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Background The anti-inflammatory effect of exclusive enteral nutrition on the gut of children with Crohn’s disease is rapidly lost after food reintroduction. This study assessed disease dietary triggers following successful treatment with exclusive enteral nutrition. Methods Nutrient intake, dietary patterns and dietary biomarkers in faeces (gluten immunogenic peptides, undigestible starch, short chain fatty acids) were assessed in 14 children with Crohn’s disease during early food reintroduction, following exclusive enteral nutrition. Groups above (Group A) and below (Group B) the median levels of faecal calprotectin after food reintroduction were assigned for comparative analysis. Results Intakes of fibre, gluten-containing cereals and red and processed meat were significantly higher in Group A than Group B; (median [Q1, Q3], g/day; Fibre: 12.1 [11.2, 19.9] vs. 9.9 [7.6, 12.1], p = 0.03; Red and processed meat: 151 [66.7, 190] vs. 63.3 [21.7, 67], p = 0.02; gluten-containing cereals: 289 [207, 402] vs. 203 [61, 232], p = 0.035). A diet consisting of cereals and meat products was predictive (92% accuracy) of higher faecal calprotectin levels after food reintroduction. In faeces, butyrate levels, expressed as absolute concentration and relative abundance, were higher in Group A than Group B by 28.4 µmol/g (p = 0.015) and 6.4% (p = 0.008), respectively. Levels of gluten immunogenic peptide and starch in faeces did not differ between the two groups. Conclusions This pilot study identified potential dietary triggers of gut inflammation in children with Crohn’s disease after food reintroduction following treatment with exclusive enteral nutrition. Trial registration: Clinical trials.gov registration number: NCT02341248; Clinical trials.gov URL: https://clinicaltrials.gov/ct2/show/NCT02341248 (retrospectively registered).

Rationale: Preschool wheezing is heterogeneous, but the underlying mechanisms are poorly understood. Objectives: To investigate lower airway inflammation and infection in preschool children with different clinical diagnoses undergoing elective bronchoscopy/bronchoalveolar lavage-BAL. Methods: We recruited 136 children aged 1-5 years (105 recurrent severe wheeze-RSW; 31 non-wheeze respiratory disorders-NWRD). RSW were assigned as episodic viral-EVW or multiple trigger wheeze-MTW. We compared lower airway inflammation/infection in different clinical diagnoses and undertook data-driven analyses to determine clusters of pathophysiological features, and investigated their relationships with pre-specified diagnostic labels. Measurements and Main Results: Blood eosinophils and allergic sensitization were significantly higher in RSW than NWRD. Blood neutrophils, BAL eosinophils and neutrophils, and positive bacterial culture and virus detection rates were similar between groups. However, pathogen distribution differed significantly, with higher detection of rhinovirus in RSW and Moraxella in sensitized RSW. EVW and MTW did not differ in blood/BAL inflammation, or bacterial/virus detection. Partition Around Medoids algorithm revealed 4 clusters of pathophysiological features: (1) Atopic (17.9%); (2) Non-atopic, low infection rate, high inhaled corticosteroids-ICS (31.3%); (3) Non-atopic, high infection rate (23.1%); and (4) Non-atopic, low infection rate, no ICS (27.6%). Cluster allocation differed significantly between RSW and NWRD (RSW evenly distributed across clusters, 60% of NWRD assigned to cluster 4, p

Background Whether young adults who are infected with SARS-CoV-2 are at risk of subsequent infection is uncertain. We investigated the risk of subsequent SARS-CoV-2 infection among young adults seropositive for a previous infection. Methods This analysis was performed as part of the prospective COVID-19 Health Action Response for Marines study (CHARM). CHARM included predominantly male US Marine recruits, aged 18–20 years, following a 2-week unsupervised quarantine at home. After the home quarantine period, upon arrival at a Marine-supervised 2-week quarantine facility (college campus or hotel), participants were enrolled and were assessed for baseline SARS-CoV-2 IgG seropositivity, defined as a dilution of 1:150 or more on receptor-binding domain and full-length spike protein ELISA. Participants also completed a questionnaire consisting of demographic information, risk factors, reporting of 14 specific COVID-19-related symptoms or any other unspecified symptom, and brief medical history. SARS-CoV-2 infection was assessed by PCR at weeks 0, 1, and 2 of quarantine and participants completed a follow-up questionnaire, which included questions about the same COVID-19-related symptoms since the last study visit. Participants were excluded at this stage if they had a positive PCR test during quarantine. Participants who had three negative swab PCR results during quarantine and a baseline serum serology test at the beginning of the supervised quarantine that identified them as seronegative or seropositive for SARS-CoV-2 then went on to basic training at Marine Corps Recruit Depot—Parris Island. Three PCR tests were done at weeks 2, 4, and 6 in both seropositive and seronegative groups, along with the follow-up symptom questionnaire and baseline neutralising antibody titres on all subsequently infected seropositive and selected seropositive uninfected participants (prospective study period). Findings Between May 11, 2020, and Nov 2, 2020, we enrolled 3249 participants, of whom 3168 (98%) continued into the 2-week quarantine period. 3076 (95%) participants, 2825 (92%) of whom were men, were then followed up during the prospective study period after quarantine for 6 weeks. Among 189 seropositive participants, 19 (10%) had at least one positive PCR test for SARS-CoV-2 during the 6-week follow-up (1·1 cases per person-year). In contrast, 1079 (48%) of 2247 seronegative participants tested positive (6·2 cases per person-year). The incidence rate ratio was 0·18 (95% CI 0·11–0·28; p

Rationale and Objectives There have been multiple investigations defining and reporting the effectiveness of focal cryoablation as a treatment option for organ-confined prostate cancer. However, the impact of cryo-needle/probe placement accuracy within the tumor and gland has not been extensively studied. We analyzed how variations in the placement of the cryo-needles, specifically errors leading to incomplete ablation, may affect prostate cancer's resulting cryoablation. Materials and Methods We performed a study based on isothermal models using Monte Carlo simulations to analyze the impact of needle placement errors on tumor coverage and the probability of positive ablation margin. We modeled the placement error as a Gaussian noise on the cryo-needle position. The analysis used retrospective MRI data of 15 patients with biopsy-proven, unifocal, and MRI visible prostate cancer to calculate the impact of placement error on the volume of the tumor encompassed by the −40°C and −20°C isotherms using one to four cryo-needles. Results When the standard deviation of the placement error reached 3 mm, the tumor coverage was still above 97% with the −20°C isotherm, and above 81% with the −40°C isotherm using two cryo-needles or more. The probability of positive margin was significantly lower considering the −20°C isotherm (0.04 for three needles) than using the −40°C isotherm (0.66 for three needles). Conclusion The results indicated that accurate cryo-needle placement is essential for the success of focal cryoablation of prostate cancer. The analysis shows that an admissible targeting error depends on the lethal temperature considered and the number of cryo-needles used.

