Sensitivity of Crosswise Model to Simplistic Selection of Nonsensitive Questions: An Application to Estimate Substance Use,Alcohol Consumption and Extramarital Sex Among Iranian College Students

Background: Nonrandomized response (NRR) models are a new generation of surveys for sensitive issues. This study aims to evaluate the validity of estimates from the crosswise model (as one of the efficient models) through employing different response probabilities of nonsensitive questions. Methods: This cross-sectional study was conducted during October and November 2015 among 1777 students of Tabriz University of Medical Sciences. Estimates of monthly alcohol consumption, and at least one instance of illicit drug use and extramarital sex over the last year were determined using direct questioning (DQ) and the Crosswise model (CM). In the last model, the probability of positive response to the nonsensitive questions was determined by using five different methods: uniform distribution (I), Benford’s law (II), and estimations based on data from three other studies (III, IV, V). Results: Crosswise estimates of sensitive behaviors with different probabilities of a positive response to nonsensitive questions differed significantly. For example, estimates of history of using illegal opioids at least once in the last year among men varied significantly from 5.0% to 16.1% with different crosswise models based on the probability of being born in Spring using method I (0.250), III (0.287), IV (0.248), and V (0.310). The model based on Benford’s law (II) was applied to estimate alcohol and cannabis consumption, and its estimates showed significant discrepancy with results of crosswise models I and V. Conclusion: Estimates from crosswise model is highly sensitive to the response probability of nonsensitive questions. It seems that if this question is not selected carefully, the mentioned models will provide overestimates or underestimates, and the more-is-better hypothesis is not always valid. To achieve valid estimates, the exact probability of a positive response to the nonsensitive question must be known for the studied population.     

Towards enhanced community genetic literacy among a minority ethnic community: a participatory action research project

BackgroundInfant mortality is a key public health outcome showing substantial socioeconomic and ethnic inequalities in the UK. The UK Pakistani population has an infant mortality rate of over nine per 1000 livebirths, more than twice that for the population as a whole. Increased risk is partly attributable to rare autosomal recessive genetic disorders linked to the practice of customary consanguineous marriage. WHO recommends community-level action to raise genetic literacy combined with enhanced genetics services. However, UK interventions are in their infancy, with varied local initiatives and no national response. A combination of a valued social practice affecting marginalised communities, complicated patterns of risk, and low professional awareness, makes this a complex and contentious issue. Indeed, some previous intervention has generated considerable backlash. This study in Sheffield, a northern English city, aimed to develop a community-level genetic literacy intervention that would be sensitive and responsive to local information needs.MethodsA participatory approach was used, drawing on a user-centred design and engaging local people as coresearchers. Two phases of insight gathering made use of group discussions, interviews, and participatory exercises to describe current understanding, gaps in knowledge, and trusted networks of communication. A series of testing-and-refinement cycles were then undertaken to coproduce a set of communication materials tailored to subgroups, with materials being tested for acceptability, appeal, and comprehension.FindingsSix local people were trained as coresearchers. Over 200 people participated in the insight and testing work. Information needs and preferred communication channels varied widely, confirming population heterogeneity and diverse perspectives to the issue. Despite some resistance, there was strong demand for information and willingness to discuss the topic. Conveying accurate and consistent information was challenging, as was meeting differing demands for detail within generic materials. Key areas of confusion and mistrust were addressed. Narrative, real life audio (for local radio) and video (for social media) were recommended and developed, supported by factual information in leaflet and website form, and contained links to religious resources plus genetics services.InterpretationDevelopment of appropriate community-level genetic literacy interventions can be achieved through participatory action research. Evaluative work is now needed to assess the effect on knowledge and service uptake.FundingGenetics Disorders UK funded the study. SS is a Senior Research Fellow funded by the National Institute for Health Research (NIHR) School for Public Health Research. Preparatory work was funded by NIHR Collaboration for Leadership in Applied Health Research & Care for South Yorkshire.     

A double‐blind,placebo‐controlled phase II study of the efficacy and safety of 2,2‐dimethylbutyrate (HQK‐1001), an oral fetal globin inducer,in sickle cell disease

