Adverse reactions following transfusion of blood components, with a focus on some rare reactions: Reports to the International Haemovigilance Network Database (ISTARE) in 2012-2016.

OBJECTIVES: The International Haemovigilance Network's (IHN) ISTARE database collects surveillance data on all adverse reactions (AR) associated with transfusion of blood and blood components, facilitating the sharing of best practice and benchmarking for improving blood safety and quality. Up to 2012, no publications discussed certain rare AR. The aim of this study is to examine ISTARE data on AR from 2012 to 2016, focusing on hypotensive reactions, post-transfusion purpura (PTP), transfusion-associated graft versus host disease (TA-GvHD), hyperkalemia and hypocalcemia. MATERIALS AND METHODS: National Haemovigilance Systems (HVS), provided aggregate annual data on AR by type of reaction, severity, imputability to transfusion, and blood component implicated. Twenty-nine HVS provided 104 annual reports covering 107,778,290 blood units issued. RESULTS: Among AR reported, 25% were serious, including 368 deaths. The 284 transfusion-transmitted infections included 187 bacterial infections, 84 viral and 13 parasitic or fungal; nine deaths resulted. AR related to the respiratory system transfusion-associated circulatory overload, transfusion-related acute lung injury and transfusion-associated dyspnoea accounted for 8.3% of all AR, 20.1% of serious, and 52.2% of deaths. Of 1634 rare AR, 1565 were hypotensive, 38 PTP, 17 GvHD, 9 hyperkalemia and 5 hypercalcemia. Half were serious and 16 fatalities were recorded (13 hypotensive, 2 GvHD, one PTP). Among 14 countries that reported any hypotensive AR, incidences diverged widely. CONCLUSIONS: ARs in this group are frequently severe or life-threatening. Hypotensive AR are the most common, but may have been overlooked and counted under allergic and other AR presenting with hypotension. Compliance with the ISBT definition may be suboptimal, thus its real incidence may be higher. Data on GvHD may contribute to clarifying the role of leukodepletion with or without irradiation. ISTARE continues to be a useful surveillance tool for all transfusion AR and provides relevant insights into overlooked and rare AR, thus offering important contributions towards maximising transfusion safety.

International haemovigilance: what have we learned and what do we need to do next?

The International Haemovigilance Network (IHN) defines haemovigilance as 'a set of surveillance procedures covering the whole transfusion chain (from the collection of blood and its components to the follow-up of recipients), intended to collect and assess information on unexpected or undesirable effects resulting from the therapeutic use of labile blood products, and to prevent their occurrence or recurrence'. IHN, the International Society of Blood Transfusion and World Health Organization work together to support both developing and established haemovigilance systems. Haemovigilance systems provide valuable data on a range of adverse events related to blood donation and clinical transfusion, from donor syncopal events to transfusion-transmitted infections, immunological complications and the impact of human errors. Harmonised definitions for most adverse reactions have been developed and validated internationally. Definitions of pulmonary complications are again under review. Haemovigilance data have resulted in changes in policy, products and practice, and can complement and inform clinical audit and research, leading to improved blood donor safety, optimised product use and better clinical outcomes after transfusion. However, more work is needed. Not all countries have haemovigilance systems in place. More robust data and careful analysis are required to improve the understanding of the causes, occurrence and clinical outcomes of these events. Wider dissemination of results will facilitate health policy development internationally, and implementation of haemovigilance recommendations will support further important progress in blood safety.

Novel functionalities of hybrid paper-polymer centrifugal devices for assay performance enhancement.

