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Abstract Background Gut microbes are important to the health and fitness of many animals. Many factors have been shown to affect gut microbial communities including diet, lifestyle, and age. Most animals have very complex physiologies, lifestyles, and microbiomes, making it virtually impossible to disentangle what factors have the largest impact on microbiota composition. Honeybees are an excellent model to study host-microbe interactions due to their relatively simple gut microbiota, experimental tractability, and eusociality. Worker honey bees have distinct gut microbiota from their queen mothers despite being close genetic relatives and living in the same environment. Queens and workers differ in numerous ways including development, physiology, pheromone production, diet, and behavior. In the prolonged absence of a queen or Queen Mandibular Pheromones (QMP), some but not all workers will develop ovaries and become “queen-like”. Using this inducible developmental change, we aimed to determine if diet and/or reproductive development impacts the gut microbiota of honey bee workers. Results Microbiota-depleted newly emerged workers were inoculated with a mixture of queen and worker gut homogenates and reared under four conditions varying in diet and pheromone exposure. Three weeks post-emergence, workers were evaluated for ovary development and their gut microbiota communities were characterized. The proportion of workers with developed ovaries was increased in the absence of QMP but also when fed a queen diet (royal jelly). Overall, we found that diet, rather than reproductive development or pheromone exposure, led to more “queen-like” microbiota in workers. However, we revealed that diet alone cannot explain the microbiota composition of workers. Conclusion The hypothesis that reproductive development explains microbiota differences between queens and workers was rejected. We found evidence that diet is one of the main drivers of differences between the gut microbial community compositions of queens and workers but cannot fully explain the distinct microbiota of queens. Thus, we predict that behavioral and other physiological differences dictate microbiota composition in workers and queens. Our findings not only contribute to our understanding of the factors affecting the honey bee microbiota, which is important for bee health, but also illustrate the versatility and benefits of utilizing honeybees as a model system to study host-microbe interactions.

Abstract Background Acute low energy pubic rami fractures in the elderly receive primarily conservative treatment. There is debate to what extent posterior ring involvement, which is detected superiorly by CT compared to X-ray, has an impact on outcome and may require modified treatment. We want to demonstrate if posterior ring involvement has an influence on different types of outcome in primarily conservatively treated acute FFP, questioning the usefulness of early CT. Additionally we analysed the early fracture pattern in cases where conservative treatment failed with need for secondary surgery. Methods A retrospective cohort study of 155 consecutive patients, recruited between 2009 and 2016, aged over 65 years diagnosed with an acute LE-PFr on X-ray at the emergency department of a single, level-one trauma centre and receiving an early CT. A set of outcome parameters was compared between patients with an isolated pubic rami fracture (CTia) and patients who had a combined posterior pelvic ring fracture (CTcp). Results There were 155 patients of whom 85.2% were female with a mean age of 83 years. 76.8% of patients living at home returned home and 15.5% moved to a nursing home. Mortality rate during hospitalisation was 6.4% and 14.8% at one year post-trauma. Secondary fracture displacement occurred in 22.6%. Secondary surgery was performed in 6 cases (3.9%). Median hospitalisation length of stay was 21 days (range 0 to 112 days). There was no significant association between the subgroups and change in residential status (p = 0.65), complications during hospitalisation (p = 0.75), mortality rate during admission (p = 0.75) and at 1 year (p = 0.88), readmission within 30 days (p = 0.46) and need for secondary surgery (p = 0.2). There was a significant increased median length of stay (p = 0.011) and rate of secondary displacement (p = 0.015) in subgroup CTcp. Secondary displacement had no impact on in-hospital complications (p = 0.7) nor mortality rate during admission (p = 0.79) or at 1 year (0.77). Early CT in patients who underwent secondary surgery showed stable B2.1 lesions in 4 of 6 cases. Conclusions Our data suggest that early CT in patients with conservatively treated acute LE-PFr in order to detect posterior lesions, has limited value in predicting failure of conservative treatment.

