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Abstract High dose-rate brachytherapy is a treatment technique for gynecologic cancers where intracavitary applicators are placed within the patient’s pelvic cavity. To ensure accurate radiation delivery, localization of the applicator at the time of insertion is vital. This study proposes a novel method for acquiring, registering, and fusing three-dimensional (3D) trans-abdominal and 3D trans-rectal ultrasound (US) images for visualization of the pelvic anatomy and applicators during gynecologic brachytherapy. The workflow was validated using custom multi-modal pelvic phantoms and demonstrated during two patient procedures. Experiments were performed for three types of intracavitary applicators: ring-and-tandem, ring-and-tandem with interstitial needles, and tandem-and-ovoids. Fused 3D US images were registered to magnetic resonance (MR) and computed tomography (CT) images for validation. The target registration error (TRE) and fiducial localization error (FLE) were calculated to quantify the accuracy of our fusion technique. For both phantom and patient images, TRE and FLE across all modality registrations (3D US versus MR or CT) resulted in mean ± standard deviation of 4.01 ± 1.01 mm and 0.43 ± 0.24 mm, respectively. This work indicates proof of concept for conducting further clinical studies leveraging 3D US imaging as an accurate, accessible alternative to advanced modalities for localizing brachytherapy applicators.

Ferrate (Fe(VI): HFeO4− /FeO42−), a potent oxidant, has been investigated as an alternative chemical disinfectant in water treatment due to its reduced production of disinfection by-products. In this study, we assessed the disinfecting ability of potassium ferrate against a variety of microorganisms, including waterborne pathogens, under varying pH and water temperature conditions. We presented CT values, a metric of ferrate concentrations (C) and contact time (T), to quantify microbial inactivation rates. Among the tested microorganisms, human adenovirus was the least resistant to ferrate, followed by waterborne bacteria such as Escherichia coli and Vibrio cholerae, and finally, the protozoan parasite Giardia duodenalis. We further investigated the impact of two pH values (7 and 8) and two temperatures (5 and 25 °C) on microbial inactivation rates, observing that inactivation rates increased with lower pH and higher temperature. In addition to showcasing ferrate's capacity to effectively inactivate a range of the tested microorganisms, we offer a ferrate CT table to facilitate the comparison of the effectiveness of various disinfection methods. HIGHLIGHTS Ferrate effectively inactivates a variety of tested microorganisms.; The inactivation rates of all tested microorganisms increased with lower pH and higher temperature.; A ferrate CT table facilitates the comparison of the effectiveness of various disinfection methods.; Ferrate disinfection could be a promising strategy for practical water treatment applications.;

Abstract Individuals that isolate themselves to give birth can use more than one strategy in choosing birth sites to maximize reproductive success. Previous research has focused on the consistency in the use of the same birth‐site across years (i.e., spatial fidelity), but individuals alternatively may use similar habitat conditions across years (i.e., habitat fidelity). Using GPS telemetry, we determined whether woodland caribou expressed spatial or habitat fidelity during calving, and evaluated intrinsic and extrinsic factors associated with expressing either type of fidelity. We identified 56 individuals with ≥2 putative birth events, via a movement‐based model, across northern Ontario between 2010 and 2014. Individuals were classified as expressing (1) spatial fidelity by comparing sequential calving locations to a random spatial distribution of available calving locations, (2) habitat fidelity using a logistic use model compared to a null (intercept only) model, (3) no fidelity (neither criterion met), or (4) both spatial and habitat fidelity (both criteria met). Across all individuals, 37% expressed no fidelity (36 of 98), 15% expressed only spatial fidelity (15 of 99), 35% expressed only habitat fidelity (34 of 98), and 14% expressed both spatial and habitat fidelity (14 of 98). Older individuals were more likely to express spatial fidelity, whereas lower availability of upland and lowland conifer forests without linear features increased the probability an individual expressed habitat fidelity. Our results indicate that managing for caribou calving needs to consider protecting both specific, known birthing sites, but also broad‐scale areas of preferred habitat for calving. Understanding the mechanisms that influence caribou expressing calving fidelity, and associated fitness costs, is crucial for the conservation of the species.

