Malaria is an important cause of global morbidity and mortality. The fact that some people are bitten more often than others has a large effect on the relationship between risk factors and prevalence ...of vector-borne diseases. Here we develop a mathematical framework that allows us to estimate the heterogeneity of infection rates from the relationship between rates of infectious bites and community prevalence. We apply this framework to a large, published data set that combines malaria measurements from more than 90 communities. We find strong evidence that heterogeneous biting or heterogeneous susceptibility to infection are important and pervasive factors determining the prevalence of infection: 20% of people receive 80% of all infections. We also find that individual infections last about six months on average, per infectious bite, and children who clear infections are not immune to new infections. The results have important implications for public health interventions: the success of malaria control will depend heavily on whether efforts are targeted at those who are most at risk of infection.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Genomic analysis of circulating tumor DNA (ctDNA) is increasingly incorporated into the clinical management of patients with advanced cancer. Beyond tumor profiling, ctDNA analysis also can enable ...calculation of circulating tumor fraction (TF), which has previously been found to be prognostic. While most prognostic models in metastatic cancer are tumor type specific and require significant patient-level data, quantification of TF in ctDNA has the potential to serve as a pragmatic, tumor-agnostic prognostic tool.
This study utilized a cohort of patients in a nationwide de-identified clinico-genomic database with metastatic castration-resistant prostate cancer (mCRPC), metastatic breast cancer (mBC), advanced non-small-cell lung cancer (aNSCLC), or metastatic colorectal cancer (mCRC) undergoing liquid biopsy testing as part of routine care. TF was calculated based on single-nucleotide polymorphism aneuploidy across the genome. Clinical, disease, laboratory, and treatment data were captured from the electronic health record. Overall survival (OS) was evaluated by TF level while controlling for relevant covariables.
A total of 1725 patients were included: 198 mCRPC, 402 mBC, 902 aNSCLC, and 223 mCRC. TF ≥10% was highly correlated with OS in univariable analyses for all cancer types: mCRPC hazard ratio (HR) 3.3, 95% confidence interval (CI) 2.04-5.34, P < 0.001, mBC (HR 2.4, 95% CI 1.71-3.37, P < 0.001), aNSCLC (HR 1.68, 95% CI 1.34-2.1, P < 0.001), and mCRC (HR 2.11, 95% CI 1.39-3.2, P < 0.001). Multivariable assessments of TF had similar point estimates and CIs, suggesting a consistent and independent association with survival. Exploratory analysis showed that TF remained consistently prognostic across a wide range of cutpoints.
Plasma ctDNA TF is a pragmatic, independent prognostic biomarker across four advanced cancers with potential to guide clinical conversations around expected treatment outcomes. With further prospective validation, ctDNA TF could be incorporated into care paradigms to enable precision escalation and de-escalation of cancer therapy based on patient-level tumor biology.
•Circulating TF is an independent prognostic factor for most common advanced cancer types in real-world settings.•Prospective interventional validation might enable rational escalation or de-escalation strategies.
Malaria burden is increasing in sub-Saharan cities because of rapid and uncontrolled urbanization. Yet very few studies have studied the interactions between urban environments and malaria. ...Additionally, no standardized urban land-use/land-cover has been defined for urban malaria studies. Here, we demonstrate the potential of local climate zones (LCZs) for modeling malaria prevalence rate (PfPR 2−10) and studying malaria prevalence in urban settings across nine sub-Saharan African cities. Using a random forest classification algorithm over a set of 365 malaria surveys we: (i) identify a suitable set of covariates derived from open-source earth observations; and (ii) depict the best buffer size at which to aggregate them for modeling PfPR 2−10. Our results demonstrate that geographical models can learn from LCZ over a set of cities and be transferred over a city of choice that has few or no malaria surveys. In particular, we find that urban areas systematically have lower PfPR 2−10 (5%-30%) than rural areas (15%-40%). The PfPR 2−10 urban-to-rural gradient is dependent on the climatic environment in which the city is located. Further, LCZs show that more open urban environments located close to wetlands have higher PfPR 2−10. Informal settlements-represented by the LCZ 7 (lightweight lowrise)-have higher malaria prevalence than other densely built-up residential areas with a mean prevalence of 11.11%. Overall, we suggest the applicability of LCZs for more exploratory modeling in urban malaria studies.