Abstract Background There exists a vast number of surgical treatment options for acromioclavicular (AC) joint injuries, and the current literature has yet to determine an equivocally superior treatment. AC joint repair has a long history and dates back to the beginning of the twentieth century. Main body Since then, over 150 different techniques have been described, covering open and closed techniques. Low grade injuries such as Type I-II according to the modified Rockwood classification should be treated conservatively, while high-grade injuries (types IV-VI) may be indicated for operative treatment. However, controversy exists if operative treatment is superior to nonoperative treatment, especially in grade III injuries, as functional impairment due to scapular dyskinesia or chronic pain remains concerning following non-operative treatment. Patients with a stable AC joint without overriding of the clavicle and without significant scapular dysfunction (Type IIIA) may benefit from non-interventional approaches, in contrast to patients with overriding of the clavicle and therapy-resistant scapular dysfunction (Type IIIB). If these patients are considered non-responders to a conservative approach, an anatomic AC joint reconstruction using a hybrid technique should be considered. In chronic AC joint injuries, surgery is indicated after failed nonoperative treatment of 3 to 6 months. Anatomic AC joint reconstruction techniques along with biologic augmentation (e.g. Hybrid techniques, suture fixation) should be considered for chronic high-grade instabilities, accounting for the lack of intrinsic healing and scar-forming potential of the ligamentous tissue in the chronic setting. However, complication and clinical failure rates remain high, which may be a result of technical failures or persistent horizontal and rotational instability. Conclusion Future research should focus on addressing horizontal and rotational instability, to restore native physiological and biomechanical properties of the AC joint.

Abstract Background The proportion of patients with post-traumatic stress disorder (PTSD) that remain undiagnosed may be substantial. Without an accurate diagnosis, these patients may lack PTSD-targeted treatments and experience adverse health outcomes. This study used a machine learning approach to identify and describe civilian patients likely to have undiagnosed PTSD in the US commercial population. Methods The IBM® MarketScan® Commercial Subset (10/01/2015–12/31/2018) was used. A random forest machine learning model was developed and trained to differentiate between patients with and without PTSD using non–trauma-based features. The model was applied to patients for whom PTSD status could not be confirmed to identify individuals likely and unlikely to have undiagnosed PTSD. Patient characteristics, symptoms and complications potentially related to PTSD, treatments received, healthcare costs, and healthcare resource utilization were described separately for patients with PTSD (Actual Positive PTSD cohort), patients likely to have PTSD (Likely PTSD cohort), and patients without PTSD (Without PTSD cohort). Results A total of 44,342 patients were classified in the Actual Positive PTSD cohort, 5683 in the Likely PTSD cohort, and 2,074,471 in the Without PTSD cohort. While several symptoms/comorbidities were similar between the Actual Positive and Likely PTSD cohorts, others, including depression and anxiety disorders, suicidal thoughts/actions, and substance use, were more common in the Likely PTSD cohort, suggesting that certain symptoms may be exacerbated among those without a formal diagnosis. Mean per-patient-per-6-month healthcare costs were similar between the Actual Positive and Likely PTSD cohorts ($11,156 and $11,723) and were higher than those of the Without PTSD cohort ($3616); however, cost drivers differed between cohorts, with the Likely PTSD cohort experiencing more inpatient admissions and less outpatient visits than the Actual Positive PTSD cohort. Conclusions These findings suggest that the lack of a PTSD diagnosis and targeted management of PTSD may result in a greater burden among undiagnosed patients and highlights the need for increased awareness of PTSD in clinical practice and among the civilian population.

Abstract Background Attention-deficit/hyperactivity disorder (ADHD) is a common neurobehavioral disorder affecting approximately 10.0% of children and 6.5% of adolescents in the United States (US). A comprehensive assessment of the current treatment landscape is warranted to highlight potential unmet needs of children and adolescents with ADHD. Therefore, this study described treatment patterns and healthcare costs among commercially insured children and adolescents with ADHD in the US. Methods Children and adolescents with ADHD initiating pharmacological treatment indicated for ADHD were identified from IBM MarketScan Commercial Database (2014–2018). A treatment sequence algorithm was used to examine treatment patterns, including discontinuation (≥ 180 days following the last day of supply of any ADHD treatment), switch, add-on, and drop (discontinuation of an agent in combination therapy), during the 12-month study period following the index date (i.e., first observed ADHD treatment). Total adjusted annual healthcare costs were compared between patients with and without treatment changes. Results Among 49,756 children and 29,093 adolescents included, mean age was 9 and 15 years, respectively, and 31% and 38% were female. As the first treatment regimen observed, 92% of both children and adolescents initiated a stimulant and 11% initiated combination therapy. Over half of the population had a treatment change over 12 months—59% of children and 68% of adolescents. Treatment discontinuation over 12 months was common in both populations—21% of children and 36% of adolescents discontinued treatment. Healthcare costs increased with the number of treatment changes observed; children and adolescents with treatment changes (i.e., 1, 2, or ≥ 3) incurred an incremental annual cost of up to $1,443 and $2,705, respectively, compared to those without a treatment change (p