The presented work demonstrates novel functionalities of hybrid paper-polymer centrifugal devices for assay performance enhancement that leverage the advantages of both paper-based and centrifugal microfluidic platforms. The fluid flow is manipulated by balancing the capillary force of paper inserts with the centrifugal force generated by disc rotation to enhance the signal of a colorimetric lateral flow immunoassay for pathogenic E. coli. Low-cost centrifugation for pre-concentration of bacteria was demonstrated by sample sedimentation at high rotational speeds before supernatant removal by a paper insert via capillary force after deceleration. The live bacteria capture efficiency of the device was similar to a commercial centrifuge. This pre-concentrated sample when combined with gold nanoparticle immunoconjugate probes resulted in a detection limit that is 10× lower than a non-concentrated sample for a lateral flow immunoassay. Signal enhancement was also demonstrated through rotational speed variation to prevent the flow for on-device incubation and to reduce the flow rate, thus increasing the sample residence time for the improved capture of gold nanoparticle-bacteria complexes in an integrated paper microfluidic assay. Finally, multiple sequential steps including sample pre-concentration, filtration, incubation, target capture by an integrated paper microfluidic assay, silver enhancement and quenching, and index matching were completed within a single device. The detection limit was 105 colony forming units per ml, a 100× improvement over a similar paper-based lateral flow assay. The techniques utilize the advantages of paper-based microfluidic devices, while facilitating additional functionalities with a centrifugal microfluidic platform for detection performance enhancement in a low-cost, automated platform amenable to point-of-care environments.

Blood banks meet the paradox of Gabriel's Horn: what are the options to maintain supply as demand decreases?

Blood services worldwide have observed a decline in the demand for red blood cells (RBC). Despite this general decline, the demand profile has changed significantly with the demand for O D negative RBCs being maintained; whereas B D positive and AB D positive RBC demand has been reduced. In 2015, the blood type O D negative was seen in 6·3% of the combined first time donors among the five American Blood Centres involved in this study and 7·4% of first time Australian donors in 2014/2015, whereas O D negative distributions accounted for 10·5% of all red cell units issued by the American centres and 13·9% by the Australian centres. Inventory can therefore be of sufficient overall quantity but may not be adequate for the demand for units with specific blood types. Recruitment of new donors may need to become more targeted and/or financial or inventory control measures could also be required to ensure inventory matches demand. Blood Services will need to consider the available options in order to ensure that sufficiency of supply is secure and the donor panel is optimised to meet the new demand paradigm.

Development of standard definitions for surveillance of complications related to blood donation.

Standard definitions of donor reactions allow each blood establishment to monitor donor adverse events and compare with other organizations to develop best practices. The ISBT Haemovigilance Working Party leads a multi-organizational effort to update the 2008 ISBT standard for surveillance of complications related to blood donation. Revised definitions have been developed and endorsed by the ISBT, AABB, International Haemovigilance Network (IHN) and other international organizations.

Antibodies to the HLA-A2 antigen prime neutrophils and serve as the second event in an in vitro model of transfusion-related acute lung injury.

BACKGROUND: Transfusion-related acute lung injury (TRALI) is the most common cause of transfusion-related mortality and has been linked to the infusion of donor antibodies directed against recipient HLA class I antigens. We hypothesize that antibodies against HLA class I antigens bind to the antigens on the neutrophil (PMN) surface and induce priming and PMN cytotoxicity as the second event in a two-event in vitro model of PMN-mediated cytotoxicity. METHODS: Isolated PMNs from HLA-A2 homozygotes, heterozygotes and null donors were incubated with a monoclonal antibody to HLA-A2 and a human polyclonal IgG to HLA-A2 and priming of the oxidase was measured. The monoclonal antibodies and PMNs from these three groups were then used in a two-event model of PMN cytotoxicity. RESULTS: The antibodies to HLA-A2 both primed PMNs from HLA-A2 homozygotes but not from heterozygotes or nulls. Antibodies to HLA-A2 also served as the second event in a two-event model to induce PMN cytotoxicity of HLA-A2 homozygous PMNs. CONCLUSION: Antibodies to HLA class I antigens may directly prime/activate PMNs through the ligation of the antigen on the cell surface, and the antigen density appears to be important for these changes in PMN physiology.

Proteomic analysis of the supernatant of red blood cell units: the effects of storage and leucoreduction.

