Schizophrenia copy number variants and associative learning.

Large-scale genomic studies have made major progress in identifying genetic risk variants for schizophrenia. A key finding from these studies is that there is an increased burden of genomic copy number variants (CNVs) in schizophrenia cases compared with controls. The mechanism through which these CNVs confer risk for the symptoms of schizophrenia, however, remains unclear. One possibility is that schizophrenia risk CNVs impact basic associative learning processes, abnormalities of which have long been associated with the disorder. To investigate whether genes in schizophrenia CNVs impact on specific phases of associative learning we combined human genetics with experimental gene expression studies in animals. In a sample of 11 917 schizophrenia cases and 16 416 controls, we investigated whether CNVs from patients with schizophrenia are enriched for genes expressed during the consolidation, retrieval or extinction of associative memories. We show that CNVs from cases are enriched for genes expressed during fear extinction in the hippocampus, but not genes expressed following consolidation or retrieval. These results suggest that CNVs act to impair inhibitory learning in schizophrenia, potentially contributing to the development of core symptoms of the disorder.

Parenchymal pattern in women with dense breasts. Variation with age and impact on screening outcomes: observations from a UK screening programme.

OBJECTIVES: To assess patterns of parenchymal tissue on mammography in women with dense breasts and to determine how this varies with age and affects recall to assessment and cancer diagnosis. METHOD: Breast density data was obtained in women attending routine mammographic screening from April 2013 to March 2015 using automated breast density assessment software. Women with the densest breasts were selected for visual interpretation of parenchymal pattern (PP). One hundred non-assessed women, aged 50, 55, 60, 65 and 69-71 years (total = 500), provided controls. Cases included women recalled for assessment (mastectomy or implants excluded) (total = 280). Mammograms reviewed by ten readers and PP classified as: (1) very smooth; (2) mainly smooth; (3) mixed; (4) mainly nodular; (5) very nodular. The ratio of women in each category at each age and screening outcomes were compared by Pearson's chi-squared test. RESULTS: Reader agreement for scoring PP was good (intraclass correlation = 0.6302). Proportions of women in each PP category were similar at all ages for controls (p = 0.147) and cases (p = 0.657). The ratio of PP categories did not vary significantly with age in those who underwent biopsy (p = 0.484). Thirty-four cancers were diagnosed. There was a significant correlation between a diagnosis of cancer and nodular PP compared to not nodular PP (p = 0.043). CONCLUSIONS: The ratio of smooth to nodular pattern in women with the densest breasts did not vary with age. The PP of the breast tissue did not affect likelihood of recall to assessment or biopsy. There was a significant relationship between a nodular parenchymal pattern and diagnosis of cancer. KEY POINTS: • This paper shows that there is good agreement between mammogram readers when classifying mammographic PP on a five-point scale from very smooth to very nodular. • In non-assessed women with the densest breasts, there is no significant change in the proportions of smooth to nodular patterns with increasing age. • The likelihood of recall for further assessment or biopsy at assessment is not related to PP in women with highest breast density. • When recalled for further assessment, significantly more women are diagnosed with cancer in the group with nodular PP on mammography when compared with smooth and mixed patterns.

NHS Breast Screening multidisciplinary working group guidelines for the diagnosis and management of breast lesions of uncertain malignant potential on core biopsy (B3 lesions).

Needle core biopsy is considered the histological diagnostic method of choice for screen-detected breast lesions. Although the majority are definitively diagnosed as normal, benign, or malignant, approximately 7% are categorised as B3, of uncertain malignant potential. These include a wide range of lesions with different risks of associated malignancy from <2% to approaching 40% from literature review in UK practice. Historically, these have typically been surgically excised as a diagnostic procedure but the majority are then proven to be benign. An alternative approach, for many of these lesions, is thorough sampling/excision by vacuum-assisted biopsy techniques to exclude the presence of co-existing carcinoma. This would potentially reduce the benign open biopsy rate whilst maintaining accuracy of cancer diagnosis. A group from the Radiology, Surgery, and Pathology NHS Breast Screening Programme Co-ordinating Committees and an additional co-opted expert were charged with review and development of guidelines for the clinical management of B3 lesions. The guidelines reflect suggested practice as stated by the NHS Breast Screening Programme and approved by the Royal College of Radiologists.