Background Early life represents a major risk window for asthma development. However, the mechanisms controlling the threshold for establishment of allergic airway inflammation in early life are incompletely understood. Airway macrophages (AMs) regulate pulmonary allergic responses and undergo TGF-β–dependent postnatal development, but the role of AM maturation factors such as TGF-β in controlling the threshold for pathogenic immune responses to inhaled allergens remains unclear. Objective Our aim was to test the hypothesis that AM-derived TGF-β1 regulates pathogenic immunity to inhaled allergen in early life. Methods Conditional knockout (Tgfb1ΔCD11c) mice, with TGF-β1 deficiency in AMs and other CD11c+ cells, were analyzed throughout early life and following neonatal house dust mite (HDM) inhalation. The roles of specific chemokine receptors were determined by using in vivo blocking antibodies. Results AM-intrinsic TGF-β1 was redundant for initial population of the neonatal lung with AMs, but AMs from Tgfb1ΔCD11c mice failed to adopt a mature homeostatic AM phenotype in the first weeks of life. Evidence of constitutive TGF-β1 signaling was also observed in pediatric human AMs. TGF-β1–deficient AMs expressed enhanced levels of monocyte-attractant chemokines, and accordingly, Tgfb1ΔCD11c mice exposed to HDM throughout early life accumulated CCR2-dependent inflammatory CD11c+ mononuclear phagocytes into the airway niche that expressed the proallergic chemokine CCL8. Tgfb1ΔCD11c mice displayed augmented TH2, group 2 innate lymphoid cell, and airway remodeling responses to HDM, which were ameliorated by blockade of the CCL8 receptor CCR8. Conclusion Our results highlight a causal relationship between AM maturity, chemokines, and pathogenic immunity to environmental stimuli in early life and identify TGF-β1 as a key regulator of this., Graphical abstract

The heroine of Kahaani, in taking on a powerful persona in the quintessentially female garment of the sari, represents a sharp contrast with conventional ways of dressing powerful women in western cinematic tradition. There is ample cultural and mythological precedent in India for coding action and violence as female, but Kahaani’s affinity with the contemporary superhero film emerges in an unexpected way in its treatment of costume, specifically the use of the sari as a distinct article of clothing that the heroine assumes only for the first time as she embarks upon the dispensation of justice. Demarcating an ordinary set of clothing from the ‘special’ sari mirrors the superhero division of the everyday person from the heroic one, only here the sari, which is a quotidian form of dress, performs as an exceptional one. The copious symbolic potential of the sari permits this move, while at the same time pointing to many of the tensions and contradictions of life that engage contemporary metropolitan audiences in India. The sari thus functions to help solidify the film’s complex positioning in twenty-first-century Hindi filmmaking.

Aims Gender bias and sexual discrimination (GBSD) have been widely recognized across a range of fields and are now part of the wider social consciousness. Such conduct can occur in the medical workplace, with detrimental effects on recipients. The aim of this review was to identify the prevalence and impact of GBSD in orthopaedic surgery, and to investigate interventions countering such behaviours. Methods A systematic review was conducted by searching Medline, EMCARE, CINAHL, PsycINFO, and the Cochrane Library Database in April 2020, and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to which we adhered. Original research papers pertaining to the prevalence and impact of GBSD, or mitigating strategies, within orthopaedics were included for review. Results Of 570 papers, 27 were eligible for inclusion. These were published between 1998 and 2020. A narrative review was performed in light of the significant heterogeneity displayed by the eligible studies. A total of 13 papers discussed the prevalence of GBSD, while 13 related to the impact of these behaviours, and six discussed mitigating strategies. GBSD was found to be common in the orthopaedic workplace, with all sources showing women to be the subjects. The impact of this includes poor workforce representation, lower salaries, and less career success, including in academia, for women in orthopaedics. Mitigating strategies in the literature are focused on providing female role models, mentors, and educational interventions. Conclusion GBSD is common in orthopaedic surgery, with a substantial impact on sufferers. A small number of mitigating strategies have been tested but these are limited in their scope. As such, the orthopaedic community is obliged to participate in more thoughtful and proactive strategies that mitigate against GBSD, by improving female recruitment and retention within the specialty. Cite this article: Bone Joint J 2020;102-B(11):1446–1456.

RATIONALE AND OBJECTIVES: To explore a role for multiparametric MRI (mpMRI) as a biomarker of response to neoadjuvant androgen deprivation therapy (ADT) for prostate cancer (PCa). MATERIALS AND METHODS: This prospective study was approved by the institutional review board and was HIPAA compliant. Eight patients with localized PCa had a baseline mpMRI, repeated after 6-months of ADT, followed by prostatectomy. mpMRI indices were extracted from tumor and normal regions of interest (TROI/NROI). Residual cancer burden (RCB) was measured on mpMRI and on the prostatectomy specimen. Paired t-tests compared TROI/NROI mpMRI indices and pre/post-treatment TROI mpMRI indices. Spearman’s rank tested for correlations between MRI/pathology-based RCB, and between pathological RCB and mpMRI indices. RESULTS: At baseline, TROI apparent diffusion coefficient (ADC) was lower and dynamic contrast enhanced (DCE) metrics were higher, compared to NROI (ADC: 806 ± 137 × 10(−6) vs. 1277 ± 213 × 10(−6) mm(2)/sec, p = 0.0005; K(trans): 0.346 ± 0.16 vs. 0.144 ± 0.06 min(−1), p = 0.002; AUC(90): 0.213 ± 0.08 vs. 0.11 ±1 0.03, p = 0.002). Post-treatment, there was no change in TROI ADC, but a decrease in TROI K(trans) (0.346 ± 0.16 to 0.188 ± 0.08 min; p = 0.02) and AUC(90) (0.213 ± 0.08 to 0.13 ± 0.06; p = 0.02). Tumor volume decreased with ADT. There was no difference between mpMRI-based and pathology-based RCB, which positively correlated (⍴ = 0.74–0.81, p < 0.05). Pathology-based RCB positively correlated with post-treatment DCE metrics (⍴ = 0.76–0.70, p< 0.05) and negatively with ADC (⍴ = −0.79, p = 0.03). CONCLUSION: Given the heterogeneity of PCa, an individualized approach to ADT may maximize potential benefit. This pilot study suggests that mpMRI may serve as a biomarker of ADT response and as a surrogate for RCB at prostatectomy.

First-generation highly crosslinked polyethylene (HXLPE) was developed to reduce polyethylene wear debris and subsequent osteolysis. Two thermal stabilization strategies were developed, annealing and remelting, to remove free radicals remaining in the polymer. Both types of HXLPEs have demonstrated better wear resistance to conventional polyethylene in hip arthroplasty. However, few studies have directly compared the mid- to long-term clinical outcomes of first-generation HXLPEs. We sought to address the following research questions: (1) is there a difference between the revision reasons for HXLPE formulations (annealed and remelted), (2) is there a difference in oxidation between annealed and remelted HXLPEs, (3) is there a difference in the linear penetration rate of annealed and remelted HXLPEs, and (4) does the formulation of first-generation HXLPEs affect the prevalence of osteolysis? A total of 129 first-generation HXLPE acetabular liners were collected in a multicenter retrieval program. These components were implanted for 5 or more years and were fabricated from annealed or remelted HXLPE. Reasons for revision, body mass index, age, sex, and activity levels were collected from medical records. Oxidation was measured at four regions of interest: bearing surface, backside surface, locking mechanism, and rim. Liner penetration was directly measured from retrievals using a micrometer. Osteolysis was reported in the operative notes by the revising surgeon and a thorough review of the operative notes and radiographs. Revision reasons included infection, instability, pain, and loosening. The annealed liners had higher oxidation indices than remelted liners. There was no difference in linear penetration rates between cohorts. There was no difference in osteolysis prevalence between cohorts. We found remelted HXLPE to be more oxidatively stable than annealed HXLPE but did not find a significant difference in the linear penetration rates or the prevalence of osteolysis. Our findings demonstrate sustained long-term wear resistance of both cohorts of HXLPE. We did not find evidence to support a long-term clinical difference between the formulations of HXLPE.