BACKGROUND: Red blood cell (RBC) transfusion is a life-saving intervention for critically ill patients; however, it has been linked to increased morbidity and mortality. We hypothesize that a number of important proteins accumulate during routine storage of RBCs, which may explain some of the adverse effects seen in transfused patients. STUDY DESIGN: Five RBC units were drawn and divided (half prestorage leucoreduced (LR-RBC) and half left as an unmodified control (RBC). The supernatant was separated on days 1 and 42 of storage and proteomic analyses completed with in-gel tryptic digestion and nano-liquid chromatography tandem mass spectrometry. RESULTS: In RBC supernatants, 401 proteins were identified: 203 increased with storage, 114 decreased, and 84 were unchanged. In LR-RBC supernatant, 231 proteins were identified: 84 increased with storage, 30 decreased, and 117 were unchanged. Prestorage leucoreduction removed many platelet- and leucocyte-derived structural proteins; however, a number of intracellular proteins accumulated including peroxiredoxins (Prdx) 6 and latexin. The increases were confirmed by immunoblotting, including the T-phosphorylation of Prdx-6, indicating that it may be functioning as an active phospholipase. Active matrix metalloproteinase-9 also increased with a coinciding decrease in the metalloproteinase inhibitor 1 and cystatin C. CONCLUSION: We conclude that a number of proteins increase with RBC storage, which is partially ameliorated with leucoreduction, and transfusion of stored RBCs may introduce mediators that result in adverse events in the transfused host.

The quadratic hazard model for analyzing longitudinal data on aging, health, and the life span.

A better understanding of processes and mechanisms linking human aging with changes in health status and survival requires methods capable of analyzing new data that take into account knowledge about these processes accumulated in the field. In this paper, we describe an approach to analyses of longitudinal data based on the use of stochastic process models of human aging, health, and longevity which allows for incorporating state of the art advances in aging research into the model structure. In particular, the model incorporates the notions of resistance to stresses, adaptive capacity, and "optimal" (normal) physiological states. To capture the effects of exposure to persistent external disturbances, the notions of allostatic adaptation and allostatic load are introduced. These notions facilitate the description and explanation of deviations of individuals' physiological indices from their normal states, which increase the chances of disease development and death. The model provides a convenient conceptual framework for comprehensive systemic analyses of aging-related changes in humans using longitudinal data and linking these changes with genotyping profiles, morbidity, and mortality risks. The model is used for developing new statistical methods for analyzing longitudinal data on aging, health, and longevity.

The pro-inflammatory effects of platelet contamination in plasma and mitigation strategies for avoidance.

BACKGROUND AND OBJECTIVES: Plasma and platelet concentrates are disproportionately implicated in transfusion-related acute lung injury (TRALI). Platelet-derived pro-inflammatory mediators, including soluble CD40 ligand (sCD40L), accumulate during storage. We hypothesized that platelet contamination induces sCD40L generation that causes neutrophil [polymorphonuclear leucocyte (PMN)] priming and PMN-mediated cytotoxicity. MATERIALS AND METHODS: Plasma was untreated, centrifuged (12,500 g) or separated from leucoreduced whole blood (WBLR) prior to freezing. Platelet counts and sCD40L concentrations were measured 1-5 days post-thaw. The plasma was assayed for PMN priming activity and was used in a two-event in vitro model of PMN-mediated human pulmonary microvascular endothelial cell (HMVEC) cytotoxicity. RESULTS: Untreated plasma contained 42±4·2×10(3)/µl platelets, which generated sCD40L accumulation (1·6-eight-fold vs. controls). Priming activity and HMVEC cytotoxicity were directly proportional to sCD40L concentration. WBLR and centrifugation reduced platelet and sCD40L contamination, abrogating the pro-inflammatory potential. CONCLUSION: Platelet contamination causes sCD40L accumulation in stored plasma that may contribute to TRALI. Platelet reduction is potentially the first TRALI mitigation effort in plasma manufacturing.

Cosmological constraints from type ia supernovae peculiar velocity measurements.