Abstract Background Type 2 diabetes (T2D) is common and increasing in prevalence. It is possible to prevent or delay T2D using lifestyle intervention programmes. Entry to these programmes is usually determined by a measure of glycaemia in the ‘intermediate’ range. This paper investigated the relationship between HbA1c and future diabetes risk and determined the impact of varying thresholds to identify those at high risk of developing T2D. Methods We studied 4227 participants without diabetes aged ≥ 40 years recruited to the Exeter 10,000 population cohort in South West England. HbA1c was measured at study recruitment with repeat HbA1c available as part of usual care. Absolute risk of developing diabetes within 5 years, defined by HbA1c ≥ 48 mmol/mol (6.5%), according to baseline HbA1c, was assessed by a flexible parametric survival model. Results The overall absolute 5-year risk (95% CI) of developing T2D in the cohort was 4.2% (3.6, 4.8%). This rose to 7.1% (6.1, 8.2%) in the 56% (n = 2358/4224) of participants classified ‘high-risk’ with HbA1c ≥ 39 mmol/mol (5.7%; ADA criteria). Under IEC criteria, HbA1c ≥ 42 mmol/mol (6.0%), 22% (n = 929/4277) of the cohort was classified high-risk with 5-year risk 14.9% (12.6, 17.2%). Those with the highest HbA1c values (44–47 mmol/mol [6.2–6.4%]) had much higher 5-year risk, 26.4% (22.0, 30.5%) compared with 2.1% (1.5, 2.6%) for 39–41 mmol/mol (5.7–5.9%) and 7.0% (5.4, 8.6%) for 42–43 mmol/mol (6.0–6.1%). Changing the entry criterion to prevention programmes from 39 to 42 mmol/mol (5.7–6.0%) reduced the proportion classified high-risk by 61%, and increased the positive predictive value (PPV) from 5.8 to 12.4% with negligible impact on the negative predictive value (NPV), 99.6% to 99.1%. Increasing the threshold further, to 44 mmol/mol (6.2%), reduced those classified high-risk by 59%, and markedly increased the PPV from 12.4 to 23.2% and had little impact on the NPV (99.1% to 98.5%). Conclusions A large proportion of people are identified as high-risk using current thresholds. Increasing the risk threshold markedly reduces the number of people that would be classified as high-risk and entered into prevention programmes, although this must be balanced against cases missed. Raising the entry threshold would allow limited intervention opportunities to be focused on those most likely to develop T2D.

The photonic liquid crystalline (LC) dispersion of graphene oxide (GO) is prepared using centrifugation-induced size-fractionization. Under gravity, a series of successive centrifugations enable large GO sheets to sediment and fractionize into a narrowed size distribution. The resulting large GO sheets display large-area monodomain structures with uniform orientation, forming a photonic LC phase. The single lyotropic LC phase forms at the concentration > 0.34 wt% and structural coloring occurs at the concentration > 0.59 wt%. The structural color with different wavelength is tuned with various concentrations (0.59–0.92 wt%). GO membranes are supported on porous poly(ether sulphone) membranes from photonic LC dispersions by a vacuum-spin method. The photonic GO membrane demonstrates dramatic enhancement of water permeance (169.3 Lm−2 hr−1 bar−1), which is 12 times faster than the control GO membrane (13.2 Lm−2 hr−1 bar−1). The ion rejection of the photonic GO membrane (45–60%) is also significantly improved, as compared to the control GO membrane (30–48%). Organic dye rejection testing shows that the photonic GO membrane remains as high molecular rejection (> 90%) as the control GO membrane. This work may provide a new way to fabricate ordered GO membranes for fast nanofiltration.

Background The 23-valent pneumococcal polysaccharide vaccine (PPV23) is recommended for UK older adults, but how age moderates effectiveness is unclear. Methods Three annual cohorts of primary-care patients aged≥65y from the Clinical Practice Research Datalink selected from 2003–5 created a natural experiment (n = 324,804), reflecting the staged introduction of the vaccine. The outcome was symptoms consistent with community-acquired pneumococcal pneumonia (CAP) requiring antibiotics or hospitalisation. We used the prior event rate ratio (PERR) approach to address bias from unmeasured confounders. Results Vaccinated patients had higher rates of CAP in the year before vaccination than their controls, indicating the potential for confounding bias. After adjustment for confounding using the prior event rate ratio (PERR) method, PPV23 was estimated to be effective against CAP for two years after vaccination in all age sub-groups with hazard ratios (95% confidence intervals) of 0.86 (0.80 to 0.93), 0.74 (0.65 to 0.85) and 0.65 (0.57 to 0.74) in patients aged 65–74, 75–79 and 80+ respectively in the 2005 cohort. Age moderated the effect of vaccination with predicted risk reductions of 8% at 65y and 29% at 80y. Conclusions PPV23 is moderately effective at reducing CAP among UK patients aged≥65y, in the two years after vaccination. Vaccine effectiveness is maintained, and may increase, in the oldest age groups in step with increasing susceptibility to CAP.

