPOSE: To identify practices common to both the General Practice Research Database and The Health Improvement Network database for purposes of combining the databases for analysis without duplicate records. METHODS: We developed two independent algorithms to identify practices common to the two databases. The first used the total number of patients in the therapy and clinical data sets and the total number of etoricoxib and celecoxib users each year during the study period. The second used the total number of patients stratified by gender and four different categories of birth year. Further checking of potential matched practice pairs identified by the two algorithms was performed by comparing the patient-level medical records by birth year, dates of clinical visits, and diagnosis codes. RESULTS: Three hundred twelve potential matched pairs of practices were found by both algorithms. Fifteen additional potential pairs were matched by only one algorithm: 13 by algorithm 1 (A1) only and 2 by algorithm 2 (A2) only. The examination of the patient-level visit dates and diagnosis codes for the matches revealed that all of the 327 potential pairs of duplicate practices were in fact the same practice in the two databases. CONCLUSIONS: The two algorithms successfully found the practices common to the two different databases without de-identifying the practices. The identification of the common practices allows for combining the two databases without duplicate records to create a larger data set for analysis, with 168 more practices than when using the General Practice Research Database alone, or with 268 more practices than when using The Health Improvement Network alone. Copyright © 2012 John Wiley & Sons, Ltd.

A national study of plasma use in critical care: clinical indications, dose and effect on prothrombin time.

INTRODUCTION: Fresh frozen plasma (FFP) is widely used, but few studies have described patterns of plasma use in critical care. We carried out a multicentre study of coagulopathy in intensive care units (ICUs) and here describe overall FFP utilisation in adult critical care, the indications for transfusions, factors indicating the doses used and the effects of FFP use on coagulation. METHODS: We conducted a prospective, multicentre, observational study of all patients sequentially admitted to 29 adult UK general ICUs over 8 weeks. Daily data throughout ICU admission were collected concerning coagulation, relevant clinical outcomes (including bleeding), coagulopathy (defined as international normalised ratio (INR) >1.5, or equivalent prothrombin time (PT)), FFP and cryoprecipitate use and indications for transfusion. RESULTS: Of 1,923 admissions, 12.7% received FFP in the ICU during 404 FFP treatment episodes (1,212 FFP units). Overall, 0.63 FFP units/ICU admission were transfused (0.11 units/ICU day). Reasons for FFP transfusion were bleeding (48%), preprocedural prophylaxis (15%) and prophylaxis without planned procedure (36%). Overall, the median FFP dose was 10.8 ml kg⁻¹, but doses varied widely (first to third quartile, 7.2 to 14.4 ml kg⁻¹). Thirty-one percent of FFP treatments were to patients without PT prolongation, and 41% were to patients without recorded bleeding and only mildly deranged INR (<2.5). Higher volumes of FFP were administered when the indication was bleeding (median doses: bleeding 11.1 ml kg⁻¹, preprocedural prophylaxis 9.8 ml kg⁻¹, prophylaxis without procedure 8.9 ml kg⁻¹; P = 0.009 across groups) and when the pretransfusion INR was higher (ranging from median dose 8.9 ml kg⁻¹ at INR ≤ 1.5 to 15.7 ml kg⁻¹ at INR >3; P < 0.001 across ranges). Regression analyses suggested bleeding was the strongest predictor of higher FFP dose. Pretransfusion INR was more frequently normal when the transfusion indication was bleeding. Overall, posttransfusion corrections of INR were consistently small unless the pretransfusion INR was >2.5, but administration during bleeding was associated with greater INR corrections. CONCLUSIONS: There is wide variation in FFP use by ICU clinicians, and a high proportion of current FFP transfusions are of unproven clinical benefit. Better evidence from clinical trials could significantly alter patterns of use and modify current treatment costs.

Novel Crosslinking System for Poly-Chloroprene Rubber to Enable Recyclability and Introduce Self-Healing.

The introduction of dynamic bonds capable of mediating self-healing in a fully cross-linked polychloroprene network can only occur if the reversible moieties are carried by the cross-linker itself or within the main polymer backbone. Conventional cross-linking is not suitable for such a purpose. In the present work, a method to develop a self-healable and recyclable polychloroprene rubber is presented. Dynamic disulfide bonds are introduced as part of the structure of a crosslinker (liquid polysulfide polymer, Thiokol LP3) coupled to the polymer backbone via thermally initiated thiol-ene reaction. The curing and kinetic parameters were determined by isothermal differential scanning calorimetry and by moving die rheometer analysis; tensile testing was carried to compare the tensile strength of cured compound, healed compounds and recycled compounds, while chemical analysis was conducted by surface X-ray Photoelectron Spectroscopy. Three formulations with increasing concentrations of Thiokol LP-3 were studied (2, 4, 6 phr), reaching a maximum ultimate tensile strength of 22.4 MPa and ultimate tensile strain of 16.2 with 2 phr of Thiokol LP-3, 11.7 MPa and 10.7 strain with 4 phr and 5.6 MPa and 7.3 strain with 6 phr. The best healing efficiencies were obtained after 24 h of healing at 80 °C, increasing with the concentration of Thiokol LP-3, reaching maximum values of 4.5% 4.4% 13.4% with 2 phr, 4 phr and 6 phr, respectively, while the highest recycling efficiency was obtained with 4 phr of Thiokol LP-3, reaching 11.2%.

Prevalence, management, and outcomes of critically ill patients with prothrombin time prolongation in United Kingdom intensive care units.

