The clinical spectrum of HbSC sickle cell disease-not a benign condition.

Sickle cell disease (SCD) includes a group of heterogenous disorders that result in significant morbidities. HbSS is the most common type of SCD and HbSC is the second most common type of SCD. The prevalence of HbSC disease in the United States and United Kingdom is ~1 in 7174 births and 1 in 6174 births respectively. Despite its frequency, however, HbSC disease has been insufficiently studied and was historically categorized as a more 'mild' form of SCD. We conducted this study of HbSC disease as part of the NHLBI funded Sickle Cell Disease Implementation Consortium (SCDIC). The SCDIC registry included 2282 individuals with SCD, ages 15-45 years of whom 502 (22%) had HbSC disease. Compared with people with sickle cell anaemia (SCA), the study found that people with HbSC disease had a higher frequency of splenomegaly (n (%) = 169 (33.7) vs. 392 (22.1)) and retinopathy (n (%) = 116 (23.1) vs. 189 (10.6)). A Many people with HbSC also had avascular necrosis (n (%) = 112 (22.3)), pulmonary embolism (n (%) = 43 (8.6)) and acute chest syndrome (n (%) = 228 (45.4)) demonstrating significant disease severity. HbSC disease is more clinically severe than was previously recognized and deserves additional evaluation and targeted treatments.

Infectious Disease Dynamics Inferred from Genetic Data via Sequential Monte Carlo.

Genetic sequences from pathogens can provide information about infectious disease dynamics that may supplement or replace information from other epidemiological observations. Most currently available methods first estimate phylogenetic trees from sequence data, then estimate a transmission model conditional on these phylogenies. Outside limited classes of models, existing methods are unable to enforce logical consistency between the model of transmission and that underlying the phylogenetic reconstruction. Such conflicts in assumptions can lead to bias in the resulting inferences. Here, we develop a general, statistically efficient, plug-and-play method to jointly estimate both disease transmission and phylogeny using genetic data and, if desired, other epidemiological observations. This method explicitly connects the model of transmission and the model of phylogeny so as to avoid the aforementioned inconsistency. We demonstrate the feasibility of our approach through simulation and apply it to estimate stage-specific infectiousness in a subepidemic of human immunodeficiency virus in Detroit, Michigan. In a supplement, we prove that our approach is a valid sequential Monte Carlo algorithm. While we focus on how these methods may be applied to population-level models of infectious disease, their scope is more general. These methods may be applied in other biological systems where one seeks to infer population dynamics from genetic sequences, and they may also find application for evolutionary models with phenotypic rather than genotypic data.

Pertussis immunity and epidemiology: mode and duration of vaccine-induced immunity.

The resurgence of pertussis in some countries that maintain high vaccination coverage has drawn attention to gaps in our understanding of the epidemiological effects of pertussis vaccines. In particular, major questions surround the nature, degree and durability of vaccine protection. To address these questions, we used mechanistic transmission models to examine regional time series incidence data from Italy in the period immediately following the introduction of acellular pertussis (aP) vaccine. Our results concur with recent animal-challenge experiments wherein infections in aP-vaccinated individuals proved as transmissible as those in naive individuals but much less symptomatic. On the other hand, the data provide evidence for vaccine-driven reduction in susceptibility, which we quantify via a synthetic measure of vaccine impact. As to the precise nature of vaccine failure, the data do not allow us to distinguish between leakiness and waning of vaccine immunity, or some combination of these. Across the range of well-supported models, the nature and duration of vaccine protection, the age profile of incidence and the range of projected epidemiological futures differ substantially, underscoring the importance of the remaining unknowns. We identify key data gaps: sources of data that can supply the information needed to eliminate these remaining uncertainties.

Evaluating the implementation of a multi-level mHealth study to improve hydroxyurea utilization in sickle cell disease.