Young Black males (YBM) ages 18 to 24 years are more at risk of contracting sexually transmitted infections (STIs) and have a substantially greater need for sexual reproductive health (SRH) services than other groups. Despite this significant need, the extant literature does not provide a comprehensive picture of how YBM seek preventive care services (e.g., STI testing). Therefore, the purpose of this review is to address YBM’s SRH access and use of STI/HIV testing and screening in this population, with a specific emphasis on young heterosexual Black males, by identifying barriers and facilitators of engaging with SRH care. An electronic search was performed using Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycInfo, PubMed, and Scopus online databases. Keywords were adapted to each database and included variations of “Black males,” “sexual reproductive healthcare services,” “youth (18-24 years old),” and “healthcare access and utilization.” Studies from the review reported that barriers to engaging in SRH care included lack of health insurance, ideas of masculinity that conflict with SRH care, stigma related to accessing services, and lack of knowledge regarding available services and care options. The top facilitators for utilizing SRH care were engagement on behalf of health clinics, confidence gained from social support, access to quality health care in one’s community, and trust in the health care system and providers. This review contributes to the current state of the science and is important to the improvement of high-quality services for this population, including respect, choice in care, confidentially, and compassion.

A 24-year-old man with of Gilles de la Tourette (TS) syndrome experienced a marked remission of 2 years after heat-induced dehydration. Further investigation of the effects of heat and dehydration on TS may be useful.

Broad scale analyses of winter population survey data collected between 1985 and 2015 were conducted to provide a synthesis of the current status and historical performance of 14 moose (Alces alces) populations residing in the Boreal Plain Ecozone of Saskatchewan and western Manitoba. Population time series models indicated a broad scale decline averaging 30% in moose populations across the Boreal Plain Ecozone since 2000 relative to the long-term (1985 to 2015) cumulative mean population size. Demographic patterns and rates of population change were variable among and within populations across years. We found an inverse relationship between adult sex ratio (bull:cow) and population density (R² = 0.48, P < 0.001), which suggests negative population growth (λ < 1.0) when the adult sex ratio falls below a density-dependent threshold for population growth. Winter calf recruitment (calves/cow) was positively correlated (R² = 0.12, P = 0.027) with adult sex ratio. Stable or increasing populations (λ ≥ 1.0) tended to have lower adult sex ratios relative to winter calf recruitment ratios than declining populations. Population state and vital rate relationships are useful to assess population performance and guide science-based moose management strategies in a Management-by-Objective decision-analytic framework.

BackgroundBacterial infections of the upper and lower respiratory tract are a frequent complication of influenza and contribute to the widespread use of antibiotics. Influenza vaccination may help reduce both appropriate and inappropriate prescribing of antibiotics. Electronic health records provide a rich source of information for assessing secondary effects of influenza vaccination.MethodsWe conducted a retrospective study to estimate effects of influenza vaccine on antibiotic (amoxicillin) prescription in the elderly based on data from the Clinical Practice Research Datalink. The introduction of UK policy to recommend the influenza vaccine to older adults in 2000 led to a substantial increase in uptake, creating a natural experiment. Of 259,753 eligible patients that were unvaccinated in 1999 and aged≥65y by January 2000, 88,519 patients received influenza vaccination in 2000. These were propensity score matched 1:1 to unvaccinated patients. Time-to-amoxicillin was analysed using the Prior Event Rate Ratio (PERR) Pairwise method to address bias from time-invariant measured and unmeasured confounders. A simulation study and negative control outcome were used to help strengthen the validity of results.ResultsCompared to unvaccinated patients, those from the vaccinated group were more likely to be prescribed amoxicillin in the year prior to vaccination: hazard ratio (HR) 1.90 (95% confidence interval 1.83, 1.98). Following vaccination, the vaccinated group were again more likely to be prescribed amoxicillin, HR 1.64 (1.58,1.71). After adjusting for prior differences between the two groups using PERR Pairwise, overall vaccine effectiveness was 0.86 (0.81, 0.92). Additional analyses suggested that provided data meet the PERR assumptions, these estimates were robust.ConclusionsOnce differences between groups were taken into account, influenza vaccine had a beneficial effect, lowering the frequency of amoxicillin prescribing in the vaccinated group. Ensuring successful implementation of national programmes of vaccinating older adults against influenza may help contribute to reducing antibiotic resistance.