Abstract Background In 2015 and 2018, European Society of Cardiology guidelines for percutaneous coronary intervention (PCI) favoring radial access over femoral access were published. These recommendations were based on randomized trials suggesting that patients treated radially experienced reduced bleeding complications and all-cause mortality. We aimed to assess acceptance and results of radial access in a real-world scenario by analyzing all PCI cases in the Quality Assurance in Invasive Cardiology (QuIK) registry. Methods The QuIK registry prospectively collects data on all diagnostic and interventional coronary procedures from 148 private practice cardiology centers in Germany. Major adverse cardiac and cerebrovascular events (MACE) were defined as myocardial infarction, stroke, or death during hospitalization. Results From 2012 to 2018, 189,917 patients underwent PCI via either access method. The rate of radial approach steadily increased from 13 to 49%. The groups did not differ significantly with respect to age or extent of coronary disease. Femoral approach was significantly more common in patients with ST elevation myocardial infarction and cardiogenic shock. Overall, there were significant differences in MACE (radial 0.12%; femoral 0.24%; p

Abstract ELISA methods are the diagnostic tools recommended for the serological diagnosis of Coxiella burnetii infection in ruminants but their respective diagnostic performances are difficult to assess because of the absence of a gold standard. This study focused on three commercial ELISA tests with the following objectives (1) assess their sensitivity and specificity in sheep, goats and cattle, (2) assess the between- and within-herd seroprevalence distribution in these species, accounting for diagnostic errors, and (3) estimate optimal sample sizes considering sensitivity and specificity at herd level. We comparatively tested 1413 cattle, 1474 goat and 1432 sheep serum samples collected in France. We analyzed the cross-classified test results with a hierarchical zero-inflated beta-binomial latent class model considering each herd as a population and conditional dependence as a fixed effect. Potential biases and coverage probabilities of the model were assessed by simulation. Conditional dependence for truly seropositive animals was high in all species for two of the three ELISA methods. Specificity estimates were high, ranging from 94.8% [92.1; 97.8] to 99.2% [98.5; 99.7], whereas sensitivity estimates were generally low, ranging from 39.3 [30.7; 47.0] to 90.5% [83.3; 93.8]. Between- and within-herd seroprevalence estimates varied greatly among geographic areas and herds. Overall, goats showed higher within-herd seroprevalence levels than sheep and cattle. The optimal sample size maximizing both herd sensitivity and herd specificity varied from 3 to at least 20 animals depending on the test and ruminant species. This study provides better interpretation of three widely used commercial ELISA tests and will make it possible to optimize their implementation in future studies. The methodology developed may likewise be applied to other human or animal diseases.

Abstract Background Genome-wide association studies (GWAS) have uncovered many genetic risk loci for psoriasis, yet many remain uncharacterised in terms of the causal gene and their biological mechanism in disease. This is largely a result of the findings that over 90% of GWAS variants map outside of protein-coding DNA and instead are enriched in cell type- and stimulation-specific gene regulatory regions. Results Here, we use a disease-focused Capture Hi-C (CHi-C) experiment to link psoriasis-associated variants with their target genes in psoriasis-relevant cell lines (HaCaT keratinocytes and My-La CD8+ T cells). We confirm previously assigned genes, suggest novel candidates and provide evidence for complexity at psoriasis GWAS loci. For one locus, uniquely, we combine further epigenomic evidence to demonstrate how a psoriasis-associated region forms a functional interaction with the distant (> 500 kb) KLF4 gene. This interaction occurs between the gene and active enhancers in HaCaT cells, but not in My-La cells. We go on to investigate this long-distance interaction further with Cas9 fusion protein-mediated chromatin modification (CRISPR activation) coupled with RNA-seq, demonstrating how activation of the psoriasis-associated enhancer upregulates KLF4 and its downstream targets, relevant to skin cells and apoptosis. Conclusions This approach utilises multiple functional genomic techniques to follow up GWAS-associated variants implicating relevant cell types and causal genes in each locus; these are vital next steps for the translation of genetic findings into clinical benefit.