Background Plastic surgery training in the UK continues to evolve towards an outcome-based rather than time-served curriculum. UK plastic surgery trainees are appointed nationally, and are assessed according to national standards, but training is delivered regionally. This study sought opinion from current UK plastic surgery trainees in order to highlight strengths and shortcomings of the higher surgical training programme. Method A cross-sectional study was designed and administered by the UK Plastic Surgery Trainees Association (PLASTA). A questionnaire was distributed to all UK plastic surgery trainees holding a National Training Number, using the REDCap web-based application. Results Of the 320 UK plastic surgery trainees, 131 (41%) participated in this survey, with responses from all 12 UK training regions. The most common subspecialty career aspirations for trainees were hand surgery, cleft lip and palate, lower limb and oncoplastic breast reconstruction. The survey highlighted regional variation in teaching programmes, the ability to achieve indicative operative logbook numbers, and training in aesthetic surgery. Of the trainees, 82% expressed a desire to undertake a fellowship within their training, but most did not know whether their deanery would support this. Fifteen per cent of the respondents were currently training flexibly and the majority of these had experienced negative behaviours towards their less than full time working status. Of the respondents, 44% reported stress, 25% reported a lack of autonomy and 17% reported feeling burnt out at work at least once a week. A total of 85% perceived that they did not have access to a mentoring service. Conclusions Plastic surgery remains a popular and highly competitive surgical speciality in the UK, and many trainees reported high levels of satisfaction during their training. Aspects of training that could be improved have been highlighted and recommendations made accordingly.

Background. Evidence-based approaches to improve function in individuals with cerebral palsy are needed. Purpose. To investigate the effectiveness of the Cognitive Orientation to daily Occupational Performance approach™ (CO-OP) to improve performance on self-chosen, functional goals as compared to traditional occupational therapy for cerebral palsy. Method. Crossover design with 12 participants, aged 6–15 years, randomly assigned to CO-OP and traditional intervention groups, followed by crossover and a 3-month follow-up. The participants identified three occupation-based goals for CO-OP and each group received ten 45-minutes intervention twice weekly in clinical context. Occupational performance, manual dexterity and Gross Motor Function Measures were analysed using generalized estimating equations. Findings. There were clinical and statistically significant improvements in functional goals following CO-OP and not traditional therapy. There were gains in dexterity but not in gross motor skills. Implications. CO-OP was effective to improve functional performance in young people with cerebral palsy and should be more utilized.

An 11-year-old girl with no relevant medical history experienced acute-onset confusion and speech arrest without loss of consciousness, eye deviation, tonic stiffening, or convulsion. At an outside emergency department, her examination included expressive aphasia, right lower facial droop, and right-sided hemiparesis. Noncontrast head CT was negative for acute intracranial pathology, CT angiogram showed patent vasculature, and CT perfusion showed no areas of perfusion mismatch. The patient was transferred to our institution for further management.

Recurrence of congenital diaphragmatic hernia (CDH) was retrospectively evaluated after correction with or without a patch in an institution where tension-free repair is advocated.Demographics and outcomes of patients with a postero-lateral CDH repaired (2000-2016) were analyzed (univariate tests and binary logistic regression adjusting for time since start of study, gender, defect side, liver herniation, patch, surgical approach, absence of postero-lateral rim and length of follow-up).Of 203 patients, 107 received a patch (P), and 96 were not patched (NP). Groups were not different for gestational age birthweight, gender, defect side and minimally invasive approach rate. Preoperative ECMO incidence (P:29.9% vs. NP:2.1%, p 0.01), liver herniation (P:57.0% vs. NP:22.9%, p 0.01) and absence of a postero-lateral rim (P:61.7% vs. NP:8.3%, p 0.01) were higher in the P group. The mortality rate was 10.8% (P:15.0% vs. NP:6.2%, p = 0.07). Recurrence was not different (P:9.3% vs. NP:4.2%, p = 0.15). Multivariate analysis showed that recurrence was higher after thoracoscopy compared to open (OR = 12.2 [2.2-68], p 0.01); neither the use of patch (OR = 2.3, [0.5-10.4], p = 0.28) nor any other factors were associated with recurrence.In this single centre series where tension-free repair was advocated, patch repair of CDH was not associated with higher recurrence, though access route was.Cohort Study.Level III.

BACKGROUND Infants born moderate to late preterm constitute the majority of preterm births, yet guidelines for their nutritional care are unclear. Maternal milk is the most appropriate nutrition for these infants; however, its composition can be influenced by environmental factors. The present study therefore investigated perinatal predictors of human milk composition in a preterm cohort. METHODS Milk was collected during the DIAMOND trial (DIfferent Approaches to Moderate and late preterm Nutrition: Determinants of feed tolerance, body composition and development) from 169 mothers of 191 infants at three time-points (5 and 10 days post partum and 4 months' corrected age). Leptin, adiponectin and insulin-like growth factor-1 (IGF-1) were analysed by enzyme-linked immunosorbent assay. Generalised mixed models were used to evaluate associations between milk composition and maternal/infant/perinatal factors. RESULTS Most findings were independent of collection time-point. Gestational diabetes was associated with lower adiponectin. Higher adiponectin and lower leptin were associated with higher socioeconomic status, higher maternal education and ability to fully breastfeed at discharge from hospital. Higher leptin was associated with high perceived stress during hospital admission. Milk IGF-1 displayed sex-specific patterns in association with maternal social deprivation. CONCLUSION Maternal, infant and environmental factors during the perinatal period were associated with milk compositional profiles throughout lactation. Further clinical trials should investigate the impact of such changes in terms of long-term infant outcomes. IMPACT Human milk is the best nutrition for the infant. However, its composition may be susceptible to alterations determined by pathological conditions mother and infant may face throughout pregnancy and in the perinatal period. This study found that perinatal factors are associated with human milk composition from early to late lactation. If human milk composition throughout lactation is "programmed" during pregnancy or early lactation, infants who were exposed in utero to environmental insults may still be exposed to them during lactation. The impact of human milk compositional alteration on infant growth following perinatal pathological events requires further investigation.

Background: Respiratory syncytial virus (RSV) causes exacerbations of asthma and preschool wheeze (PSW). However, the anti-viral and repair responses of the bronchial epithelium in children with severe therapy-resistant asthma (STRA) and PSW are poorly understood. Methods: Children with STRA (age 12 [6-16] years), PSW (age 2 [1-5] years) and non-asthmatic controls (age 7 [2-14] years) underwent bronchoscopy with endobronchial brushings and biopsies. Anti-viral, wound injury responses were quantified in biopsies and primary bronchial epithelial cells (PBECs) in response to RSV, poly(I:C), house dust mite (HDM) or IL-33 using RT-qPCR, Luminex and live cell imaging. Collagen deposition and tissue expression of epithelial growth factor receptor (EGFR), IL-33 and receptor ST2 were investigated in bronchial biopsies. Results: PBECs from STRA and PSW had increased TLR3 gene expression and increased secretion of anti-viral and pro-inflammatory cytokines (IFN-γ, IL-6 and IL-13) in response to RSV compared to controls. Exposure of PBECs to concomitant TLR3 agonist poly(I:C) and HDM resulted in a significant reduction in epithelial cell proliferation in PSW compared to controls. Wound-healing was also impaired in PSW compared to controls at baseline and following IL-33 stimulation. In addition, tissue EGFR expression was significantly reduced in PSW and correlated with collagen deposition in endobronchial biopsies. Conclusions: Despite increased anti-viral responses, preschool children with severe wheeze had impaired airway epithelial proliferative responses following damage. This might be connected to the low expression of EGFR in PSW which may affect epithelial function and contribute to asthma pathogenesis. (Less)

The role of multiparametric MRI in diagnosis, staging and treatment planning for prostate cancer is well established. However, there remain several challenges to widespread adoption. One such challenge is the duration and cost of the examination. Abbreviated exams omitting contrast-enhanced sequences may help address this challenge. In this review, we will discuss the rationale for biparametric MRI for detection and characterization of clinically significant prostate cancer prior to biopsy and synthesize the published literature. We will weigh up the advantages and disadvantages to this approach and lay out a conceptual cost/benefit analysis regarding adoption of biparametric MRI.