Introduction To identify risk factors, absolute risk, and impact on treatment discontinuation of genital infections with sodium-glucose co-transporter-2 inhibitors (SGLT2i).Research design and methods We assessed the relationship between baseline characteristics and genital infection in 21 004 people with type 2 diabetes initiating SGLT2i and 55 471 controls initiating dipeptidyl peptidase-4 inhibitors (DPP4i) in a UK primary care database. We assessed absolute risk of infection in those with key risk factors and the association between early genital infection and treatment discontinuation.Results Genital infection was substantially more common in those treated with SGLT2i (8.1% within 1 year) than DPP4i (1.8%). Key predictors of infection with SGLT2i were female sex (HR 3.64; 95% CI 3.23 to 4.11) and history of genital infection; 5 years (HR 1.79; 1.55 to 2.07). Baseline HbA1c was not associated with infection risk for SGLT2i, in contrast to DPP4i where risk increased with higher HbA1c. One-year absolute risk of genital infection with SGLT2i was highest for those with a history of prior infection (females 23.7%, males 12.1%), compared with those without (females 10.8%, males 2.7%). Early genital infection was associated with a similar discontinuation risk for SGLT2i (HR 1.48; 1.21–1.80) and DPP4i (HR 1.58; 1.21–2.07).Conclusions Female sex and history of prior infection are simple features that can identify subgroups at greatly increased risk of genital infections with SGLT2i therapy. These data can be used to risk-stratify patients. High HbA1c is not a risk factor for genital infections with SGLT2i.

Both declining and increasing moose (Alces alces) populations have been reported across North America over the last decade. We surveyed all jurisdictions with extant moose populations to determine the extent of these population trends. In 2014–2015, the North American moose population was estimated at ~1,000,000 animals distributed in 30 jurisdictions, which is unchanged since the turn of the century. Populations occurred in 12 Canadian provinces or territories, and in at least 18 states. In the past 5 years, moose density is believed to be increasing in 9, relatively stable in 8, and declining in 11 jurisdictions; estimates of change were unavailable in 2 jurisdictions. In 2014–2015, an estimated 425,537 licensed moose hunters harvested 82,096 moose in 23 jurisdictions. Hunter numbers increased by 39,118, whereas total harvest remained virtually unchanged from a decade earlier. Harvests by Indigenous and subsistence users, although largely unquantified, are believed substantial and important to quantify in certain jurisdictions. A variety of active and passive harvest strategies used to manage moose are discussed.

Agricultural management decisions on factors such as tillage, fertilization, and cropping system determine the fate of much of the world’s soils, and soil microbes both mediate and respond to these changes. However, relationships between management practices and soil microbial properties are poorly understood, especially in semiarid regions. To address this knowledge gap, we reviewed research papers published between 2000 and 2020 that analyzed soil microorganisms in semiarid wheat fields. We aimed to determine if and how soil microbial properties reliably respond to management, and how these properties indicate long-term changes in soil health, carbon (C) sequestration, and crop yield. We found that reducing tillage increases microbial activity as much as 50% in upper soil layers and stratifies both bacteria and fungi by depth. Higher cropping intensity (reduced fallow) increases C storage, microbial activity, and biomass, and particularly fungal biomass, which can be three times greater under continuous wheat than wheat-fallow. Chemical and organic fertilizers both increase bacterial biomass, though only organic inputs provide lasting benefits by promoting C storage and increasing fungal as well as bacterial biomass. We found microbial properties to be sensitive indicators of long-term changes in soil health and productivity, and formed recommendations on appropriate sampling, analysis, and interpretation of microbial data depending on the system studied.