Abstract Background Administering anti-vascular endothelial growth factor (anti-VEGF) by intraocular injection has been shown to have a safe systemic profile. Nevertheless, incidents of acute kidney injury following anti-VEGF injection have been reported. We assessed the long-term effect of multiple intravitreal anti-VEGF injections on measures of renal function in patients with diabetes including rate of change of estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (ACR). Methods A retrospective review of patients receiving diabetic macular oedema (DMO) treatment was undertaken. Serum creatinine, ACR, number of intravitreal anti-VEGF injections and clinical characteristics were collected from electronic healthcare records (EHR). A co-efficient of eGFR and ACR change with time was calculated over a mean duration of 2.6 years. Regression modelling was used to assess variation in the number of anti-VEGF injections and change in eGFR and ACR. Results The EHR of 85 patients with DMO (59% male, 78% type 2 diabetes mellitus [T2DM]) were reviewed. On average, 26.8 intravitreal anti-VEGF injections were given per patient over a mean duration of 31 months. No association between increasing number of anti-VEGF injections and rate of eGFR decline (beta = 0.04, 95% confidence intervals [CI]: − 0.02, 0.09; p = 0.22) or ACR change over time (beta = 0.02, CI: − 0.19, 0.23; p = 0.86) was detected, following adjustment for hypertension, cerebrovascular disease, T2DM, and medications taken. Conclusion Our data suggests regular long-term intravitreal VEGF inhibition does not significantly alter the rate of change in eGFR and/or ACR with increasing number of treatment injections.

Abstract Background Malaria accounts for the largest portion of healthcare demand in Angola. A pillar of malaria control in Angola is the appropriate management of malaria illness, including testing of suspect cases with rapid diagnostic tests (RDTs) and treatment of confirmed cases with artemisinin-based combination therapy (ACT). Periodic systematic evaluations of malaria case management are recommended to measure health facility readiness and adherence to national case management guidelines. Methods Cross-sectional health facility surveys were performed in low-transmission Huambo and high-transmission Uíge Provinces in early 2016. In each province, 45 health facilities were randomly selected from among all public health facilities stratified by level of care. Survey teams performed inventories of malaria commodities and conducted exit interviews and re-examinations, including RDT testing, of a random selection of all patients completing outpatient consultations. Key health facility readiness and case management indicators were calculated adjusting for the cluster sampling design and utilization. Results Availability of RDTs or microscopy on the day of the survey was 71% (54–83) in Huambo and 85% (67–94) in Uíge. At least one unit dose pack of one formulation of an ACT (usually artemether–lumefantrine) was available in 83% (66–92) of health facilities in Huambo and 79% (61–90) of health facilities in Uíge. Testing rates of suspect malaria cases in Huambo were 30% (23–38) versus 69% (53–81) in Uíge. Overall, 28% (13–49) of patients with uncomplicated malaria, as determined during the re-examination, were appropriately treated with an ACT with the correct dose in Huambo, compared to 60% (42–75) in Uíge. Incorrect case management of suspect malaria cases was associated with lack of healthcare worker training in Huambo and ACT stock-outs in Uíge. Conclusions The results reveal important differences between provinces. Despite similar availability of testing and ACT, testing and treatment rates were lower in Huambo compared to Uíge. A majority of true malaria cases seeking care in health facilities in Huambo were not appropriately treated with anti-malarials, highlighting the importance of continued training and supervision of healthcare workers in malaria case management, particularly in areas with decreased malaria transmission.

Abstract Most parasites co-occur with other parasites, although the importance of such multiparasitism has only recently been recognised. Co-infections may result when hosts are independently infected by different parasites at the same time or when interactions among parasite species facilitate co-occurrence. Such interactions can have important repercussions on human or animal health because they can alter host susceptibility, infection duration, transmission risks, and clinical symptoms. These interactions may be synergistic or antagonistic and thus produce diverse effects in infected humans and animals. Interactions among parasites strongly influence parasite dynamics and therefore play a major role in structuring parasite populations (both within and among hosts) as well as host populations. However, several methodological challenges remain when it comes to detecting parasite interactions. The goal of this review is to summarise current knowledge on the causes and consequences of multiparasitism and to discuss the different methods and tools that researchers have developed to study the factors that lead to multiparasitism. It also identifies new research directions to pursue.