Disinhibited eating mediates differences in attachment insecurity between bariatric surgery candidates/recipients and lean controls.

Previous research has shown that attachment anxiety is a good predictor of body mass index. This relationship is significantly mediated by disinhibited (over-) eating and is likely to reflect a specific form of affect regulation. This study explored whether obese bariatric surgery candidates (BSC; N=34) and bariatric surgery recipients (BSR; N=15) would show higher levels of attachment insecurity (higher attachment anxiety and/or higher attachment avoidance) than a group of age and gender-matched lean controls (N=54). Mediation analyses showed that compared to lean controls (M=2.96, SE=0.1), both BSC (M=3.5, SE=0.2) and BSR (M=3.4, SE=0.2) groups had a more insecure attachment orientation. These relationships were significantly mediated by disinhibited eating (BSC: lower limit confidence interval (LLCI)=0.06 and upper limit confidence interval (ULCI)=0.62; BSR: LLCI=0.02 and ULCI=0.76). There was no such relationship when the BSC and BSR groups were compared (LLCI=-0.15 & ULCI=0.3). These observations suggest that attachment insecurity may be a risk factor for obesity and bariatric surgery because of associated disinhibited eating. Moreover, these factors may be important to consider when bariatric surgery results in poor outcomes.

Image processing can cause some malignant soft-tissue lesions to be missed in digital mammography images.

AIM: To investigate the effect of image processing on cancer detection in mammography. METHODS AND MATERIALS: An observer study was performed using 349 digital mammography images of women with normal breasts, calcification clusters, or soft-tissue lesions including 191 subtle cancers. Images underwent two types of processing: FlavourA (standard) and FlavourB (added enhancement). Six observers located features in the breast they suspected to be cancerous (4,188 observations). Data were analysed using jackknife alternative free-response receiver operating characteristic (JAFROC) analysis. Characteristics of the cancers detected with each image processing type were investigated. RESULTS: For calcifications, the JAFROC figure of merit (FOM) was equal to 0.86 for both types of image processing. For soft-tissue lesions, the JAFROC FOM were better for FlavourA (0.81) than FlavourB (0.78); this difference was significant (p=0.001). Using FlavourA a greater number of cancers of all grades and sizes were detected than with FlavourB. FlavourA improved soft-tissue lesion detection in denser breasts (p=0.04 when volumetric density was over 7.5%) CONCLUSIONS: The detection of malignant soft-tissue lesions (which were primarily invasive) was significantly better with FlavourA than FlavourB image processing. This is despite FlavourB having a higher contrast appearance often preferred by radiologists. It is important that clinical choice of image processing is based on objective measures.

Women's interest in a personal breast cancer risk assessment and lifestyle advice at NHS mammography screening.

Background: Although mortality from breast cancer is declining, incidence continues to increase and is often detected at routine NHS screening. Most middle aged and older women in England attend for screening every 3 years. Assessing their personal breast cancer risk and providing preventative lifestyle advice could help to further reduce breast cancer incidence. Methods: A cross-sectional, self-complete postal survey measured attendees' interest in having a personal risk assessment, expected impact on screening attendance, knowledge of associations between lifestyle and breast cancer and preferred ways of accessing preventative lifestyle advice. Results: A total of 1803/4948 (36.4%) completed questionnaires were returned. Most participants (93.7%) expressed interest in a personal risk assessment and 95% (1713/1803) believed it would make no difference or encourage re-attendance. Two-thirds (1208/1803) associated lifestyle with breast cancer, but many were unaware of specific risks such as weight gain, obesity, alcohol consumption and physical inactivity. NHS sourced advice was expected to be more credible than other sources, and booklets, brief counselling or an interactive website were most preferred for accessing this. Conclusions: Attendees appear to welcome an intervention that would facilitate more proactive clinical and lifestyle prevention and address critical research gaps in breast cancer prevention and early detection.

Waterscape determinants of net mercury methylation in a tropical wetland.