We detect the correlated peculiar velocities of nearby type Ia supernovae (SNe), while highlighting an error in some of the literature. We find sigma8 = 0.79 +/- 0.22 from SNe, and examine the potential of this method to constrain cosmological parameters in the future. We demonstrate that a survey of 300 low-z SNe (such as the nearby SNfactory) will underestimate the errors on w by approximately 35% if the coherent peculiar velocities are not included.

Cumulative index of health disorders as an indicator of aging-associated processes in the elderly: results from analyses of the National Long Term Care Survey.

BACKGROUND: We employ an approach based on the elaborated frailty index (FI), which is capable of taking into account variables with mild effect on the aging, health and survival outcomes, and investigate the connections between the FI, chronological age and the aging-associated outcomes in the elderly. METHODS: Cross-sectional analysis of pooled data from the National Long Term Care Survey (NLTCS) assessing health and functioning of the U.S. elderly in 1982, 1984, 1989, 1994, and 1999. RESULTS: Distributions of frequency, residual life span, mortality rate, and relative risk of death are remarkably similar over age and FI. Coefficients of correlation between FI and age are low both for males (0.127, p<.01) and females (0.221, p<.01). The FI-specific age patterns show deceleration at advanced ages. The FI can provide order of magnitude better resolution in estimating mean remaining life span compared to age. Males have smaller FI than females while males' mortality risks are higher. For short-time horizons, the FI and age are largely independently associated with mortality risks. CONCLUSIONS: The FI: (i) can be considered as an adequate sex-specific indicator of the aging-associated processes in the elderly, (ii) can characterize these processes independently of age, and (iii) is a better characteristic of the aging phenotype than chronological age.

A 3-year double-blind, randomized, controlled study on the influence of two oral contraceptives containing either 20 microg or 30 microg ethinylestradiol in combination with levonorgestrel on bone mineral density.

In this first prospective, double-blind, randomized, parallel-group study we evaluated the influence of two combined oral contraceptives on bone mineral density (BMD) and metabolic bone parameters. One dose-reduced preparation contained 20 microg ethinylestradiol (EE) in combination with 100 microg levonorgestrel (LNG) (20/100) was compared with the reference preparation which contained 30 microg EE in combination with 150 microg LNG (30/150). Data from 48 volunteers aged 20-35 years were obtained over an observation period of 36 treatment cycles. The direction of the change (increase or decrease) in all investigated bone-related variables was similar in both treatment groups. As compared to baseline, bone mineral density decreased by 0.4% in the 20/100 group and by 0.8% in the 30/150 group after 36 treatment cycles. These changes were not significantly different between the two treatment groups (p = 0.902). For bone-specific alkaline phosphatase, we measured a mean increase of 55.4% (20/100 group) and of 113.2% (30/150 group) after 36 treatment cycles. The two treatments did not differ statistically significantly (p = 0.522). With respect to cross-linked N-telopeptides (NTx), we detected a decrease of the mean NTx urine concentrations of 21.1% (20/100) and of 13.4% (30/150). These changes also did not significantly differ between the two treatments (p = 0.613). Both study treatments were safe and well-tolerated by all volunteers participating in the study. In conclusion, BMD did not change during the 3-year observation period. Thus, both trial preparations containing either 20 or 30 microg EE in combination with LNG were capable of maintaining BMD in young fertile women. There is no reason to assume that the EE dose reduction had any negative impact on BMD. Because there were no differences in BMD between the treatment groups, it can be assumed that even lower dosages than 20 microg EE might be sufficient for bone protection. Biochemical markers provided evidence for a reduced bone resorption.

Loss of multiple hydrogenosomal proteins associated with organelle metabolism and high-level drug resistance in trichomonads.