In this data article we describe synthetic and characterisation data for four members of the 5-acyl-6,7-dihydrothieno[3,2-c]pyridine (termed “RU-SKI”) class of inhibitors of Hedgehog acyltransferase, including associated NMR spectra for final compounds. RU-SKI compounds were selected for synthesis based on their published high potencies against the enzyme target. RU-SKI 41 (9a), RU-SKI 43 (9b), RU-SKI 101 (9c), and RU-SKI 201 (9d) were profiled for activity in the related article “Click chemistry armed enzyme linked immunosorbent assay to measure palmitoylation by Hedgehog acyltransferase” (Lanyon-Hogg et al., 2015) [1]. 1H NMR spectral data indicate different amide conformational ratios between the RU-SKI inhibitors, as has been observed in other 5-acyl-6,7-dihydrothieno[3,2-c]pyridines. The synthetic and characterisation data supplied in the current article provide validated access to the class of RU-SKI inhibitors. Keywords: Synthesis, Inhibitors, Hedgehog acyltransferase, Conformation

Amyloid beta (Aβ) is a peptide cleaved from amyloid precursor protein that contributes to the formation of senile plaques in Alzheimer’s disease (AD). The relationship between Aβ and astrocyte proliferation in AD remains controversial. Despite pathological findings of increased astrocytic mitosis in AD brains, in vitro studies show an inhibitory effect of Aβ on astrocyte proliferation. In this study, we determined the effect of an active fragment of Aβ (Aβ25-35) on the cell cycle progression of primary rat astrocytes. We found that Aβ25-35 (0.3–1.0 μg/ml) enhanced astrocyte proliferation in vitro in a time- and concentration-dependent manner. Increased DNA synthesis by Aβ25-35 was observed during the S phase of the astrocyte cell cycle, as indicated by proliferation kinetics and bromodeoxyuridine immunocytochemical staining. Aggregation of Aβ25-35 abolished the upregulatory effect of Aβ on astrocyte proliferation. Further examination indicated that Aβ25-35 affected astrocyte proliferation during early or mid-G1 phase but had no effect on DNA synthesis at the peak of S phase. These results provide insight into the relationship between Aβ25-35 and astrocyte cell cycling in AD.

Abstract Predator space use influences ecosystem dynamics, and a fundamental goal assumed for a foraging predator is to maximize encounter rate with prey. This can be achieved by disproportionately utilizing areas of high prey density or, where prey are mobile and therefore spatially unpredictable, utilizing patches of their prey's preferred resources. A third, potentially complementary strategy is to increase mobility by using linear features like roads and/or frozen waterways. Here, we used novel population‐level predator utilization distributions (termed “localized density distributions”) in a single‐predator (wolf), two‐prey (moose and caribou) system to evaluate these space‐use hypotheses. The study was conducted in contrasting sections of a large boreal forest area in northern Ontario, Canada, with a spatial gradient of human disturbances and predator and prey densities. Our results indicated that wolves consistently used forest stands preferred by moose, their main prey species in this part of Ontario. Direct use of prey‐rich areas was also significant but restricted to where there was a high local density of moose, whereas use of linear features was pronounced where local moose density was lower. These behaviors suggest that wolf foraging decisions, while consistently influenced by spatially anchored patches of prey forage resources, were also determined by local ecological conditions, specifically prey density. Wolves appeared to utilize prey‐rich areas when regional preferred prey density exceeded a threshold that made this profitable, whereas they disproportionately used linear features that promoted mobility when low prey density made directly tracking prey distribution unprofitable.