Background: Sickle Cell Disease (SCD) is a progressive genetic disease that causes organ damage and reduces longevity. Hydroxyurea is an underutilized evidence-based medication that reduces complications and improves survival in SCD. In a multi-site clinical trial, part of the NIH-funded Sickle Cell Disease Implementation Consortium (SCDIC), we evaluate the implementation of a multi-level and multi-component mobile health (mHealth) patient and provider intervention to target the determinants and context of low hydroxyurea use. Given the complexity of the intervention and contextual variability in its implementation, we combined different behavioral and implementation theories, models, and frameworks to facilitate the evaluation of the intervention implementation. In this report, we describe engagement with stakeholders, planning of the implementation process, and final analytical plan to evaluate the implementation outcomes. Methods: During 19 meetings, a 16-member multidisciplinary SCDIC implementation team created, conceived, and implemented a project that utilized Intervention Mapping to guide designing an intervention and its evaluation plan. The process included five steps: (1) needs assessment of low hydroxyurea utilization, (2) conceptual framework development, (3) intervention design process, (4) selection of models and frameworks, and (5) designing evaluation of the intervention implementation. Results: Behavioral theories guided the needs assessment and the design of the multi-level mHealth intervention. In designing the evaluation approach, we combined two implementation frameworks to best account for the contextual complexity at the organizational, provider, and patient levels: (1) the Consolidated Framework for Implementation Research (CFIR) that details barriers and facilitators to implementing the mHealth intervention at multiple levels (users, organization, intervention characteristics, broader community), and (2) the Technology Acceptance Model (TAM), a conceptual model specific for explaining the intent to use new information technology (including mHealth). The Reach Effectiveness Adoption Implementation and Maintenance (RE-AIM) framework was used to measure the outcomes. Discussion: Our research project can serve as a case study of a potential approach to combining different models/frameworks to help organize and plan the evaluation of interventions to increase medication adherence. The description of our process may serve as a blueprint for future studies developing and testing new strategies to foster evidence-based treatments for individuals living with SCD.

American Society of Hematology 2020 guidelines for sickle cell disease: prevention, diagnosis, and treatment of cerebrovascular disease in children and adults.

BACKGROUND: Central nervous system (CNS) complications are among the most common, devastating sequelae of sickle cell disease (SCD) occurring throughout the lifespan. OBJECTIVE: These evidence-based guidelines of the American Society of Hematology are intended to support the SCD community in decisions about prevention, diagnosis, and treatment of the most common neurological morbidities in SCD. METHODS: The Mayo Evidence-Based Practice Research Program supported the guideline development process, including updating or performing systematic evidence reviews. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, including GRADE evidence-to-decision frameworks, to assess evidence and make recommendations. RESULTS: The panel placed a higher value on maintaining cognitive function than on being alive with significantly less than baseline cognitive function. The panel developed 19 recommendations with evidence-based strategies to prevent, diagnose, and treat CNS complications of SCD in low-middle- and high-income settings. CONCLUSIONS: Three of 19 recommendations immediately impact clinical care. These recommendations include: use of transcranial Doppler ultrasound screening and hydroxyurea for primary stroke prevention in children with hemoglobin SS (HbSS) and hemoglobin Sß0 (HbSß0) thalassemia living in low-middle-income settings; surveillance for developmental delay, cognitive impairments, and neurodevelopmental disorders in children; and use of magnetic resonance imaging of the brain without sedation to detect silent cerebral infarcts at least once in early-school-age children and once in adults with HbSS or HbSß0 thalassemia. Individuals with SCD, their family members, and clinicians should become aware of and implement these recommendations to reduce the burden of CNS complications in children and adults with SCD.

Lattice effects observed in chaotic dynamics of experimental populations.

Animals and many plants are counted in discrete units. The collection of possible values (state space) of population numbers is thus a nonnegative integer lattice. Despite this fact, many mathematical population models assume a continuum of system states. The complex dynamics, such as chaos, often displayed by such continuous-state models have stimulated much ecological research; yet discrete-state models with bounded population size can display only cyclic behavior. Motivated by data from a population experiment, we compared the predictions of discrete-state and continuous-state population models. Neither the discrete- nor continuous-state models completely account for the data. Rather, the observed dynamics are explained by a stochastic blending of the chaotic dynamics predicted by the continuous-state model and the cyclic dynamics predicted by the discrete-state models. We suggest that such lattice effects could be an important component of natural population fluctuations.

Age-structure and transient dynamics in epidemiological systems.

Mathematical models of childhood diseases date back to the early twentieth century. In several cases, models that make the simplifying assumption of homogeneous time-dependent transmission rates give good agreement with data in the absence of secular trends in population demography or transmission. The prime example is afforded by the dynamics of measles in industrialized countries in the pre-vaccine era. Accurate description of the transient dynamics following the introduction of routine vaccination has proved more challenging, however. This is true even in the case of measles which has a well-understood natural history and an effective vaccine that confers long-lasting protection against infection. Here, to shed light on the causes of this problem, we demonstrate that, while the dynamics of homogeneous and age-structured models can be qualitatively similar in the absence of vaccination, they diverge subsequent to vaccine roll-out. In particular, we show that immunization induces changes in transmission rates, which in turn reshapes the age distribution of infection prevalence, which effectively modulates the amplitude of seasonality in such systems. To examine this phenomenon empirically, we fit transmission models to measles notification data from London that span the introduction of the vaccine. We find that a simple age-structured model provides a much better fit to the data than does a homogeneous model, especially in the transition period from the pre-vaccine to the vaccine era. Thus, we propose that age structure and heterogeneities in contact rates are critical features needed to accurately capture transient dynamics in the presence of secular trends.