Land, K. M., Clemens, D. L., and Johnson, P. J. 2001. Loss of multiple hydrogenosomal proteins associated with organelle metabolism and high-level drug resistance in trichomonads. Experimental Parasitology 97, 102-110. In trichomonads, metronidazole is activated to its cytotoxic form in a specialized energy-producing organelle called the hydrogenosome. Electron transport components in the organelle, pyruvate:ferredoxin oxidoreductase and ferredoxin, donate a single electron to the drug, converting it to a cytotoxic free radical. Previous biochemical analyses of enzyme activities of highly resistant strains of both Trichomonas vaginalis and Tritrichomonas foetus reveal undetectable activity for pyruvate:ferredoxin oxidoreductase and another hydrogenosomal enzyme, hydrogenase. We have chosen to analyze a highly drug-resistant strain of T. foetus and its parental drug-sensitive strain from which it was derived to study the molecular basis for these enzyme defects. Quantitation of pyruvate:ferredoxin oxidoreductase and ferredoxin levels in sensitive and resistant cells shows a marked reduction of these proteins in the resistant strain. RNA analysis reveals an approximately 60% reduction in pyruvate:ferredoxin oxidoreductase mRNA and 90-98% reduction in mRNA levels encoding hydrogenosomal proteins hydrogenase, ferredoxin, and malic enzyme. We have measured the levels of transcription of these genes and observed 60% reduction of pyruvate:ferredoxin oxidoreductase gene transcription and 85% reduction in malic enzyme gene transcription in the resistant strain. The reduction or absence of these organellar proteins is likely to reduce or eliminate the ability of the cell to activate the drug, giving rise to the highly resistant phenotype. Ultrastructural analysis of thin sections revealed that resistant cells are 20% smaller in size and hydrogenosomes in resistant cells are approximately one-third the size of those in the drug-sensitive parental strain. These data suggest that altered gene expression of multiple hydrogenosomal proteins results in the modification of the organelle and leads to drug resistance.

Teaching acute care nurses cognitive assessment using LOCFAS: what's the best method?

The Levels of Cognitive Functioning Assessment Scale (LOCFAS) is a behavioral checklist used by nurses in the acute care setting to assess the level of cognitive functioning in severely brain-injured patients in the early post-trauma period. Previous research studies have supported the reliability and validity of LOCFAS. For LOCFAS to become a more firmly established method of cognitive assessment, nurses must become familiar with and proficient in the use of this instrument. The purpose of this study was to find the most effective method of instruction by comparing three methods: a self-directed manual, a teaching video, and a classroom presentation. Videotaped vignettes of actual brain-injured patients were presented at the end of each training session, and participants were required to categorize these videotaped patients by using LOCFAS. High levels of reliability were observed for both the self-directed manual group and the teaching video group, but an overall lower level of reliability was observed for the classroom presentation group. Examination of the accuracy of overall LOCFAS ratings revealed a significant difference for instructional groups; the accuracy of the classroom presentation group was significantly lower than that of either the self-directed manual group or the teaching video group. The three instructional groups also differed on the average accuracy of ratings of the individual behaviors; the accuracy of the classroom presentation group was significantly lower than that of the teaching video group, whereas the self-directed manual group fell in between. Nurses also rated the instructional methods across a number of evaluative dimensions on a 5-point Likert-type scale. Evaluative statements ranged from average to good, with no significant differences among instructional methods.

A sensitivity analysis of the Bongaarts-Feeney method for adjusting bias in observed period total fertility rates.

Our sensitivity analysis shows that the adjusted TFR'(t) using the formula of Bongaarts and Feeney (1998), which assumes an invariant shape for the fertility schedule, usually does not differ significantly from an adjusted TFR"(t) that allows the shape of the fertility schedule to change at a constant annual rate. Because annual changes in the shape of the fertility schedules often are approximately constant except in abnormal conditions, the Bongaarts-Feeney (B-F) method is generally robust for producing reasonable estimates of the adjusted TFR'(t). The adjusted TFR'(t) neither represents any real cohort experiences from the past nor forecasts any future trend. It merely provides an improved reading of the period fertility measure, which reduces the tempo distortion.

Active life expectancy estimates for the U.S. elderly population: a multidimensional continuous-mixture model of functional change applied to completed cohorts, 1982-1996.