Ultrafine particles (UFPs, diameter
<
100
nm) and co-emitted pollutants from traffic are a potential health threat to nearby populations. During summertime in Raleigh, North Carolina, UFPs were ...simultaneously measured upwind and downwind of a major roadway using a spatial matrix of five portable industrial hygiene samplers (measuring total counts of 20–1000
nm particles). While the upper sampling range of the portable samplers extends past the defined “ultrafine” upper limit (100
nm), the 20–1000
nm number counts had high correlation (Pearson
R
=
0.7–0.9) with UFPs (10–70
nm) measured by a co-located research-grade analyzer and thus appear to be driven by the ultrafine range. Highest UFP concentrations were observed during weekday morning work commutes, with levels at 20
m downwind from the road nearly fivefold higher than at an upwind station. A strong downwind spatial gradient was observed, linearly approximated over the first 100
m as an 8% drop in UFP counts per 10
m distance. This result agreed well with UFP spatial gradients estimated from past studies (ranging 5–12% drop per 10
m). Linear regression of other vehicle-related air pollutants measured in near real-time (10-min averages) against UFPs yielded moderate to high correlation with benzene (
R
2
=
0.76), toluene (
R
2
=
0.49), carbon monoxide (
R
2
=
0.74), nitric oxide (
R
2
=
0.80), and black carbon (
R
2
=
0.65). Overall, these results support the notion that near-road levels of UFPs are heavily influenced by traffic emissions and correlate with other vehicle-produced pollutants, including certain air toxics.
Familial adenomatous polyposis (FAP) is a colorectal cancer predisposition syndrome caused by mutations in the adenomatous polyposis coli (APC) gene. Clinical genetic testing fails to identify ...disease causing mutations in up to 20% of clinically apparent FAP cases. Following the inclusion of multiplex ligation‐dependent probe amplification (MLPA) probes specific for APC promoter 1B, seven probands were identified with a deletion of promoter 1B. Using haplotype analysis spanning the APC locus, the seven families appear to be identical by descent from a common founder. The clinical phenotype of 19 mutation carriers is classical FAP with colectomy at an average age of 24. The majority of cases had a large number of duodenal and gastric polyps. Measurements of allele‐specific expression of APC mRNA using TaqMan assay confirmed that relative expression in the allele containing the promoter 1B deletion was reduced 42–98%, depending on tissue type. This study confirms the importance of APC promoter deletions as a cause of FAP and identifies a founder mutation in FAP patients from the United States.
BackgroundClear case definitions of malaria are an essential means of evaluating the effectiveness of present and proposed interventions in malaria. The clinical signs of malaria are nonspecific, and ...parasitemia accompanied by a fever may not be sufficient to define an episode of clinical malaria in endemic areas. We defined and quantified cases of malaria in people of different age groups from 2 areas with different rates of transmission of malaria MethodsA total of 1602 people were followed up weekly for 2 years, and all the cases of fever accompanied by parasitemia were identified. Logistic regression methods were used to derive case definitions of malaria ResultsTwo case definitions of malaria were derived: 1 for children 1–14 years old and 1 for infants (<1 year old) and older children and adults (⩾15 years old). We also found a higher number of episodes of clinical malaria per person per year in people from an area of low transmission of malaria, compared with the number of episodes in those from an area of higher transmission (0.84 vs. 0.55 episodes/person/year; incidence rate ratio, 0.66 95% confidence interval, 0.61–0.72; P<.001) ConclusionsCase definitions of malaria are bound to be altered by factors that affect immunity, such as age and transmission. Case definitions may, however, be affected by other immunity-altering factors, such as HIV and vaccination status, and this needs to be borne in mind during vaccine trials
The contribution of malaria to morbidity and mortality among people in Africa has been a subject of academic interest, political advocacy, and speculation. National statistics for much of sub-Saharan ...Africa have proved to be an unreliable source of disease-specific morbidity and mortality data. Credible estimates of disease-specific burdens are required for setting global and national priorities for health in order to rationalize the use of limited resources and lobby for financial support. We have taken an empirical approach to defining the limits of Plasmodium falciparum transmission across the continent and interpolated the distributions of projected populations in 1995. By combining a review of the literature on malaria in Africa and models of acquired functional immunity, we have estimated the age-structured rates of the fatal, morbid and disabling sequelae following exposure to malaria infection under different epidemiological conditions.