Commentary: resolving pertussis resurgence and vaccine immunity using mathematical transmission models.

The epidemiology of pertussis-a vaccine-preventable respiratory infection typically caused by the bacterium Bordetella pertussis-remains puzzling. Indeed, the disease seems nowhere close to eradication and has even re-emerged in certain countries-such as the US-that have maintained high vaccination coverage. Because the dynamics of pertussis are shaped by past vaccination and natural infection rates, with the relevant timescale spanning decades, the interpretation of such unexpected trends is not straightforward. In this commentary, we propose that mathematical transmission models play an essential role in helping to interpret the data and in closing knowledge gaps in pertussis epidemiology. We submit that recent advances in statistical inference methods now allow us to estimate key parameters, such as the nature and duration of vaccinal immunity, which have to date been difficult to quantify. We illustrate these points with the results of a recent study based on data from Massachusetts (Domenech de Cellès, Magpantay, King, and Rohani, Sci. Transl. Med. 2018;10: eaaj1748. doi:10.1126/scitranslmed.aaj1748), in which we used such methods to elucidate the mechanisms underlying the ongoing resurgence of pertussis. In addition, we list a number of safety checks that can be used to critically assess mathematical models. Finally, we discuss the remaining uncertainties surrounding pertussis vaccines, in particular the acellular vaccines used for teenage booster immunizations.

Mouse GATA-4: a retinoic acid-inducible GATA-binding transcription factor expressed in endodermally derived tissues and heart.

We report the cDNA cloning and characterization of mouse GATA-4, a new member of the family of zinc finger transcription factors that bind a core GATA motif. GATA-4 cDNA was identified by screening a 6.5-day mouse embryo library with oligonucleotide probes corresponding to a highly conserved region of the finger domains. Like other proteins of the family, GATA-4 is approximately 50 kDa in size and contains two zinc finger domains of the form C-X-N-C-(X17)-C-N-X-C. Cotransfection assays in heterologous cells demonstrate that GATA-4 trans activates reporter constructs containing GATA promoter elements. Northern (RNA) analysis and in situ hybridization show that GATA-4 mRNA is expressed in the heart, intestinal epithelium, primitive endoderm, and gonads. Retinoic acid-induced differentiation of mouse F9 cells into visceral or parietal endoderm is accompanied by increased expression of GATA-4 mRNA and protein. In vitro differentiation of embryonic stem cells into embryoid bodies is also associated with increased GATA-4 expression. We conclude that GATA-4 is a tissue-specific, retinoic acid-inducible, and developmentally regulated transcription factor. On the basis of its tissue distribution, we speculate that GATA-4 plays a role in gene expression in the heart, intestinal epithelium, primitive endoderm, and gonads.

Monte Carlo profile confidence intervals for dynamic systems.

Monte Carlo methods to evaluate and maximize the likelihood function enable the construction of confidence intervals and hypothesis tests, facilitating scientific investigation using models for which the likelihood function is intractable. When Monte Carlo error can be made small, by sufficiently exhaustive computation, then the standard theory and practice of likelihood-based inference applies. As datasets become larger, and models more complex, situations arise where no reasonable amount of computation can render Monte Carlo error negligible. We develop profile likelihood methodology to provide frequentist inferences that take into account Monte Carlo uncertainty. We investigate the role of this methodology in facilitating inference for computationally challenging dynamic latent variable models. We present examples arising in the study of infectious disease transmission, demonstrating our methodology for inference on nonlinear dynamic models using genetic sequence data and panel time-series data. We also discuss applicability to nonlinear time-series and spatio-temporal data.

The expression of Streptomyces and Escherichia coli drug-resistance determinants cloned into the Streptomyces phage phi C31.

