A high and increasing HPV prevalence in tonsillar cancers in Eastern Denmark, 2000–2010: The largest registry‐based study to date

The aim was to explore whether the incidence of tonsillar squamous cell carcinomas (TSCCs) increased in Eastern Denmark, 2000–2010, and whether human papillomavirus (HPV) could explain the increase, and to assess the association of HPV prevalence with gender, age, and origin (i.e., the certainty of tonsillar tumor origin). We applied HPV DNA PCR and p16 immunohistochemistry to all TSCCs registered in the Danish Head and Neck Cancer Group (DAHANCA) and in the Danish Pathology Data Bank (n = 632). Pathologists reviewed and subdivided the tumors into two groups: specified and nonspecified TSCCs. Approximately 10% of HPV‐positive tumors was genotyped by amplicon next‐generation sequencing. The overall crude incidence of TSCCs increased significantly (2.7% per year) and was explained by an increasing incidence of HPV‐positive TSCCs (4.9% per year). The overall HPV prevalence was 58%, with HPV16 being the predominant HPV type. In multivariate analysis, the HPV prevalence was associated with age (<55 vs. >60 years) (OR, 1.72; 95% CI 1.13–2.63) and origin (nonspecified vs. specified TSCCs) (OR, 0.15; 95% CI 0.11–0.22). The association of HPV prevalence with origin increased over time in specified TSCCs (OR per year, 1.10; 95% CI 1.01–1.19), whereas no change over time was observed among nonspecified TSCCs (OR per year, 0.99; 95% CI 0.90–1.08). In conclusion, the observed increase in the number of HPV‐positive TSCCs can explain the increasing number of TSCCs in Eastern Denmark, 2000–2010. HPV prevalence was associated with younger age (<55 years) and a high certainty of tonsillar tumor origin.     

Acute central nervous system toxicity during treatment of pediatric acute lymphoblastic leukemia: phenotypes,risk factors and genotypes

Central nervous system (CNS) toxicity is common at diagnosis and during treatment of pediatric acute lymphoblastic leukemia (ALL). We studied CNS toxicity in 1,464 children aged 1.0–17.9 years, diagnosed with ALL and treated according to the Nordic Society of Pediatric Hematology and Oncology ALL2008 protocol. Genome-wide association studies, and a candidate single-nucleotide polymorphism (SNP; n=19) study were performed in 1,166 patients. Findings were validated in an independent Australian cohort of children with ALL (n=797) in whom two phenotypes were evaluated: diverse CNS toxicities (n=103) and methotrexate-related CNS toxicity (n=48). In total, 135/1,464 (9.2%) patients experienced CNS toxicity for a cumulative incidence of 8.7% (95% confidence interval: 7.31–10.20) at 12 months from diagnosis. Patients aged ≥10 years had a higher risk of CNS toxicity than had younger patients (16.3% vs. 7.4%; P<0.001). The most common CNS toxicities were posterior reversible encephalopathy syndrome (n=52, 43 with seizures), sinus venous thrombosis (n=28, 9 with seizures), and isolated seizures (n=16). The most significant SNP identified by the genome-wide association studies did not reach genomic significance (lowest P-value: 1.11x10^-6), but several were annotated in genes regulating neuronal functions. In candidate SNP analysis, ATXN1 rs68082256, related to epilepsy, was associated with seizures in patients <10 years (P=0.01). ATXN1 rs68082256 was validated in the Australian cohort with diverse CNS toxicities (P=0.04). The role of ATXN1 as well as the novel SNP in neurotoxicity in pediatric ALL should be further explored.     

Increasing crop field size does not consistently exacerbate insect pest problems

Increasing diversity on farms can enhance many key ecosystem services to and from agriculture, and natural control of arthropod pests is often presumed to be among them. The expectation that increasing the size of monocultural crop plantings exacerbates the impact of pests is common throughout the agroecological literature. However, the theoretical basis for this expectation is uncertain; mechanistic mathematical models suggest instead that increasing field size can have positive, negative, neutral, or even nonlinear effects on arthropod pest densities. Here, we report a broad survey of crop field-size effects: across 14 pest species, 5 crops, and 20,000 field years of observations, we quantify the impact of field size on pest densities, pesticide applications, and crop yield. We find no evidence that larger fields cause consistently worse pest impacts. The most common outcome (9 of 14 species) was for pest severity to be independent of field size; larger fields resulted in less severe pest problems for four species, and only one species exhibited the expected trend of larger fields worsening pest severity. Importantly, pest responses to field size strongly correlated with their responses to the fraction of the surrounding landscape planted to the focal crop, suggesting that shared ecological processes produce parallel responses to crop simplification across spatial scales. We conclude that the idea that larger field sizes consistently disrupt natural pest control services is without foundation in either the theoretical or empirical record.