Habitat alteration and climate change are two important environmental stressors posing increasing threats to woodland caribou, Rangifer tarandus caribou, in Ontario. Our first objective was to identify the importance of linear features, habitat, and climate on the occurrence of woodland caribou during the winter season using over 30 years of records (1980-2012). Our second objective was to forecast the impacts of climate change on the future occurrence and range of woodland caribou. Woodland caribou occurrence and environmental data collected during 1980 to 2012 were obtained from the Ontario Ministry of Natural Resources (OMNR). Logistic regression models were used to identify the importance of linear features, habitat, and climate on woodland caribou. We then forecast future caribou occurrences using 126 future climate projections. Woodland caribou preferred coniferous forests and mixed forests that tended to be associated with increased lichen coverage, and regions with colder winters. Woodland caribou also avoided anthropogenically disturbed regions, such as areas associated with high road density or developed areas. Caribou range extent was projected to contract by 57.2-100% by 2050 and 58.9-100% by 2070. Furthermore, all 126 climate change scenarios forecast a range loss of at least 55% for woodland caribou in Ontario by 2050. We project complete loss of woodland caribou in Ontario if winter temperatures increase by more than 5.6°C by 2070. We found that woodland caribou in Ontario are sensitive to changes in climate and forecasted that an average of 95% of Ontario’s native wood­land caribou could become extirpated by 2070. The greatest extirpations were projected to occur in the northernmost regions of Ontario as well as northeastern Ontario, while regions in western Ontario were projected to have the lowest rates of extirpation. This underscores the importance of mitigating greenhouse gases as a means to protect this iconic species.

Neurogenesis is a highly-regulated process occurring in the dentate gyrus that has been linked to learning, memory, and antidepressant efficacy. MicroRNAs (miRNAs) have been previously shown to play an important role in the regulation of neuronal development and neurogenesis in the dentate gyrus via modulation of gene expression. However, this mode of regulation is both incompletely described in the literature thus far and highly multifactorial. In this study, we designed sensors and detected relative levels of expression of 10 different miRNAs and found miR-338-3p was most highly expressed in the dentate gyrus. Comparison of miR-338-3p expression with neuronal markers of maturity indicates miR-338-3p is expressed most highly in the mature neuron. We also designed a viral "sponge" to knock down in vivo expression of miR-338-3p. When miR-338-3p is knocked down, neurons sprout multiple primary dendrites that branch off of the soma in a disorganized manner, cellular proliferation is upregulated, and neoplasms form spontaneously in vivo. Additionally, miR-338-3p overexpression in glioblastoma cell lines slows their proliferation in vitro. Further, low miR-338-3p expression is associated with increased mortality and disease progression in patients with glioblastoma. These data identify miR-338-3p as a clinically relevant tumor suppressor in glioblastoma.

Woodland caribou (Rangifer tarandus caribou) in Ontario are a threatened species that have experienced a substantial retraction of their historic range. Part of their decline has been attributed to increasing densities of anthropogenic linear features such as trails, roads, railways, and hydro lines. These features have been shown to increase the search efficiency and kill rate of wolves. However, it is unclear whether selection for anthropogenic linear features is additive or compensatory to selection for natural (water) linear features which may also be used for travel. We studied the selection of water and anthropogenic linear features by 52 resident wolves (Canis lupus x lycaon) over four years across three study areas in northern Ontario that varied in degrees of forestry activity and human disturbance. We used Euclidean distance-based resource selection functions (mixed-effects logistic regression) at the seasonal range scale with random coefficients for distance to water linear features, primary/secondary roads/railways, and hydro lines, and tertiary roads to estimate the strength of selection for each linear feature and for several habitat types, while accounting for availability of each feature. Next, we investigated the trade-off between selection for anthropogenic and water linear features. Wolves selected both anthropogenic and water linear features; selection for anthropogenic features was stronger than for water during the rendezvous season. Selection for anthropogenic linear features increased with increasing density of these features on the landscape, while selection for natural linear features declined, indicating compensatory selection of anthropogenic linear features. These results have implications for woodland caribou conservation. Prey encounter rates between wolves and caribou seem to be strongly influenced by increasing linear feature densities. This behavioral mechanism-a compensatory functional response to anthropogenic linear feature density resulting in decreased use of natural travel corridors-has negative consequences for the viability of woodland caribou.

The present study examines the consequences of perceived interpersonal discrimination on stress, health, and performance in a sample of 210 STEM academicians. Using a path model, we test the relation that perceived interpersonal discrimination has on stress and the relation of stress to physical health maladies and on current and future performance. In so doing, we assess the link between discrimination and decrements in performance over time. Additionally, we test supervisor social support as a moderator of the discrimination–stress relation. Findings support relations between perceived interpersonal discrimination and stress, which in turn relates to declines in physical health and performance outcomes. Moreover, supervisory support is shown to mitigate the influence of interpersonal discrimination on stress in STEM academicians.