Lysogens obtained by infecting Streptomyces albus G with a phi C31-pBR322 chimaeric prophage or its delta W12 deletion derivative had increased tetracycline resistance. The ability of the delta W12 derivative to transduce tetracycline resistance was inactivated by inserting a viomycin resistance determinant (vph) into the BamHI site of the pBR322 tet gene, and restored by excising the vph gene. Another deletion mutant (delta W17) of the chimaera, carrying an intact tet gene, was normally unable to transduce tetracycline resistance. This inability was correlated with the finding, by Southern hybridisation analysis, that the att site required for insertion of phi C31 prophage into the host chromosome was located within the delta W17 deletion. Use of phi C31 lysogenic recipient permitted the integration of the att-deleted phage, presumably by homologous recombination, giving tetracycline-resistant double lysogens. This technique was extended to S. coelicolor A3(2) in the detection of derivatives of the att-deleted phage into which a thiostrepton-resistance determinant (tsr) had been inserted in vitro. Phage released from double lysogens were mainly recombinants. One such recombinant is a PstI vector for DNA cloning, able to accommodate up to 6 kb of introduced DNA.

Malignant peripheral nerve sheath tumors in neurofibromatosis 1.

One of the most clinically aggressive cancers associated with neurofibromatosis 1 (NF1) is the malignant peripheral nerve sheath tumor (MPNST). To determine the incidence and relative risk (RR) of MPNSTs in individuals with NF1, 1,475 individuals with NF1 were included from a cohort of patients examined by a single experienced geneticist from 1977 to 1996. The end points were incidence of MPNST, relative risk of MPNST, and relative risk associated with specific NF1 physical findings. Thirty-four individuals were identified with MPNST (2%). The relative risk of MPNST was higher than expected with an RR value of 113 (95% confidence interval [CI] = 78-158). The average 10-year annual incidence of MPNST between the second and fifth decade of life was roughly the same with a range of 0.0013 and 0.0068 MPNST per patient year. Most lesions occurred in the limbs (n = 18; 53%), and those with limb lesions survived longer than those with nonlimb MPNSTs. Pain associated with a mass was the greatest risk factor associated with MPNST development (RR = 31.4; 95% CI = 13.2-75.1). Further biological and epidemiological studies are needed to determine other factors that influence the risk of MPNST development in individuals affected with NF1. Am. J. Med. Genet. 93:388-392, 2000. Published 2000 Wiley-Liss, Inc.

Hypoglycemia in Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome associated with macrosomia, macroglossia, abdominal wall defects, hypoglycemia in the neonatal period and embryonal cancers of infancy and early childhood. The frequency of hypoglycemia in this population is between 30% and 50%. The majority of infants with hypoglycemia will be asymptomatic and have resolution of the hypoglycemia within the first 3 days of life. Less than 5% will have hypoglycemia beyond the neonatal period requiring either continuous feeding or a partial pancreatectomy. The cause of hypoglycemia is unclear, but direct and indirect evidence supports a hyperinsulinemia as the major factor. Recent identification of the majority of genes associated with BWS in the 11p15 region and the genotype of persistent hyperinsulinemia hypoglycemia of childhood also in the 11p15 region may provide a molecular basis for hypoglycemia in BWS, particularly for the occasional patients with hypoglycemia requiring a partial pancreatectomy. Detailed genotype phenotype evaluations are needed and should provide an insight as to why patients with BWS have hypoglycemia.

Rabies and mortality in Ethiopian wolves (Canis simensis).

Between October 1991 and February 1992, 41 of 53 known adult and subadult Ethiopian wolves (Canis simensis) in five adjacent packs in the Bale Mountains National Park, Ethiopia, died or disappeared. Brain smears from two carcasses were positive for rabies by the immunofluorescence test, and rabies virus was isolated from the brains by mouse inoculation. Based on monoclonal antibody tests on the mouse brains, we identified the virus as a minor variant of the serotype 1 rabies viruses found in domestic dogs and wild canids of Africa. Sera from two of 15 Ethiopian wolves had rabies virus neutralizing antibody.

Efficacy of SAD (Berne) rabies vaccine given by the oral route in two species of jackal (Canis mesomelas and Canis adustus).

Eight black-backed jackals (Canis mesomelas) and seven side-striped jackals (Canis adustus) were given SAD (Berne) rabies vaccine by direct oral instillation. Three different vaccine doses were used: 10(6.3), 10(6.8) and 10(7.5) median tissue culture infectious doses. Two additional jackals were given vaccine in chicken heads. One group of jackals was challenged with a lethal dose of jackal-derived rabies virus 1 mo after vaccination and a second group 12 mo after vaccination. All 17 vaccinated jackals developed high and persistent serum neutralizing antibody titers. All challenged jackals resisted a lethal dose of rabies virus, whereas three control jackals given the same challenge succumbed to rabies.

Monoclonal antibody studies on rabies-related viruses.