Agroecology suggests that augmenting the diversity of plant communities in working landscapes can enhance biodiversity and a variety of important ecosystem services, including pollination and natural pest control (1–17). The effects of plant diversity are thought to operate across spatial scales. Within a single field, agroecologists have shown that polycultures, mixtures of different crop species grown within a single field, will often enhance the suppression of pest populations (2, 18). At the single-field scale, agroecologists have warned that increasing the spatial extent of single monocultural crops, a consistent feature of the increasing industrialization of farming (3, 14, 19, 20), will worsen pest problems (2, 4, 10, 11, 17, 21). Field size has thus become a proxy for diverse and sustainable production. And finally, at the landscape level, agroecologists have promoted the retention of natural habitat patches, the cultivation of a greater diversity of crop plant species, and the design of landscapes with greater edge densities (2, 4, 7, 9–12, 15, 16).The prediction that larger monocultural fields exacerbate pest problems has a somewhat murky origin (22). Most authors seem to refer this expectation to the general idea that concentrating host plant resources either facilitates their exploitation by specialist herbivores (the resource concentration hypothesis; (23)) or impedes the effective action of natural enemies, which may require a diversity of plants to overwinter or acquire alternate prey, nectar, or pollen (the natural enemies hypothesis; 2, 4, 9, 21, 23). Nonetheless, formal mathematical and simulation models that examine the relationship between crop field size and pest dynamics after explicitly incorporating movement processes, overwintering, and predator-prey interactions do not support the expectation that increasing field size will consistently worsen pest problems. Instead, a variety of outcomes is predicted, with larger fields causing pest populations to either increase, decrease, show no response, or exhibit nonlinear dome- or U-shaped responses (22, 24–27).An extensive experimental literature has established that larger plant patches can have a variety of effects on herbivore densities, with negative and neutral relationships observed as often as positive relationships (9, 24–26, 28–30). But it is unclear whether these experiments, performed only at the very small spatial scales that are tractable for experimentalists, are relevant to the much-larger spatial scales of production agriculture (31). Larger-scale observational studies of patch size effects on herbivores have been reported in natural ecosystems (e.g., 28, 32–35). However, it is again hard to extend these results to agricultural systems, where frequent strong disturbances (e.g., pesticide applications, plowing, and replanting) are likely to amplify the importance of colonization processes relative to in situ birth and death processes.Surprisingly, direct empirical studies of the effect of commercial agricultural field size on pest pressure are rare. A recent elegant study by Gagic et al. (36) in Australian cotton fields confirmed the conventional wisdom that larger fields are associated with higher pest densities, increased pesticide use, and depressed crop yield. However, three other studies in Swedish willow plantations, Israeli citrus groves, and Canadian soybean fields instead found either no effect of larger fields on pest densities (37, 38) or a negative effect on pest densities (39) and a positive effect on predator densities (37).Several studies have also attempted to understand relationships between pests and field size by examining pesticide applications, seemingly confirming the agroecological expectation that more pesticides would be applied on larger fields (10, 11). However, this finding may result from field size shaping pest populations or from field size changing the cost-benefit calculus of pesticide use, independent of pest population densities. Indeed, heavier use of pesticides on larger fields may be favored by reduced per-hectare costs of pesticide applications (economies of scale) or because mobile pests represent a “public bad” that can be managed more effectively by individual farmers on a single-field basis if fields are larger and the speed of pest recolonization from adjacent properties is slowed (40). Because an effect of field size on pest pressure could be registered either by changes in observed pest densities or by changes in pesticide use (5, 41), data on pesticide use are most readily understood when combined with data on underlying pest densities. Patterns of pesticide use are also important in their own right, as pesticide applications are an immediate cost for farmers and a key externality of agricultural production (42).Ultimately, what many view as a core paradigm in agroecology, namely that larger monocultural crop fields worsen the impact of pests, appears to lack clear theoretical or empirical support. To address the paucity of empirical evidence, we compiled several large observational datasets of pest abundances, pesticide applications, and crop yields from commercial agriculture. Together, our datasets encompassed more than 20,000 field years of observations of 14 pest and 1 natural enemy species across both annual and perennial agroecosystems in the United States (cotton and citrus), Peru (potatoes), and Spain (grapes and olives). The pest taxa studied include, for each crop, the arthropod species that generate the greatest economic damage (43–48). Field sizes varied widely both between and within each of the studied cropping systems. Specifically, systems included subsistence farming conducted in very small fields (in Peru, potatoes: median field size = 360 m², range: 50–1,430 m²), agriculture being performed at an intermediate level of intensification (in Spain, grapes: median field size = 41,700 m², range: 600–242.78 × 10⁴ m²; olives: median field size = 62,700 m², range: 50–2.22 × 10⁷ m²), and highly industrialized farming (in California, citrus: median field size = 83,400 m², range: 2,020–57.53 × 10⁴ m²; cotton: median field size = 40.47 × 10⁴ m², range: 4,100–239.98 × 10⁴ m²).Our datasets also include information on field size and the amounts of the focal crop and, for four of the five datasets, natural habitat remnants in the broader landscape. To separate the effects of field size from other potentially correlated aspects of agricultural intensification, we included the identity of the farm (RanchID) or the pest control advisor who had responsibility for pest monitoring and control decisions (TechnicianID) in our statistical models. Finally, our dataset did not include information on smaller landscape elements, such as cover crops, insectary plantings, or hedgerows that are often specifically designed to enhance natural pest control. Thus, our analyses do not address the potential efficacy of these landscape elements.We addressed four questions. First, is the classical expectation for a positive relationship between field size and pest density consistently supported or, instead, are a variety of outcomes (positive, negative, neutral, and nonlinear) observed? Second, how do pesticide application frequencies change as field sizes increase? Third, are crop yields also sensitive to changes in field size? Crop productivity is of central importance both for the agricultural economy and for global food security (4, 5, 9, 42). Fourth, and finally, is there a correlation between pest responses to field size and their responses to amount of the same crop species in the broader, surrounding landscape? Agricultural landscape theory and crop-patch size theory have largely been developed separately; a finding of parallel influences would suggest that common ecological processes may be operating across spatial scales.     