Background: \ud The SARS-CoV-2 delta (B.1.617.2) variant was first detected in England in March, 2021. It has since rapidly become the predominant lineage, owing to high transmissibility. It is suspected that the delta variant is associated with more severe disease than the previously dominant alpha (B.1.1.7) variant. We aimed to characterise the severity of the delta variant compared with the alpha variant by determining the relative risk of hospital attendance outcomes.\ud \ud Methods: \ud This cohort study was done among all patients with COVID-19 in England between March 29 and May 23, 2021, who were identified as being infected with either the alpha or delta SARS-CoV-2 variant through whole-genome sequencing. Individual-level data on these patients were linked to routine health-care datasets on vaccination, emergency care attendance, hospital admission, and mortality (data from Public Health England's Second Generation Surveillance System and COVID-19-associated deaths dataset; the National Immunisation Management System; and NHS Digital Secondary Uses Services and Emergency Care Data Set). The risk for hospital admission and emergency care attendance were compared between patients with sequencing-confirmed delta and alpha variants for the whole cohort and by vaccination status subgroups. Stratified Cox regression was used to adjust for age, sex, ethnicity, deprivation, recent international travel, area of residence, calendar week, and vaccination status.\ud \ud Findings: \ud Individual-level data on 43 338 COVID-19-positive patients (8682 with the delta variant, 34 656 with the alpha variant; median age 31 years [IQR 17–43]) were included in our analysis. 196 (2·3%) patients with the delta variant versus 764 (2·2%) patients with the alpha variant were admitted to hospital within 14 days after the specimen was taken (adjusted hazard ratio [HR] 2·26 [95% CI 1·32–3·89]). 498 (5·7%) patients with the delta variant versus 1448 (4·2%) patients with the alpha variant were admitted to hospital or attended emergency care within 14 days (adjusted HR 1·45 [1·08–1·95]). Most patients were unvaccinated (32 078 [74·0%] across both groups). The HRs for vaccinated patients with the delta variant versus the alpha variant (adjusted HR for hospital admission 1·94 [95% CI 0·47–8·05] and for hospital admission or emergency care attendance 1·58 [0·69–3·61]) were similar to the HRs for unvaccinated patients (2·32 [1·29–4·16] and 1·43 [1·04–1·97]; p=0·82 for both) but the precision for the vaccinated subgroup was low.\ud \ud Interpretation: \ud This large national study found a higher hospital admission or emergency care attendance risk for patients with COVID-19 infected with the delta variant compared with the alpha variant. Results suggest that outbreaks of the delta variant in unvaccinated populations might lead to a greater burden on health-care services than the alpha variant.\ud \ud Funding: \ud Medical Research Council; UK Research and Innovation; Department of Health and Social Care; and National Institute for Health Research.

OBJECTIVES: The objectives of this exploratory study were to investigate the feasibility of multidimensional diffusion magnetic resonance imaging (MddMRI) in assessing diffusion heterogeneity at both a macroscopic and microscopic level in prostate cancer (PCa). MATERIALS AND METHODS: Informed consent was obtained from 46 subjects who underwent 3.0-T prostate multiparametric MRI, complemented with a prototype spin echo–based MddMRI sequence in this institutional review board–approved study. Prostate cancer tumors and comparative normal tissue from each patient were contoured on both apparent diffusion coefficient and MddMRI-derived mean diffusivity (MD) maps (from which microscopic diffusion heterogeneity [MKi] and microscopic diffusion anisotropy were derived) using 3D Slicer. The discriminative ability of MddMRI-derived parameters to differentiate PCa from normal tissue was determined using the Friedman test. To determine if tumor diffusion heterogeneity is similar on macroscopic and microscopic scales, the linear association between SD of MD and mean MKi was estimated using robust regression (bisquare weighting). Hypothesis testing was 2 tailed; P values less than 0.05 were considered statistically significant. RESULTS: All MddMRI-derived parameters could distinguish tumor from normal tissue in the fixed-effects analysis (P < 0.0001). Tumor MKi was higher (P < 0.05) compared with normal tissue (median, 0.40; interquartile range, 0.29–0.52 vs 0.20–0.18; 0.25), as was tumor microscopic diffusion anisotropy (0.55; 0.36–0.81 vs 0.20–0.15; 0.28). The MKi could not be predicted (no significant association) by SD of MD. There was a significant correlation between tumor volume and SD of MD (R(2) = 0.50, slope = 0.008 μm(2)/ms per millimeter, P < 0.001) but not between tumor volume and MKi. CONCLUSIONS: This explorative study demonstrates that MddMRI provides novel information on MKi and microscopic anisotropy, which differ from measures at the macroscopic level. MddMRI has the potential to characterize tumor tissue heterogeneity at different spatial scales.

Rust fungi (order: Pucciniales) constitute the largest group of plant parasitic fungi and include many species of agricultural importance. This includes the three wheat rust fungi (Puccinia graminis f. sp. tritici, Puccinia striiformis f. sp. tritici and Puccinia triticina) that have posed a threat to crop production throughout history. This chapter provides an overview of the wheat rust pathogen lifecycle that has been critical to the design of effective disease management strategies and discusses recent integration of basic biological knowledge and genomic-led tools within an epidemiological framework. Furthermore, we include a case study on the “field pathogenomics” technique, illustrating the value of genomic-based tools in disease surveillance activities. Bringing together advances in understanding basic pathogen biology, developments in modelling for disease forecasting and identification, alongside genomic-led advances in surveillance and resistance gene cloning, holds great promise for curtailing the threat of these notorious pathogens.

As influenza season was approaching in 2020, public health officials feared that influenza would worsen the COVID-19 situation [...]