The periphyton associated with freshwater macrophyte roots is the main site of Hg methylation in different wetland environments in the world. The aim of this study was to test the use of connectivity metrics of water bodies, in the context of patches, in a tropical waterscape wetland (Guapore River, Amazonia, Brazil) as a predictor of potential net methylmercury (MeHg) production by periphyton communities. We sampled 15 lakes with different patterns of lateral connectivity with the main river channel, performing net mercury methylation potential tests in incubations with local water and Eichhornia crassipes root-periphyton samples, using (203)HgCl2 as a tracer. Physico-chemical variables, landscape data (morphological characteristics, land use, and lateral connection type of water bodies) using GIS resources and field data were analyzed with Generalized Additive Models (GAM). The net Me(203)Hg production (as % of total added (203)Hg) was expressive (6.2-25.6%) showing that periphyton is an important matrix in MeHg production. The model that best explained the variation in the net Me(203)Hg production (76%) was built by the variables: connection type, total phosphorus and dissolved organic carbon (DOC) in water (AICc=48.324, p=0.001). Connection type factor was the best factor to model fit (r(2)=0.32; p=0.008) and temporarily connected lakes had higher rates of net mercury methylation. Both DOC and total phosphorus showed positive significant covariation with the net methylation rates (r(2)=0.26; p=0.008 and r(2)=0.21; p=0.012 respectively). Our study suggests a strong relationship between rates of net MeHg production in this tropical area and the type of water body and its hydrological connectivity within the waterscape.

Mid- to late term hypoxia in the mouse alters placental morphology, glucocorticoid regulatory pathways and nutrient transporters in a sex-specific manner.

Maternal hypoxia is a common perturbation that can disrupt placental and thus fetal development, contributing to neonatal impairments. Recently, evidence has suggested that physiological outcomes are dependent upon the sex of the fetus, with males more susceptible to hypoxic insults than females. This study investigated the effects of maternal hypoxia during mid- to late gestation on fetal growth and placental development and determined if responses were sex specific. CD1 mice were housed under 21% or 12% oxygen from embryonic day (E) 14.5 until tissue collection at E18.5. Fetuses and placentas were weighed before collection for gene and protein expression and morphological analysis. Hypoxia reduced fetal weight in both sexes at E18.5 by 7% but did not affect placental weight. Hypoxia reduced placental mRNA levels of the mineralocorticoid and glucocorticoid receptors and reduced the gene and protein expression of the glucocorticoid metabolizing enzyme HSD11B2. However, placentas of female fetuses responded differently to maternal hypoxia than did placentas of male fetuses. Notably, morphology was significantly altered in placentas from hypoxic female fetuses, with a reduction in placental labyrinth blood spaces. In addition mRNA expression of Glut1, Igf2 and Igf1r were reduced in placentas of female fetuses only. In summary, maternal hypoxia altered placental formation in a sex specific manner through mechanisms involving placental vascular development, growth factor and nutrient transporter expression and placental glucocorticoid signalling. This study provides insight into how sex differences in offspring disease development may be due to sex specific placental adaptations to maternal insults.

Medical service redesign shares the load saving 6000 bed days and improving morale.

BACKGROUND AND AIMS: In 2010, demand on the Auckland City Hospital general medical service exceeded capacity. A review by the Royal Australasian College of Physicians was critical of training offered to registered medical officers, and low morale was a problem across the service. Management offered support for an improved model that would solve these problems. METHODS: A project to redesign the general medical service was undertaken. Baseline analysis found uneven workload and insufficient capacity at peak times for patient presentations. Workshops involving the entire service led to a new model that splits workload and teams into patients likely to have a short stay from those requiring longer, ward-based care. Admissions are now distributed over 12 teams on weekdays and 4 on the weekends. There was an increase of approximately 2.5 in consultant full time equivalents but no change in registrar or house officer staffing. RESULTS: Since the introduction of the new model, the average length of stay has fallen from 3.7 to 3.2 days (14%) and the median length of stay by 28%, resulting in a saving of 6000 bed days per year. Readmission, inpatient and 30-day mortality rates are unchanged. These results have been sustained over 18 months with signs of continuing improvement. CONCLUSION: This project owes its success to the following factors - management support; iterative engagement of a range of staff; provision of timely data analysis; increases in senior medical officer staffing and reorganisation leading to more predictable and fair work practices. One challenge is discontinuity, whether between doctors and patients or within the medical team.