An increment-decrement stochastic-process life table model that continuously mixes measures of functional change is developed to represent age transitions among highly refined disability states interacting simultaneously with mortality. The model is applied to data from the National Long Term Care Surveys of elderly persons in the years 1982 to 1996 to produce active life expectancy estimates based on completed-cohort life tables. At ages 65 and 85, comparisons with extant period estimates for 1990 show that our active life expectancy estimates are larger for both males and females than are extant period estimates based on coarse disability states.

Effects of the status of women on the first-birth interval in Indian urban society.

The status of women, which is relative and multidimensional, has an important bearing on any long-term reduction in fertility. In Indian society, where cohabitation and childbearing are socially sanctioned only after marriage, the length of the first-birth interval affects the completed family size by influencing the spacing and childbearing pattern of a family. This study examines the influence of certain aspects of the status of married women--education, employment, role in family decision making, and age at marriage--along with three socioeconomic variables--per capita income of the family, social position of the household, and the caste system--on the duration of the first-birth interval in an urban Hindu society of the north-east Indian state of Assam. The data were analysed by applying life table and hazard regression techniques. The results indicate that a female's age at marriage, education, current age, role in decision making, and the per capita income of the household are the main covariates that strongly influence the length of the first-birth interval of Hindu females of urban Assam. Of all the covariates studied, a female's education appears to be a key mediating factor, through its influence on her probability of employment outside the home and thereby an earned income and on her role in family decision making. Unlike other Indian communities, the effect of the caste system does not have a significant effect on first-birth timing in this urban Hindu society.

PIP: This study examined determinants of first birth intervals (FBIs) among urban Hindu women in the northeastern state of Assam, India. Explanatory factors include women's status (education, employment, marriage age, role in family decision-making) and socioeconomic factors (family income, social position in the household, and caste). Data were obtained from a survey conducted in Guwati, the capital city of Assam, among 1650 eligible couples in 1991-92. Life table techniques and the guidelines of Rindfuss, Palmore, and Bumpass (1982) were followed to correct for censoring and sample selectivity. Analysis was based on Cox's hazard regression model. Findings indicate that mean age of marriage was about 21 years. Higher mean age at marriage was associated with education, wage earners, belonging to a higher monthly income group, having higher social status, and contributions to all household decisions. Marriage age varied more among low income groups, low status groups, those with little or no education, and those who do not take part in all household decisions. Life table techniques reveal that the median length of the FBI was under 16 months. Only 2% failed to give birth within 97 months of their marriage. In the full model with all 8 covariates, female occupation and position in the caste system did not have significant effects on FBI. Hazards of first births were higher when marriage age was under 17 years. Female education was negatively associated with first birth. Education delays marriage and increases the opportunity for paid employment.

Glial tumors in the MNU rat model: induction of pure and mixed gliomas that do not require typical missense mutations of p53.

Gliomas were induced in adult male Sprague-Dawley rats by continuous exposure to 100 ppm of N-nitrosmethylurea (MNU) in drinking water. Latency periods for such tumors were 20 and 50 weeks following completion of exposure intervals of 20, 15, and 10 weeks, respectively. Based on histomorphology and the pattern of GFAP immunoreactivity, a large percentage of MNU-induced tumors (>40%) were anaplastic mixed gliomas, having both neoplastic astrocytic and oligodendroglial components. Typical oligodendrogliomas and astrocytomas also occurred less frequently. Unlike the majority of tumors induced by ethylnitrosourea (ENU), MNU yielded glial tumors that did not express synaptophysin. Anaplastic mixed gliomas and glioblastoma multiforme (GBMs) had no missense p53 mutations in the commonly mutated exons 4 through 8 and did not overexpress wild-type p53, suggesting that MNU-induced oncogenesis in rat brain tumors may not require inactivation/alteration of the p53 tumor suppressor gene. The K-ras gene was also analyzed and found to have no activating mutations in brain tumors. This model is suitable for studying genetic events leading to the majority of gliomas that apparently express functional p53.