Rabies and rabies-related viruses are divided into four serotypes, although it has been suggested that the inclusion of European bat lyssaviruses results in six genotypes. Sixty-four rabies-related viruses were tested against a panel of 36 anti-nucleocapsid monoclonal antibodies prepared from the immunization of Balb/c mice with five prototypic rabies-related viruses. Reaction patterns obtained confirmed the original distinction between serotype 1-4 viruses and revealed multiple variants of Lagos bat and Mokola viruses. In addition, two biotypes of European bat lyssavirus were identified and a clear distinction was shown between these biotypes and Duvenhage virus of Africa. The origins and importance of the rabies-related viruses are discussed.

Canid and viverrid rabies viruses in South Africa.

Historical records suggest that in South Africa rabies was present in viverrids in the early 1800s. In the early 1950s a wave of canine rabies spread from Namibia through Botswana into the northern Transvaal and by 1961 a second front had penetrated south from Mozambique into Swaziland and northern Natal. Today, rabies is regularly confirmed in a number of canid and viverrid species in most regions of South Africa. A panel of anti-nucleoprotein monoclonal antibodies was used to examine 83 virus isolates from these species. Two major reaction patterns, one chiefly confined to viruses from canids and the other to viruses from viverrids, were obtained. In addition, some variation in the reaction patterns of viverrid viruses was observed and spill-over of viverrid virus into canids and vice versa was recorded. Rabies in South Africa appears to behave as two distinct disease entities.

Rabies in the Masai Mara, Kenya: preliminary report.

A serosurvey of rabies antibodies among domestic dogs (Canis familiaris, n = 178), spotted hyaenas (Crocuta crocuta, n = 72) and African wild dogs (Lycaon pictus, n = 18) of the Masai Mara, Kenya, was carried out. Rabies antibodies were found in 9.6% of the domestic dog sera, but all wild dog and hyaena sera were negative. Rabies has been confirmed in this region among the above species as well as in a domestic cat (Felis catus) and a cow (Bos indicus) by fluorescent antibody tests (FAT) and/or histopathology. The disease was confirmed in three wild dogs in 1989 and in a fourth dog in early 1991. In 1992, a spotted hyaena attacked six people, one of whom died; the hyaena brain was positive for rabies. To date, rabies has been confirmed in one domestic cow (n = 22; 4.5%), one domestic cat (n = 9; 11.1%) and five domestic dogs (n = 32; 15.6%). The wild dog cases exhibited paralytic rabies whereas in the hyaena, domestic cat and domestic dogs furious rabies was observed. The dynamics of rabies in this ecosystem is not yet fully understood, but based on these preliminary data it is suspected that domestic dogs play a primary role in its maintenance.

Aspects of rabies infection and control in the conservation of the African wild dog (Lycaon pictus) in the Serengeti region, Tanzania.

Lycaon pictus is amongst the most endangered wildlife species in Africa. In 1990 rabies virus was isolated from the brain of an adult Lycaon found dead in the Serengeti region of Tanzania. One adult and six pups of the same pack feeding on the carcass showed clinical signs and rabies was suspected; within two days they had disappeared and are presumed to have died. Subsequently, two Lycaon packs in the Serengeti National Park were given inactivated rabies vaccine either by dart or by parenteral inoculation following anaesthesia. Lycaon sera which had been collected over the previous two years and sera collected pre- and post-vaccination were examined for the presence of rabies virus neutralizing antibody. Three of 12 unvaccinated Lycaon had antibody levels > 0.5 IU/ml; post-vaccination samples from two Lycaon showed increased antibody levels. Between four and ten months post-vaccination, at least four of the vaccinated animals had died from unknown causes. Issues relating to wildlife vaccination and veterinary intervention in conservation are discussed.

Ten-year survey of British bats for the existence of rabies.

In 1985, a notable increase in the number of recorded cases of rabies in European bats was observed, indicating a possible spread of the rabies virus in these bats. Because of concern that the disease could be introduced into the United Kingdom by bats crossing from mainland Europe, a programme of screening dead bats for the presence of rabies and rabies-related viruses was initiated at the Rabies Research and Diagnostic Unit at the Central Veterinary Laboratory. Over a period of 10 years (January 1986 to December 1995), 1882 bats belonging to 23 species from all parts of England, Scotland and Wales have been screened for rabies antigen. All of these bats were found to be negative. Forty-one serotine bats (Eptesicus serotinus), the species of bat most commonly infected in Europe, were included in the total. Subsequent to this survey, in June 1996, a European bat lyssavirus 2 was isolated from a Daubenton's bat (Myotis daubentonii) in Newhaven, East Sussex. It is possible that this bat originated from mainland Europe but this cannot be established with certainty.