The gut microbiota in adults with cystic fibrosis compared to colorectal cancer.

BACKGROUND: Gut dysbiosis is implicated in colorectal cancer (CRC) pathogenesis. Cystic fibrosis (CF) is associated with both gut dysbiosis and increased CRC risk. We therefore compared the faecal microbiota from individuals with CF to CRC and screening samples. We also assessed changes in CRC-associated taxa before and after triple CF transmembrane conductance regulator (CFTR) modulator therapy. METHODS: Bacterial DNA amplification comprising V4 16S rRNA analysis was conducted on 84 baseline and 53 matched follow-up stool samples from adults with CF. These data were compared to an existing cohort of 430 CRC and 491 control gFOBT samples from the NHS Bowel Cancer Screening Programme. Data were also compared to 26 previously identified CRC-associated taxa from a published meta-analysis. RESULTS: Faecal CF samples had a lower alpha diversity and clustered distinctly from both CRC and control samples, with no clear clinical variables explaining the variation. Compared to controls, CF samples had an increased relative abundance in 6 of the 20 enriched CRC-associated taxa and depletion of 2 of the 6 taxa which have been reported as reduced in CRC. Commencing triple modulator therapy had subtle influence on the relative abundance of CRC-associated microbiota (n = 23 paired CF samples). CONCLUSIONS: CF stool samples were clearly dysbiotic, clustering distinctly from both CRC and control samples. Several bacterial shifts in CF samples resembled those observed in CRC. Studies assessing the impact of dietary or other interventions and the longer-term use of CFTR modulators on reducing this potentially pro-oncogenic milieu are needed.

Transgenic expression of the FTDP-17 tauV337M mutation in brain dissociates components of executive function in mice.

Frontotemporal lobe dementia (FTD) is a heterogeneous range of disorders, a subset of which arise from fully penetrant, autosomal dominant point mutations in the gene coding for the microtubule associated protein tau. These genetic tauopathies are associated with complex behavioural/cognitive disturbances, including compromised executive function. In the present study, we modelled the effects of the FTD with Parkinsonism linked to chromosome 17 (FTDP-17) tauV337M mutation (known as the Seattle Family A mutation) expressed in mice on executive processes using a novel murine analogue of the Stroop task. Employing biconditional discrimination procedures, Experiment 1 showed that normal mice, but not mice with excitotoxic lesions of the medial prefrontal cortex, were able to use context cues to resolve response conflict generated by incongruent stimulus compounds. In contrast to predictions, response conflict resolution was not disrupted by the tauV337M mutation (Experiment 2). However, while context appropriate actions were goal-directed in wild-type mice, performance of tauV337M mice was not goal-directed (Experiment 3). The results indicate that the tauV337M mutation in mice disrupts, selectively, a subset of processes related to executive function.

Human risk assessment of ash soil after 2020 wildfires in Pantanal biome (Brazil).

Wildfires have increased in the last years and, when caused by intentional illegal burnings, are frequently run out of control. Wildfire has been pointed out as an important source of polycyclic aromatic hydrocarbons (PAHs) and trace elements (TEs) - such as, As, Ni, and Pb - to environmental compartments, and thus may pose a risk to human health and to the ecosystem. In 2020, the Brazilian biome, Pantanal, faced the largest losses by wildfires in the last 22 years. Ashes from the topsoil layer in Pantanal were collected after these wildfires at 20 sites divided into the sediment, forest, PF, PS, and degraded sites. Toxicity and associated risks for human health were also evaluated. The areas highly impacted by wildfires and by artisanal gold mining activities showed higher concentrations for TEs and PAHs than the protected areas. Pb varied from 8 ± 4 to 224 ± 81 mg kg-1, and total PAH concentration ranged between 880 ± 314 and 1350 ± 70 ng g-1, at sites impacted by anthropogenic activities. Moreover, health risk assessments for TE and PAH indicated a potentially great risk for children and adults, via ingestion, inhalation, and dermal pathway. The carcinogenic risks exceeded reference values, for both TE and PAH, suggesting harmful conditions, especially for vulnerable groups, such as children and the elderly. Supplementary Information: The online version contains supplementary material available at 10.1007/s11869-022-01248-2.