OBJECTIVE: Coagulopathy occurs frequently in critically ill patients, but its epidemiology, current treatment, and relation to patient outcome are poorly understood. We described the prevalence, risk factors, and treatment of prolongation of the prothrombin time in critically ill patients using the international normalized ratio to standardize data and explored its association with intensive care unit survival. DESIGN: Prospective multiple center observational cohort study. SETTING: Twenty-nine adult intensive care units in the United Kingdom. PATIENTS: All sequentially admitted patients over an 8-wk period. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Prospective daily data were collected concerning prevalence, predefined risk factors, and treatment of coagulopathy throughout intensive care unit admission. Of 1923 intensive care unit admissions, 30% developed abnormal international normalized ratio values (defined as an international normalized ratio > 1.5). Most international normalized ratio abnormalities were minor and short-lived (73% of worst international normalized ratio values 1.6-2.5). Male sex, chronic liver disease, sepsis, warfarin therapy, increments in Acute Physiology and Chronic Health Evaluation II score, severity of renal and hepatic dysfunction, and red cell transfusions were all independent risk factors for international normalized ratio abnormalities (all p < .001). In all regression models, there was a strong independent association between abnormal international normalized ratio values and greater intensive care unit mortality (p < .0001), particularly when international normalized ratio increased after intensive care unit admission. Among patients with abnormal international normalized ratios, 33% received fresh-frozen plasma transfusions during their intensive care unit stay, but the pretransfusion international normalized ratio value varied widely. Fifty-one percent of fresh-frozen plasma treatments were to nonbleeding patients and 40% to nonbleeding patients whose international normalized ratio was normal or only modestly deranged (≤ 2.5). The dose of fresh-frozen plasma administered was highly variable (median dose 10.8 mL/kg (first, third quartile 7.2, 14.4; range, 2.4-41.1 mL/kg). CONCLUSIONS: Prothrombin time prolongation is prevalent in critically ill patients and is independently associated with greater intensive care unit mortality. Wide variation in fresh-frozen plasma treatment exists suggesting clinical uncertainty regarding best practice, particularly as a prophylactic treatment.

All-trans retinoic acid potentiates the antibody response in mice to a lipopeptide antigen adjuvanted with liposomal lipid A.

Retinoic acid (RA), the bioactive metabolite of retinol, is essential for robust humoral immunity in animals and humans. Recent interest in RA as a vaccine adjuvant has been encouraged by reports showing cooperative enhancement of antibody responses to tetanus toxin in rodents by all-trans RA (ATRA) and a Toll-like receptor-3 agonist. We hypothesized that RA would augment the antibody response to a co-delivered lipopeptide immunogen derived from the membrane proximal region (MPR) of HIV-1 gp41. The MPR is weakly immunogenic and could benefit from potent new humoral adjuvants. When co-formulated in liposomes and administered to BALB/C mice, ATRA alone did not elicit serum anti-peptide antibodies to an MPR-derived lipopeptide. However, addition of ATRA, but not 13-cis RA, to a liposomal formulation containing the Toll-like receptor-4 agonist monophosphoryl lipid A resulted in a fourfold enhancement of serum anti-peptide IgG titers as compared with a formulation containing lipid A alone (P=0.00039). The difference did not arise from biophysical changes in the liposome formulation, including vesicle size, vesicle charge and liposome association of antigen. Thus, ATRA warrants further study as a vaccine adjuvant.

A multiplexed immunoassay for detection of antibodies against avian influenza virus.

Avian influenza (AI) is a highly contagious disease in poultry and outbreaks can have dramatic economic and health implications. For effective disease surveillance, rapid and sensitive assays are needed to detect antibodies against AI virus (AIV) proteins. In this study, we report the development of a multiplexed fluorescence microsphere immunoassay (FMIA) for detection of antibodies against AIV proteins in poultry. Recombinant nucleoprotein (NP), matrix protein (M1), and non-structural protein 1 (NS1) were expressed using a baculovirus expression system, purified and covalently coupled to fluorescent xMAP microspheres. Using these reagents, a triplex bead assay was developed for the Luminex platform. The assay displayed minimal cross reactivity when screened against a panel of reference sera raised against common avian viruses. For detection of anti-NP antibodies, the sensitivity and specificity of the assay were comparable to a commercially available ELISA. The assay was also employed to investigate the early kinetics of antibody response in chickens infected with AIV. Our results suggest that NP should be the protein of choice when detecting AI infections in commercial chickens, as the immune response was higher and persisted longer than that of M1 and NS1 proteins. This report provides a framework from which a more robust assay could be developed to profile exposure to many AIV subtypes in a single test.

Tris-nitrilotriacetic acids of subnanomolar affinity toward hexahistidine tagged molecules.

Nitrilotriacetic acid (NTA) has moderate affinity (10 µM) for hexahistidine (His6) and is widely used in the purification of His6-tagged proteins. The affinity can be increased significantly (10 nM) through multivalency such as using a tris-NTA. We show that the binding affinity of tris-NTA is dependent on the flexibility and length of the spacer between the mono-NTA and the scaffold: the shorter the spacer, the higher the affinity. A series of biotinylated tris-NTA having different spacers were synthesized and used to prepare tris-NTA sensor chips for surface plasmon resonance measurement of binding affinity. Subnanomolar affinity can be achieved with a short spacer. The new high-affinity tris-NTA enables the formation of stable complexes with hexahistidine containing molecules and provides a convenient method to noncovalently attach proteins to various surfaces.

Steady-state pharmacokinetics of lopinavir/ritonavir in combination with efavirenz in human immunodeficiency virus-infected pediatric patients.

The pharmacokinetics of lopinavir/ritonavir (LPV/RTV) 300 mg/m twice daily and efavirenz (EFV) 350 mg/m once daily were evaluated in HIV-infected children. The minimum concentrations for LPV contained values above the target range, and the estimated minimum concentrations for EFV contained values below the range. Our data support the current LPV/RTV dose, but EFV 350 mg/m may not be sufficient.