BackgroundThe gene for sickle hemoglobin (HbS) is a prime example of natural selection. It is generally believed that its current prevalence in many tropical populations reflects selection for the ...carrier form (sickle cell trait HbAS) through a survival advantage against death from malaria. Nevertheless, >50 years after this hypothesis was first proposed, the epidemiological description of the relationships between HbAS, malaria, and other common causes of child mortality remains incomplete MethodsWe studied the incidence of falciparum malaria and other childhood diseases in 2 cohorts of children living on the coast of Kenya ResultsThe protective effect of HbAS was remarkably specific for falciparum malaria, having no significant impact on any other disease. HbAS had no effect on the prevalence of symptomless parasitemia but was 50% protective against mild clinical malaria, 75% protective against admission to the hospital for malaria, and almost 90% protective against severe or complicated malaria. The effect of HbAS on episodes of clinical malaria was mirrored in its effect on parasite densities during such episodes ConclusionsThe present data are useful in that they confirm the mechanisms by which HbAS confers protection against malaria and shed light on the relationships between HbAS, malaria, and other childhood diseases
Summary
Objective To evaluate the accuracy of routine malaria microscopy, and appropriate use and interpretation of malaria slides under operational conditions in Kenya.
Methods Cross‐sectional ...survey, using a range of quality of care assessment tools, at government facilities with malaria microscopy in two Kenyan districts of different intensity of malaria transmission. All patients older than 5 years presenting to outpatient departments were enrolled. Two expert microscopists assessed the accuracy of the routine malaria slide results.
Results We analysed 359 consultations performed by 31 clinicians at 17 facilities. Clinical assessment was suboptimal. Blood slide microscopy was performed for 72.7% of patients, who represented 78.5% of febrile patients and 51.3% of afebrile patients. About 95.5% of patients with a positive malaria microscopy result and 79.3% of patients with a negative result received antimalarial treatment. Sulphadoxine–pyremethamine monotherapy was more commonly prescribed for patients with a negative test result (60.7%) than for patients with a positive result (32.4%). Conversely, amodiaquine or quinine were prescribed for only 14.7% of patients with a negative malaria microscopy result compared to 57.7% of patients with a positive result. The prevalence of confirmed malaria was low in both high (10.0%) and low‐(16.3%) transmission settings. Combining data from both settings, the sensitivity of routine microscopy was 68.6%; its specificity, 61.5%; its positive predictive value, 21.6% and its negative predictive value, 92.7%.
Conclusions The potential benefits of microscopy are currently not realised because of the poor quality of routine testing and irrational clinical practices. Ambiguous clinical guidelines permitting treatment of older children and adults with a negative blood slide also undermine rational use of antimalarial drugs.
Objectif Evaluer la précision de la lecture des lames et de l'interprétation des résultats dans la microscopie de la malaria sous des conditions opérationnelles.
Méthodes Etude transversale basée sur une série d'outils d’évaluation de la qualité de la prise en charge dans des services gouvernementaux réalisant une microscopie pour la malaria, dans deux districts du Kenya avec différentes intensités de la transmission de la malaria. Tous les patients de plus de 5 ans se présentant dans le département des patients ambulatoires ont été inclus dans l’étude.
Résultats 359 consultations ont été réalisées par 31 cliniciens dans 17 services. L’évaluation clinique était sub‐optimale. Une microscopie de frottis sanguin a été effectuée pour 72,7% des patients représentant 78,5% des patients fébriles et 51,3% des patients non fébriles. 95,5% des patients avec frottis microscopiquement positif et 79,3% des patients avec un frottis négatif ont reçu un traitement antimalarique. La monothérapie à sulphadoxine‐pyremethamine était plus couramment prescrite pour les patients avec un test négatif (60,7%) que pour les patients avec un test positif (32,4%). Cependant, l'amodiaquine ou la quinine était prescrite chez seulement 14,75% des patients avec un test négatif comparéà 57,7% des patients avec un test positif. La prévalence de malaria confirmée était faible autant dans la région à haute (10,0%) que dans celle à faible (16,3%) transmission de la malaria. D'après les données combinées des deux endroits, la sensitibilité de la microscopie en routine était de 68,6%, sa spécificité 61,5%; sa valeur prédictive positive 21,6% et sa valeur prédictive négative 92,7%.