This placebo‐controlled phase II study evaluated the pharmacodynamics, efficacy and safety of 2,2‐dimethylbutyrate (HQK‐1001), a fetal globin gene‐inducing short‐chain fatty acid derivative, administered orally at 15 mg/kg twice daily for 48 weeks in 76 subjects with sickle cell disease (SCD). The median age was 26 years (range: 12–55 years) and 37 subjects (49%) were treated previously with hydroxycarbamide. Sixty subjects (79%) had Hb SS and 16 (21%) had S/β⁰ thalassemia. The study was terminated after a planned interim analysis showed no significant increase in fetal hemoglobin (Hb F) and a trend for more pain crises in the HQK‐1001 group. For 54 subjects with Week 24 data, the mean absolute increase in Hb F was 0.9% (95% confidence interval (CI): 0.1–1.6%) with HQK‐1001 and 0.2% (95% CI: ?0.7–1.1%) with placebo. Absolute increases in Hb F greater than 3% were noted in 9 of 38 subjects (24%) administered HQK‐1001 and 1 of 38 subjects (3%) administered placebo. The mean changes in hemoglobin at Week 24 were comparable between the two groups. The mean annualized rate of pain crises was 3.5 with HQK‐1001 and 1.7 with placebo. The most common adverse events in the HQK‐1001 group, usually graded as mild or moderate, consisted of nausea, headache, vomiting, abdominal pain, and fatigue. Additional studies of HQK‐1001 at this dose and schedule are not recommended in SCD. Intermittent HQK‐1001 administration, rather than a daily regimen, may be better tolerated and more effective, as shown previously with arginine butyrate, and warrants further evaluation. Am. J. Hematol. 89:709–713, 2014. © 2014 Wiley Periodicals, Inc.     

Emergent Surgical Pulmonary Embolectomy in a Pregnant Woman: Case Report and Literature Review

Acute pulmonary embolism is a leading cause of death during pregnancy and delivery in the United States. We describe the case of a 25-year-old woman who presented in car-diogenic shock in week 38 of her first pregnancy. After the emergent cesarean delivery of a healthy male neonate, the mother underwent immediate surgical pulmonary embolec-tomy. We confirmed the diagnosis of pulmonary embolism intraoperatively by means of transesophageal echocardiography and removed large clots from the patient''s pulmonary arteries. Mother and child were doing well, 27 months later. In addition to presenting our patient''s case, we discuss the other relevant reports and the options for treating massive pulmonary embolism during pregnancy.     

Low-dose recombinant properdin provides substantial protection against Streptococcus pneumoniae and Neisseria meningitidis infection