PurposeConservation agriculture-based wheat production system (CAW) can serve as anex antemeasure to minimize loss due to climate risks, especially the extreme rainfall during the wheat production season in India. This study aims to examine whether farmers learn from their past experiences of exposure to climate extremes and use the knowledge to better adapt to future climate extremes.Design/methodology/approachThe authors used data collected from 184 farmers from Haryana over three consecutive wheat seasons from 2013-2014 to 2015-2016 and multivariate logit model to analyse the driver of the adoption of CAW as anex anteclimate risk mitigating strategies based on their learning and censored Tobit model to analyse the intensity of adoption of CAW as anex anteclimate risk mitigation strategy. Farmer’s knowledge and key barriers to the adoption of CAW were determined through focus group discussions.FindingsThe analysis shows that the majority of farmers who had applied CAW in the year 2014-2015 (a year with untimely excess rainfall during the wheat season) have continued to practice CAW and have increased the proportion of land area allocated to it. Many farmers shifted from CTW to CAW in 2015-2016.Practical implicationsWhile farmers now consider CAW as anex antemeasure to climate risks, a technology knowledge gap exists, which limits its adoption. Therefore, designing appropriate methods to communicate scientific evidence is crucial.Originality/valueThis paper uses three years panel data from 184 farm households in Haryana, India, together with focus groups discussions with farmers and interviews with key informants to assess if farmers learn adaptation to climate change from past climate extremes.

Purpose To evaluate MRI characteristics in vaginal recurrence of endometrial cancer (EC) including tumor volume shrinkage during salvage radiotherapy, and to identify imaging features associated with survival. Methods Patients with vaginal recurrence of EC treated with external beam radiotherapy (EBRT) followed by brachytherapy (BT), and with available pelvic MRI at two time points: baseline and/or before BT were retrospectively identified from 2004 to 2017. MRI features including recurrence location and tissue characteristics on T2- and T1-weighted images were evaluated at baseline only. Tumor volumes were measured both at baseline and pre-BT. Survival rates and associations were evaluated by Cox regression and Fisher’s exact test, respectively. Results Sixty-two patients with 36 baseline and 50 pre-BT pelvic MRIs were included (24/62 with both MRIs). Vaginal recurrence of EC was most commonly located in the vaginal apex (27/36, 75%). Tumors with a post-contrast enhancing peripheral rim or low T2 signal rim at baseline showed longer recurrence-free survival (RFS) (HR 0.2, 95% CI 0.1–0.9, P P P Conclusion Vaginal recurrences with rim enhancement at baseline MRI predicted improved RFS, while tumor volume shrinkage at pre-BT did not. Distal vaginal recurrence was more common in patients with LVSI and adjuvant RT at EC diagnosis.

Four dams on the lower Snake River in Washington State generate hydropower and allow for regional agriculture and barge shipping to Portland OR. However, the dams impede the migration of local salmon populations (Oncorhynchus spp.), which are in steep decline, and drastically impact the populations of salmon and orca whales, for whom salmon are a primary food source. For years, environmental groups have argued for breaching the dams; other interests counter that the dams are too critical to the economy of the region to lose; and federal agencies assert that the dams can remain and salmon populations will recover with mitigation techniques. Scientific and economic analyses, litigation, and elected officials’ efforts have not been able to move the issue towards a solution. Readers will examine the interests of primary actors in the issue, how they influence the policy process, the role of scientific and economic analyses, and possible approaches for resolving the issue.

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A 1.5-year-old ewe was presented with neurological signs that had been observed from about 2 days prior to death. There had been no clinical response to anti-inflammatory and antibiotic treatment. Histopathological examination of the brain revealed a severe and widespread eosinophilic meningoencephalomyelitis of unknown aetiology. Defining histological features included diffuse angiocentric eosinophilic infiltrates in the neuroparenchyma and meninges, neuronal necrosis, astrocytosis, neuropil vacuolation and occasional glial scars. Differential diagnostics for eosinophilic meningoencephalitis were taken into account and investigated by means of special stains, immunohistochemistry, bacteriology and polymerase chain reaction. No pathological changes or ancillary tests were supportive or revealed a specific aetiology for the condition and therefore it was considered idiopathic. Idiopathic meningoencephalitis is a rare disease, mainly described in man and rarely in dogs, with no apparent aetiological cause or potential breed predisposition. To our knowledge this is the first case of idiopathic eosinophilic meningoencephalitis in a sheep and provides a histopathological guideline for prospective comparative pathology studies.

ObjectiveChemotherapies of varying classes often cause neuropathy and debilitating chemotherapy-induced neuropathic pain (CINP) sufficient to limit treatment and reduce quality of life for many patients battling cancer. There are currently no effective preventative or alleviative treatments for CINP. Preclinical models have been developed to test candidate CINP treatments; however, studies using these models rarely provide direct comparisons of effects of different chemotherapies or assess the degree to which chemotherapies produce clinically relevant signs of pain-depressed behavior.MethodsMale and female Sprague-Dawley rats received four injections of vehicle, paclitaxel, oxaliplatin, vincristine, or bortezomib on alternate days. Mechanical hypersensitivity, body weight, and food-maintained operant responding were evaluated before, during, and for up to 42 days after initiation of treatment. Morphine potency and effectiveness to reverse chemotherapy-induced effects were also evaluated.ResultsAll four chemotherapies produced dose-dependent and sustained mechanical hypersensitivity in all rats. Vincristine and oxaliplatin produced transient weight loss and decreases in food-maintained operant responding in all rats, whereas paclitaxel and bortezomib produced lesser or no effect. At four weeks after treatment, operant responding was depressed only in paclitaxel-treated males. Morphine reversed mechanical hypersensitivity in all rats but failed to reverse paclitaxel-induced depression of operant responding in males.ConclusionsChemotherapy treatments sufficient to produce sustained mechanical hypersensitivity failed to produce sustained or morphine-reversible behavioral depression in rats. Insofar as pain-related behavioral depression is a cardinal sign of CINP in humans, these results challenge the presumption that these chemotherapy-dosing regimens are sufficient to model clinically relevant CINP in rats.

Glucose intolerance during pregnancy – a major driver of gestational diabetes mellitus (GDM) – has significant short- and long-term health consequences for both the mother and child. As GDM prevalence continues to escalate, there is growing need for preventative strategies. There is limited but suggestive evidence that myo-inositol (MI) and probiotics (PB) could improve glucose tolerance during pregnancy. The present study tested the hypothesis that MI and/or PB supplementation would reduce the risk of glucose intolerance during pregnancy. Female C57BL/6 mice were randomised to receive either no treatment, MI, PB (Lactobacillus rhamnosus and Bifidobacterium lactis) or both (MIPB) for 5 weeks. They were then provided with a high-fat diet for 1 week before mating commenced and throughout mating/gestation, while remaining on their respective treatments. An oral glucose tolerance test occurred at gestational day (GD) 16·5 and tissue collection at GD 18·5. Neither MI nor PB, separately or combined, improved glucose tolerance. However, MI and PB both independently increased adipose tissue expression of Ir, Irs1, Akt2 and Pck1, and PB also increased Pparγ. MI was associated with reduced gestational weight gain, whilst PB was associated with increased maternal fasting glucose, total cholesterol and pancreas weight. These results suggest that MI and PB may improve insulin intracellular signalling in adipose tissue but this did not translate to meaningful differences in glucose tolerance. The absence of fasting hyperglycaemia or insulin resistance suggests this is a very mild model of GDM, which may have affected our ability to assess the impact of these nutrients.