Risks of repeated miscarriage

There is a lack of well-designed epidemiological studies of possible risk factors for repeated miscarriage. In this Swedish population-based case-control study, we investigated the association between sociodemographic and anthropometric factors, obstetric history and life-style factors, with respect to the risks of first-trimester repeated miscarriage. Information on maternal characteristics was collected through in-person interviews. Plasma blood samples were analysed for cotinine and folate concentrations. Adjusted odds ratios (OR) with 95% confidence interval [CI] were used to estimate the relative risk of repeated miscarriage. The risks of repeated miscarriage were increased for women aged > or = 35 years (adjusted OR 2.9 [95% CI 1.4, 5.8]), as well as for women aged < or = 24 years (OR 2.8 [95% CI 1.1, 6.8]). Women with a history of at least one preceding miscarriage prior to the two index pregnancies, women reporting prolonged time to conceive, and women with a history of myoma, faced a more than fourfold increased risk of repeated miscarriage. Smokers were at an increased risk of repeated miscarriage (OR 2.1 [95% CI 1.1, 4.1]). Among non-smoking women with high caffeine intake, there was an increased risk of repeated miscarriage, whereas there was no such association among smokers. Low plasma folate levels were not associated with increased risks.     

Urodynamic biofeedback training for children with bladder-sphincter dyscoordination during voiding

Neurologically normal children with recurrent urinary tract infections (UTIs), night- and daytime wetting, and urge and painful voiding may have staccato voiding due to pelvic floor contractions. The immediate effect of non-invasive urodynamic biofeedback (BF) therapy was assessed using a historical follow-up study in 31 children aged 5–15 years suffering from urodynamically proven overactive urethra during voiding. A long-term follow-up study was performed to investigate whether improvement was maintained. Twenty-four children (77.5%) benefited from the treatment. Of these 16 (51.5%) were cured, while 8 (26%) had a pronounced reduction in their symptoms. Although the flow was normalized in 17 (55%) and nearly normalized in 7 (22.5%), there was no significant correlation between subjective and objective criteria of improvement. Similarly, no relationship was found between the initial urodynamic characteristics and the treatment outcome. During a mean follow-up time of 4 years (range: 1–7.5 years) two of the initially cured patients relapsed. They were recured with a refresher course. Three had had a single or a few episodes of cystitis in the course of several years. Of the patients with pronounced reduction in their symptoms, three relapsed. A refresher course was attempted in two patients; one was successful. It can thus be concluded that BF is an effective way of treating this disturbance and the beneficial effect is to a wide degree maintained.