Conclusion Les bénéfices potentiels de la microscopie ne sont pas actuellement atteints à cause de la faible qualité du test de routine. En plus, les directives cliniques ambiguës pour le traitement des enfants moins jeunes et des adultes à frottis sanguins négatifs compromettent l'usage rationnel des médicaments antifébriles.
Objetivo Evaluar la exactitud de la lectura por microscopía de láminas para malaria, y la interpretación correcta de los resultados, bajo condiciones operacionales en Kenia.
Métodos Estudio croseccional, utilizando una serie de herramientas para evaluar la calidad, en centros gubernamentales con microscopía para malaria en dos distritos de Kenia con diferente intensidad de transmisión de malaria. Todos los pacientes de más de 5 años que se presentaron en consultas externas fueron incluidos en el estudio. Dos microscopistas expertos evaluaron la exactitud de los resultados de las lecturas de rutina de las láminas.
Resultados Analizamos 359 consultas realizadas por 31 clínicos en 17 centros. La evaluación clínica fue deficiente: se realizaron láminas a 72.7% de los pacientes, que representaban un 78.5% de los pacientes con fiebre y 51.3% de los pacientes sin fiebre. Un 95.5% de los pacientes con un resultado positivo en la lectura de la lámina por microscopía y un 79.3% de los pacientes con un resultado negativo, recibieron tratamiento antimalárico. La monoterapia con sufadoxina‐pirimetamina más comúnmente prescrita a pacientes con una resultado negativo en la lectura de la lámina (60.7%) que a pacientes con un resultado positivo (32.4%). Por otro lado, la amodiaquina o la quinina fueron prescritas a solo un 14.7% de los pacientes con un resultado negativo por microscopía, comparado con un 57.7% de los pacientes con un resultado positivo. La prevalencia de malaria confirmada fue baja, tanto en áreas de alta (10.0%) como de baja (16.3%) transmisión. Al combinar los datos de ambos lugares, la sensibilidad de la microscopía de rutina fue del 68.6%; la especificidad del 61.5%; su valor predictivo positivo, 21.6% y su valor predictivo negativo, 92.7%.
Conclusiones Los beneficios potenciales de la microscopía no son actualmente evidentes debido a la mala calidad de las pruebas de rutina. Unas guías clínicas ambiguas que permiten el tratamiento de niños mayores y adultos con una lámina negativa, también debilitan el uso racional de los medicamentos para malaria.
Abstract
The violation of baryon number,
B
, is an essential ingredient for the preferential creation of matter over antimatter needed to account for the observed baryon asymmetry in the Universe. ...However, such a process has yet to be experimentally observed. The HIBEAM/NNBAR program is a proposed two-stage experiment at the European Spallation Source to search for baryon number violation. The program will include high-sensitivity searches for processes that violate baryon number by one or two units: free neutron–antineutron oscillation (
n
→
n
̄
) via mixing, neutron–antineutron oscillation via regeneration from a sterile neutron state (
n
→
n
′
,
n
̄
′
→
n
̄
), and neutron disappearance (
n
→
n
′); the effective
Δ
B
=
0
process of neutron regeneration (
n
→
n
′
,
n
̄
′
→
n
) is also possible. The program can be used to discover and characterize mixing in the neutron, antineutron and sterile neutron sectors. The experiment addresses topical open questions such as the origins of baryogenesis and the nature of dark matter, and is sensitive to scales of new physics substantially in excess of those available at colliders. A goal of the program is to open a discovery window to neutron conversion probabilities (sensitivities) by up to three orders of magnitude compared with previous searches. The opportunity to make such a leap in sensitivity tests should not be squandered. The experiment pulls together a diverse international team of physicists from the particle (collider and low energy) and nuclear physics communities, while also including specialists in neutronics and magnetics.
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