Objective:Maternal obesity is associated with obesity and metabolic disorders in offspring. However, there remains a paucity of data on strategies to reverse the effects of maternal obesity on maternal and offspring health. With maternal undernutrition, taurine supplementation improves outcomes in offspring mediated in part via improved glucose–insulin homeostasis. The efficacy of taurine supplementation in the setting of maternal obesity on health and well-being of offspring is unknown. We examined the effects of taurine supplementation on outcomes related to growth and metabolism in offspring in a rat model of maternal obesity.Design:Wistar rats were randomised to: 1) control diet during pregnancy and lactation (CON); 2) CON with 1.5% taurine in drinking water (CT); 3) maternal obesogenic diet (MO); or 4) MO with taurine (MOT). Offspring were weaned onto the control diet for the remainder of the study.Results:At day 150, offspring body weights and adipose tissue weights were increased in MO groups compared to CON. Adipose tissue weights were reduced in MOT versus MO males but not females. Plasma fasting leptin and insulin were increased in MO offspring groups but were not altered by maternal taurine supplementation. Plasma homocysteine concentrations were reduced in all maternal taurine-supplemented offspring groups. There were significant interactions across maternal diet, taurine supplementation and sex for response to an oral glucose tolerance test , a high-fat dietary preference test and pubertal onset in offspring.Conclusions:These results demonstrate that maternal taurine supplementation can partially ameliorate adverse developmental programming effects in offspring in a sex-specific manner.

Purpose Lumbosacral lipoma (LSL) is a severe occult spinal dysraphism, frequently associated with neurological, urological and orthopaedic complications. Whole spine imaging is typically performed to identify concomitant, but spatially separate, congenital anomalies. Our hypothesis: the incidence of additional, clinically significant abnormalities of the neuraxis is low; thus, imaging should be optimised at the lumbosacral region. We aim to assess the prevalence and relevance of LSL-associated lesions. Method A single-centre, retrospective, radiological review using a prospectively maintained operative database. Inclusion criteria: children ( Results One hundred twelve patients (40:72, M:F) aged 0.5 years (0.2–2.7) (median ± IQR) with LSL had whole spine MRI between 2001 and 2017. Classification of LSL: transitional 48 (43%); dorsal 30 (27%); caudal 28 (25%) and chaotic 6 (5%). Additional anomalies included syringohydromyelia 44 (39%), subcutaneous tract 19 (17%), abnormal vertebral segmentation 18 (16%), dermoid cyst 1 and 1 Chiari I deformity. There were no Chiari II malformations. No child required surgery for an associated lesion. Binary logistic regression revealed no factors associated with predicting secondary lesions. Conclusions In congenital LSL, additional anomalies of the neuraxis are typically loco-regional rather than pan-CNS and additional lesions are rarely clinically significant. The loco-regional distribution of anomalies suggests that only lumbosacral spinal imaging is required in the initial evaluation of LSL. Such a policy would lessen the anaesthetic/sedation time for children and reduce imaging cost per patient. MRI protocols could be refined to optimise imaging quality at the region of interest.

Climate change and extreme weather events undermine smallholder household food and income security in southern Africa. Climate Smart Agriculture (CSA) technologies comprise a suite of interventions that aim to sustainably increase productivity whilst helping farmers adapt their farming systems to climate change and to manage risk more effectively. Cost-benefit analysis (CBA) and a mixed methods approach were used to assess the likelihood of investment in various CSA technology combinations. The data were drawn respectively from 1440, 696, and 1448 sample households in Malawi, Mozambique and Zambia, covering 3622, 2106 and 5212 maize-legume plots in these countries over two years. The cost-benefit analysis and stochastic dominance results showed that CSA options that combined soil and water conservation management practices based on the principles of conservation agriculture (CA), improved varieties, and associations of cereal-legume crop species were economically viable and worth implementing for risk averse smallholder farmers. A dynamic mixed multinomial logit demonstrated that women's bargaining power, drought shock, and access to CSA technology information positively influenced the probability of investing in CSA technology combinations. This study provides evidence of the importance of cultural context, social relevance and intra-household decision-making in tailoring suitable combinations of CSA for smallholder farmers in southern Africa.

Purpose Radiation therapy is an essential intervention used in the treatment of more than half of cancer patients. With the increasing use of hypofractionated radiation regimens, concurrent use of radiation and chemotherapy, targeted agents and immunotherapy, the risk of radiation-induced toxicities is increased. However, much remains unknown about the molecular underpinnings responsible for radiation-induced toxicity. MicroRNA (miRNA) are small, non-coding RNA involved in post-transcriptional regulation of gene expression. miR-21 is an oncomiR that is dysregulated in a significant fraction of human malignancies, and its overexpression is linked to poor overall survival, chemoresistance, and radioresistance in several human cancers. However, the contribution of miR-21 in governing radiation sensitivity in normal, untransformed cells, and the impact of silencing this miRNA in normal tissues remains largely unexplored. Materials and Methods miR-21 levels were evaluated in tissues by qRT-PCR without and after total body irradiation (TBI). Mice lacking miR-21 were genetically engineered, subjected to TBI, and monitored for survival. Hematopoietic stem and progenitor cell (HSPC) numbers and function were assessed using flow cytometry, histology, complete blood cell counts, and bone marrow transplantation. Results miR-21 expression was increased in radiosensitive tissues, but not in radioinsensitive tissues following TBI in wild-type mice, suggesting it may have a critical function in the normal tissue response to irradiation. Compared to wild-type mice, mice lacking one or both alleles of miR-21 showed reduced numbers of HSPCs and increased sensitivity to an LD50/30 dose of TBI with evidence of bone marrow failure. Transplantation of wild-type bone marrow into irradiated miR-21-deficient mice rescued the mice from death. Conclusions Our data identify miR-21 as a critical component of HSPC viability and essential for bone marrow recovery following irradiation. Further investigation is warranted to determine whether miR-21 can be used to stratify patients at risk for hematopoietic toxicity following irradiation.

Food insecure families often consume inexpensive energy-dense yet nutrient-poor foods which contribute to increased chronic disease risk. This assessment quantifies the nutritional content of foods...

Diagnosis of prostate cancer is based on histologic evaluation of tumor architecture using a system known as the “Gleason score.” This diagnostic paradigm, while the standard of care, is time-consuming, shows intraobserver variability, and provides no information about the altered metabolic pathways, which result in altered tissue architecture. Characterization of the molecular composition of prostate cancer and how it changes with respect to the Gleason score (GS) could enable a more objective and faster diagnosis. It may also aid in our understanding of disease onset and progression. In this work, we present mass spectrometry imaging for identification and mapping of lipids and metabolites in prostate tissue from patients with known prostate cancer with GS from 6 to 9. A gradient of changes in the intensity of various lipids was observed, which correlated with increasing GS. Interestingly, these changes were identified in both regions of high tumor cell density, and in regions of tissue that appeared histologically benign, possibly suggestive of precancerous metabolomic changes. A total of 31 lipids, including several phosphatidylcholines, phosphatidic acids, phosphatidylserines, phosphatidylinositols, and cardiolipins were detected with higher intensity in GS (4+3) compared with GS (3+4), suggesting they may be markers of prostate cancer aggression. Results obtained through mass spectrometry imaging studies were subsequently correlated with a fast, ambient mass spectrometry method for potential use as a clinical tool to support image-guided prostate biopsy. Implications: In this study, we suggest that metabolomic differences between prostate cancers with different Gleason scores can be detected by mass spectrometry imaging.