Modern medicine has established three central antimicrobial therapeutic concepts: vaccination, antibiotics, and, recently, the use of active immunotherapy to enhance the immune response toward specific pathogens. The efficacy of vaccination and antibiotics is limited by the emergence of new pathogen strains and the increased incidence of antibiotic resistance. To date, immunotherapy development has focused mainly on cytokines. Here we report the successful therapeutic application of a complement component, a recombinant form of properdin (P_n), with significantly higher activity than native properdin, which promotes complement activation via the alternative pathway, affording protection against N. menigitidis and S. pneumoniae. In a mouse model of infection, we challenged C57BL/6 WT mice with N. menigitidis B-MC58 6 h after i.p. administration of P_n (100 µg/mouse) or buffer alone. Twelve hours later, all control mice showed clear symptoms of infectious disease while the P_n treated group looked healthy. After 16 hours, all control mice developed sepsis and had to be culled, while only 10% of P_n treated mice presented with sepsis and recoverable levels of live Meningococci. In a parallel experiment, mice were challenged intranasally with a lethal dose of S. pneumoniae D39. Mice that received a single i.p. dose of P_n at the time of infection showed no signs of bacteremia at 12 h postinfection and had prolonged survival times compared with the saline-treated control group (P < 0.0001). Our findings show a significant therapeutic benefit of P_n administration and suggest that its antimicrobial activity could open new avenues for fighting infections caused by multidrug-resistant neisserial or streptococcal strains.Pneumococcal and meningococcal infectious diseases remain a serious threat to public health. Streptococcus pneumoniae is the leading cause of community-acquired pneumonia and a major cause of otitis media, septicemia, and meningitis (1, 2). S. pneumoniae is responsible for ∼1.2 million deaths per year worldwide, with young children and immunocompromised patients at particular risk (3). Neisseria meningitidis causes epidemic bacterial meningitis and septicemia, with high mortality in children and young adults (4). The impact of meningococcal disease on human health is defined by both the risk and the severity of invasive meningococcal infections, with unacceptably high mortality rates, ranging from 10% in patients under optimal clinical therapy with the latest generation of antibiotics to up to 40% in patients with untreated septicemia. Almost one-third of those who survive invasive infections are left with long-term disabilities and long-term morbidity. Globally, the World Health Organization estimates that ∼1.2 million cases of invasive meningococcal infections occur annually, leading to more than 135,000 fatalities (5).Vaccination programs have reduced the rates of infection in developed countries, but neonates and elderly adults remain especially vulnerable (6, 7). The efficacy of vaccination is further limited by the emergence of new strains of S. pneumoniae and N. meningitidis.The complement system plays a major role in the host resistance to both pathogens (8–13). Complement is activated via three routes: the classical pathway, the lectin pathway, and the alternative pathway. Activation of the classical and lectin pathways is mediated by specific recognition molecules. Binding of C1q to the bacterial surface or the Fc region of antibody initiates the classical pathway. The lectin pathway is initiated by carbohydrate recognition molecules, including mannan-binding lectin, ficolins, and collectin 11, which bind directly to bacterial polysaccharides. Activation of the classical or lectin pathway leads to the formation of a C3 convertase (C4b2a), which splits C3 into the biologically active fragments, C3b and C3a. C3b can bind covalently to an activating surface, and hundreds of molecules of C3b can be deposited in close proximity to the C3 convertase complex. Accumulation of C3b close to C4b2a forms the classical pathway C5 convertase C4b2a(3b)_n, in which C4b and C3b form a binding site for C5, orienting it for cleavage by C2a (14, 15).The mechanisms initiating the alternative pathway are less well understood. It is widely accepted that the alternative pathway maintains a continuous state of low-rate activation, which is held in check by potent negative regulators of activation on nonactivating surfaces, such as the surface of host cells. Turnover of the alternative pathway is initiated either by the provision of C3b via the classical pathway, the lectin pathway, or complement-independent proteolysis of C3 or by the spontaneous hydrolysis of C3 to form C3(H₂O). C3b or C3(H₂O) bind factor B to form either the C3bB or C3(H₂O)B zymogen complex. In this complex, factor B is cleaved by factor D, releasing a Ba fragment. The activated C3bBb or C3(H₂O)Bb fragments are themselves C3 convertases, which in turn cleave more C3 into C3a and C3b. Unchecked, the accumulation of C3b rapidly leads to the formation of more alternative pathway convertase complexes, resulting in a physiologically critical positive feedback mechanism—the amplification loop of complement activation (16). The alternative pathway thus amplifies complement activation initiated by any of the three pathways, making it an attractive target for therapeutic intervention designed to modulate complement-mediated immunity and/or inflammatory processes (17).Deposition of C3b and iC3b on the bacterial surface is a key step in the immune response against S. pneumoniae, because complement-mediated opsonisation is essential for clearance of S. pneumoniae through phagocytosis (8). Lysis of bacteria, owing to formation of the membrane attack complex complex, is the critically important biological activity of complement in the defense against N. meningitidis (10). Inherited or acquired deficiencies of the alternative pathway are associated with a high risk of recurrent bacterial infection. Factor B deficiencies significantly increase the risk of S. pneumoniae and Pseudomonas aeruginosa infection (9, 18). In a mouse model of properdin deficiency, the severity of polymicrobial peritonitis was significantly greater in deficient mice compared with their WT littermates (19). Properdin deficiency in humans has been associated with a high risk of meningococcal infections, especially with unusual infective serotypes, such as W-135 and Y (10, 20, 21). In addition, opsonophagocytosis of S. pneumoniae was found to be severely compromised in properdin-deficient sera, and reconstitution of properdin-deficient sera with purified properdin restored the opsonic activity and killing of S. pneumoniae by polymorphonuclear leukocytes (22, 23).Properdin is the only known positive physiological regulator of complement activation. It stabilizes and extends the half-life of the surface-bound C3 convertase C3bBb, and inhibits its degradation by factor I (24–26). In their pioneering 1954 work, Pillemer et al. (26) first described properdin as a serum protein that mediates complement activation and antimicrobial activity in absence of antibodies.Properdin is present in serum at a concentration of ∼5–15 μg/mL (27). Unlike most other complement components, properdin is not synthesized in the liver but rather is expressed by other cells, including monocytes, T cells, mast cells, and granulocytes (19, 28–30). Properdin monomers can assemble into dimers (P₂), trimers (P₃), and tetramers (P₄), formed by head-to-tail association of monomers (each ∼53 kDa) (31, 32). Properdin aggregates, so-called “activated” properdin (P_n), are considered artificial higher-order oligomers formed during the purification of properdin from plasma or during subsequent freeze–thaw cycles (33). The functional activity of properdin increases with the size of the polymers formed (34). By increasing the half-life of the alternative pathway C3 convertase, properdin antagonizes the functional activity of complement factor H, an abundantly expressed plasma component, which promotes inactivation of the alternative pathway C3 convertase and of all C5 convertases of complement by accelerating the decay of these enzyme complexes through binding to complex-bound C3b and by serving as a cofactor in the factor I-mediated conversion of C3b to its inactive form, termed iC3b (35). Interestingly, the two pathogens used in this study were previously shown to express distinct microbial surface components that sequester factor H from host plasma, leading to resistance to the complement-mediated immune clearance of these pathogens (36, 37).In the present study, we addressed the role of the alternative pathway and the effect of administration of recombinant properdin as a tool for boosting alternative pathway activity to augment the immune response against S. pneumoniae or N. meningitidis.