New farming systems and management options are needed in South Asia as the intensive rice–wheat production system is set to become increasingly unsustainable under climate change. In the current study, six cropping systems options/treatments varying in tillage, crop establishment method, residue management, crop sequence and fertilizer and water management were evaluated using a cropping systems model under current (1980–2009) and future (2030 and 2050) climate scenarios in the state of Bihar, India. The treatments were current farmers' practice (CP), best fertilizer and water management practices, zero tillage (ZT) with no crop residue retention, ZT with partial crop residue retention (ZTPR), future conservation agriculture-based rice–wheat intensive cropping system (FCS-1) and future conservation agriculture-based maize–wheat intensive cropping system (FCS-2). The results indicate that climate change is likely to reduce rice–wheat system productivity under CP by 4% across Bihar. All the crop management options studied increased yield, water productivity and net returns over that of the CP under the current and future climate scenarios. However, the ZTPR treatment gave significantly higher relative yield, lower annual yield variability and a higher benefit-cost-ratio than the other treatments across cropping system components and climate periods. Although all the new cropping system treatments had a positive yield implication under the current climate (compared to CP), they did not contribute to adaptation under the future climate except FCS-2 in wheat. It is concluded that adaptation to future climate must integrate both cropping system innovations, and genetic improvements in stress tolerance.

Introduction: SARS-2-CoV infection, or COVID-19, is characterized by a heterogeneous evolution that goes from the absence of symptoms to a very serious disease, which can result in death. To date, we do not have instruments that allow us to easily predict the level of respiratory involvement in COVID-19. We hypothesized that there would be a relationship between the frequency content of patients cough sound and the severity of their disease. Methods: 36 COVID-19 patients (17 male, 52 (44 - 56) yrs.) with different degrees of severity of pneumonia were included in this study. Spontaneous cough or that obtained after induction maneuvers were recorded. Phase 1 and 2 of 129 individual cough epochs were identified, and several frequency-based features were explored. Results: Analysis shows a significant difference between groups in which pneumonia was present and absent for both maximum frequency and the variability of the frequency in phase 1 of the cough signal, as well as between the group in which pneumonia was absent and that in which pneumonia was severe (Fig. 1). Conclusions: The results presented suggest that aspects of the frequency content of the cough sound of COVID-19 patients are affected by the disease severity. Acknowledgment: This work was supported in part by Grant RTI2018-098472-B-I00 MCIU/AEI/FEDER, UE.

Livestock abortion is an important cause of productivity losses worldwide and many infectious causes of abortion are zoonotic pathogens that impact on human health. Little is known about the relative importance of infectious causes of livestock abortion in Africa, including in subsistence farming communities that are critically dependent on livestock for food, income, and wellbeing. We conducted a prospective cohort study of livestock abortion, supported by cross-sectional serosurveillance, to determine aetiologies of livestock abortions in livestock in Tanzania. This approach generated several important findings including detection of a Rift Valley fever virus outbreak in cattle; high prevalence of C. burnetii infection in livestock; and the first report of Neospora caninum, Toxoplasma gondii, and pestiviruses associated with livestock abortion in Tanzania. Our approach provides a model for abortion surveillance in resource-limited settings. Our findings add substantially to current knowledge in sub-Saharan Africa, providing important evidence from which to prioritise disease interventions.

SummarySome patients hospitalized with acute COVID19 suffer respiratory symptoms that persist for many months. To characterize the local and systemic immune responses associated with this form of ‘Long COVID’, we delineated the immune and proteomic landscape in the airway and peripheral blood of normal volunteers and patients from 3 to 6 months after hospital discharge. The bronchoalveolar lavage (but not peripheral blood) proteome was abnormal in patients with post-COVID19 lung disease with significantly elevated concentration of proteins associated with apoptosis, tissue repair and epithelial injury. This correlated with an increase in cytotoxic lymphocytes (especially tissue resident CD8+T cells), lactate dehydrogenase and albumin (biomarkers of cell death and barrier integrity). Follow-up of a subset of these patients greater than 1-year post-COVID19 indicated these abnormalities resolved over time. Collectively, these data indicate that COVID-19 results in a prolonged change to the airway immune landscape in those with persistent lung disease, with evidence of cell death and tissue repair linked to ongoing activation of cytotoxic T cells.HighlightsThe post-COVID19 airway is characterized by increased cytotoxic lymphocytes.Distinct airway proteomes are associated with the airway immune cell landscape.The peripheral blood does not predict immune-proteome alterations in the airway post-COVID19.Persistent abnormalities in the airway immune-proteome post-COVID19 airways correlate with ongoing epithelial damage.

BackgroundImmune hyperactivity is an important contributing factor to the morbidity and mortality of COVID-19 infection. Nasal administration of anti-CD3 monoclonal antibody downregulates hyperactive immune responses in animal models of autoimmunity through its immunomodulatory properties. We performed a randomized pilot study of fully-human nasal anti-CD3 (Foralumab) in patients with mild to moderate COVID-19 to determine if its immunomodulatory properties had ameliorating effects on disease.MethodsThirty-nine outpatients with mild to moderate COVID-19 were recruited at Santa Casa de Misericordia de Santos in Sao Paulo State, Brazil. Patients were randomized to three cohorts: 1) Control, no Foralumab (n=16); 2) Nasal Foralumab (100ug/day) given for 10 consecutive days with 6 mg dexamethasone given on days 1-3 (n=11); and 3) Nasal Foralumab alone (100ug/day) given for 10 consecutive days (n=12). Patients continued standard of care medication.ResultsWe observed reduction of serum IL-6 and C-reactive protein in Foralumab alonevs. untreated or Foralumab/Dexa treated patients. More rapid clearance of lung infiltrates as measured by chest CT was observed in Foralumab and Foralumab/Dexa treated subjectsvs. those that did not receive Foralumab. Foralumab treatment was well-tolerated with no severe adverse events.ConclusionsThis pilot study suggests that nasal Foralumab is well tolerated and may be of benefit in treatment of immune hyperactivity and lung involvement in COVID-19 disease and that further studies are warranted.

Rationale: Airway macrophages (AMs) are key regulators of the lung environment and are implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF), a fatal respiratory disease with no cure. However, knowledge about the epigenetics of AMs in IPF is limited. Objectives: To assess the role of epigenetic regulation of AMs during lung fibrosis. Methods: We undertook DNA methylation (DNAm) profiling by using Illumina EPIC (850k) arrays in sorted AMs from healthy donors (n = 14) and donors with IPF (n = 30). Cell-type deconvolution was performed by using reference myeloid-cell DNA methylomes. Measurements and Main Results: Our analysis revealed that epigenetic heterogeneity was a key characteristic of IPF AMs. DNAm "clock" analysis indicated that epigenetic alterations in IPF AMs were not associated with accelerated aging. In differential DNAm analysis, we identified numerous differentially methylated positions (n = 11) and differentially methylated regions (n = 49) between healthy and IPF AMs, respectively. Differentially methylated positions and differentially methylated regions encompassed genes involved in lipid (LPCAT1 [lysophosphatidylcholine acyltransferase 1]) and glucose (PFKFB3 [6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3]) metabolism, and importantly, the DNAm status was associated with disease severity in IPF. Conclusions: Collectively, our data identify that changes in the epigenome are associated with the development and function of AMs in the IPF lung.

Preoperative assessment of the proximity of critical structures to the tumors is crucial in avoiding unnecessary damage during prostate cancer treatment. A patient-specific 3D anatomical model of those structures, namely the neurovascular bundles (NVB) and the external urethral sphincters (EUS), can enable physicians to perform such assessments intuitively. As a crucial step to generate a patient-specific anatomical model from preoperative MRI in a clinical routine, we propose a multi-class automatic segmentation based on an anisotropic convolutional network. Our specific challenge is to train the network model on a unique source dataset only available at a single clinical site and deploy it to another target site without sharing the original images or labels. As network models trained on data from a single source suffer from quality loss due to the domain shift, we propose a semi-supervised domain adaptation (DA) method to refine the model’s performance in the target domain. Our DA method combines transfer learning and uncertainty guided self-learning based on deep ensembles. Experiments on the segmentation of the prostate, NVB, and EUS, show significant performance gain with the combination of those techniques compared to pure TL and the combination of TL with simple self-learning ($${p} p < 0.005 for all structures using a Wilcoxon’s signed-rank test). Results on a different task and data (Pancreas CT segmentation) demonstrate our method’s generic application capabilities. Our method has the advantage that it does not require any further data from the source domain, unlike the majority of recent domain adaptation strategies. This makes our method suitable for clinical applications, where the sharing of patient data is restricted.

Background:Differing environmental conditions experienced by mother-infant dyads may influence composition of the milk received by the infant. As a consequence, diverse milk compositional profiles may contribute to different postnatal outcomes, especially in infants facing adverse perinatal environments. We investigated whether variability in milk concentrations of key metabolic hormones is associated with different growth outcomes in infants born preterm, a perinatal complication known to impact on infant growth.Methods:Human milk samples were collected from 169 mothers of 191 infants enrolled in the DIAMOND trial, a randomized trial of nutrition for moderate-late preterm infants, at 5 and 10 days postpartum and again at 4 months' corrected age and analyzed for leptin, adiponectin and insulin-like growth factor (IGF)-1. Infant weight and body composition were measured at birth, discharge and 4 months' corrected age. Multiple linear regression models were used to examine correlations between milk hormone concentrations, weight z-scores and body composition at discharge and 4 months' corrected age, and weight gain from birth to 4 months' corrected age. Sex-specific interactions were examined.Results:Higher milk IGF-1 concentrations on day 5 after birth were associated with greater infant fat-free mass at 4 months' corrected age. Milk IGF-1 concentrations at 4 months were positively associated with fat mass and fat-free mass at 4 months in boys but not girls. Milk leptin concentrations on day 5 after birth were positively associated with fat mass at discharge from hospital, but negatively associated with fat mass at 4 months' corrected age. No significant association was found for milk adiponectin concentrations.Conclusion:Milk IGF-1 and leptin concentrations in mothers of moderate-late preterm babies are associated with different growth and body composition through to 4 months' corrected age and these associations are often different in boys and girls. The sex-specific effects of nutrient and hormone exposure during early life in preterm infants warrants further investigation to optimize the nutritional care these infants receive, particularly in hospital, where the same nutrition is provided to boys and girls.

Whether young adults who are infected with SARS-CoV-2 are at risk of subsequent infection is uncertain. We investigated the risk of subsequent SARS-CoV-2 infection among young adults seropositive for a previous infection.This analysis was performed as part of the prospective COVID-19 Health Action Response for Marines study (CHARM). CHARM included predominantly male US Marine recruits, aged 18-20 years, following a 2-week unsupervised quarantine at home. After the home quarantine period, upon arrival at a Marine-supervised 2-week quarantine facility (college campus or hotel), participants were enrolled and were assessed for baseline SARS-CoV-2 IgG seropositivity, defined as a dilution of 1:150 or more on receptor-binding domain and full-length spike protein ELISA. Participants also completed a questionnaire consisting of demographic information, risk factors, reporting of 14 specific COVID-19-related symptoms or any other unspecified symptom, and brief medical history. SARS-CoV-2 infection was assessed by PCR at weeks 0, 1, and 2 of quarantine and participants completed a follow-up questionnaire, which included questions about the same COVID-19-related symptoms since the last study visit. Participants were excluded at this stage if they had a positive PCR test during quarantine. Participants who had three negative swab PCR results during quarantine and a baseline serum serology test at the beginning of the supervised quarantine that identified them as seronegative or seropositive for SARS-CoV-2 then went on to basic training at Marine Corps Recruit Depot-Parris Island. Three PCR tests were done at weeks 2, 4, and 6 in both seropositive and seronegative groups, along with the follow-up symptom questionnaire and baseline neutralising antibody titres on all subsequently infected seropositive and selected seropositive uninfected participants (prospective study period).Between May 11, 2020, and Nov 2, 2020, we enrolled 3249 participants, of whom 3168 (98%) continued into the 2-week quarantine period. 3076 (95%) participants, 2825 (92%) of whom were men, were then followed up during the prospective study period after quarantine for 6 weeks. Among 189 seropositive participants, 19 (10%) had at least one positive PCR test for SARS-CoV-2 during the 6-week follow-up (1·1 cases per person-year). In contrast, 1079 (48%) of 2247 seronegative participants tested positive (6·2 cases per person-year). The incidence rate ratio was 0·18 (95% CI 0·11-0·28; p0·001). Among seropositive recruits, infection was more likely with lower baseline full-length spike protein IgG titres than in those with higher baseline full-length spike protein IgG titres (hazard ratio 0·45 [95% CI 0·32-0·65]; p0·001). Infected seropositive participants had viral loads that were about 10-times lower than those of infected seronegative participants (ORF1ab gene cycle threshold difference 3·95 [95% CI 1·23-6·67]; p=0·004). Among seropositive participants, baseline neutralising titres were detected in 45 (83%) of 54 uninfected and in six (32%) of 19 infected participants during the 6 weeks of observation (ID50 difference p0·0001).Seropositive young adults had about one-fifth the risk of subsequent infection compared with seronegative individuals. Although antibodies induced by initial infection are largely protective, they do not guarantee effective SARS-CoV-2 neutralisation activity or immunity against subsequent infection. These findings might be relevant for optimisation of mass vaccination strategies.Defense Health Agency and Defense Advanced Research Projects Agency.

Understanding major climate risks, adaptation strategies, and factors influencing the choice of those strategies is crucial to reduce farmers’ vulnerability. Employing comprehensive data from 2822 farm households in Ethiopia and Kenya (East Africa; EA) and 1902 farm households in Bangladesh, India, and Nepal (South Asia; SA), this study investigates the main climate risks that farmers faced and the adaptation strategies they used. Among others, excessive rainfall and heightened crop pest/disease incidence are commonly observed climate-induced risks in all study areas, while cyclones and salinity are unique to Bangladesh. Drought is prevalent in Ethiopia, India, Kenya, and Nepal. Farmers in those countries responded with strategies that include change in farming practices, sustainable land management, reduce consumption, sell assets, use savings and borrowings, seek alternative employment and assistance from government or NGO. In general, farmers faced several multiple climate risks simultaneously and they responded with multiple adaptation strategies. Therefore, this study used a multivariate probit (MVP) approach to examine the factors influencing the adoption of adaptation strategies. Unlike other studies, we also tested and corrected for possible endogeneity in model estimation. All the countries mentioned have low adaptive capacity to address climate change, which is further weakened by inadequate governance and inefficient institutions. We observed significant differences in the choice of adaptation strategies between male-headed households (MHHs) and female-headed households (FHHs), as well as across countries. Generally, MHHs are more likely to seek additional employment and change agricultural practices, while FHHs and households headed by older persons tend to reduce consumption and rely on savings and borrowings. Institutional support for adaptation is much less in EA compared to SA. Training on alternative farming practices, enhancing non-farm employment options, better institutional support, and social security for older farmers are crucial for climate change adaptation in both regions.