Silver and nanoparticles of silver in wound dressings: a review of efficacy and safety.

Wound infections present a significant clinical challenge, impacting on patient morbidity and mortality, with significant economic implications. Silver-impregnated wound dressings have the potential to reduce both wound bioburden and healing time. The silver ion Ag+ is the active antimicrobial entity; it can interfere with thiol (-SH) groups and provoke the generation of reactive oxygen species (ROS), a major contributor to its antibacterial efficacy. Recently, silver nanoparticles have gained considerable interest in wound bioburden reduction and in anti-inflammation, as they can release Ag+ ions at a greater rate than bulk silver, by virtue of their large surface area. If released from dressings, they also have the potential to cross biological compartments. This review aims to consolidate recent findings as to the efficacy and safety of different formulations of silver used as an antiseptic agent in dressings, summarising the features of silver nanomaterials, with particular attention to the dose-dependencies for biological effects, highlighting the need for information on their uptake and potential biological effects.

Rhamphotheca as a useful indicator of mercury in seabirds.

The evaluation of mercury (Hg) toxicity in wildlife species has prompted a search for sensitive indicators to accurately measure the body burden of Hg. Despite the extensive use of feathers as an indicator of Hg in birds, they do not appear to be an entirely suitable indicator of the extent of contamination in certain conditions and bird species since Hg levels are influenced by the growth period, timing of the last moult and migration. This research aimed to evaluate rhamphotheca as a potential indicator of environmental Hg concentrations in seabirds. We used culled yellow-legged gulls (Larus michahellis) (n = 20) and determined THg in rhamphotheca and feathers. We distinguished between upper and lower rhamphotheca, and divided each one into 16 equal portions along the culmen to analyse their THg content spatially. In each bird, THg was also determined in primary (P1) and secondary (S8) feathers and compared with rhamphotheca. The median (25th, 75th percentile) rhamphotheca Hg concentration was 13.44 (9.63, 17.46) µg/g, which was twofold higher than in the feathers 7.56 (4.88, 12.89) µg/g. Median THg in rhamphotheca was significantly higher (p < 0.05) in females 15.05 (10.35, 23.04) µg/g than in males 12.34 (8.57, 15.19) µg/g, whereas no differences (p > 0.05) were found in the feathers. No significant differences in Hg levels were found between upper and lower beak mandibles or along either. In contrast, significant differences in Hg concentrations were found between the P1 and S8 feathers (mean, 12.04 vs. 6.04 µg/g). No correlation was found between Hg content in rhamphotheca and feathers. Mercury levels in rhamphotheca exhibited stronger significant relationships with weight (R2 = 0.568), length (R2 = 0.524) and culmen (R2 = 0.347) than the levels in the feathers, which showed no correlation. Overall, our results suggest that rhamphotheca is a suitable tissue indicator for Hg monitoring in gulls; however, further studies are needed to extend our research to other bird species.

Attachment anxiety, disinhibited eating, and body mass index in adulthood.

Several studies report a relationship between body mass index (BMI) and disinhibited eating (a failure to restrict intake and to overeat). However, the aetiology of disinhibited eating has received scant attention. In this study, we consider a role for 'attachment orientation', a trait that reflects the quality of bonding in early life and remains stable throughout adulthood. Participants (N = 200, females = 135, BMI range from 17.4 to 41.1 kg m(-2)) completed measures of disinhibition and attachment orientation. 'Attachment anxiety' was a good predictor of disinhibited eating (P<0.001). Furthermore, mediation analysis confirmed that it is through this relationship that attachment anxiety also predicts BMI (P=0.02). These findings are consistent with other studies, showing an association between attachment orientation and other disinhibited behaviours, including alcohol and substance abuse. Our interpretation is that disinhibited eaters engage in external affect regulation. In doing so, they seek to mitigate the anxiety associated with poor interpersonal attachments.

Effects of anesthetic agents on socially transmitted olfactory memories in mice.

Mice can learn a food preference from odor cues transmitted on the breath of a conspecific, even if the "demonstrator" is anesthetized. To our knowledge there are no studies examining the effect of anesthetizing the "observer" on development of memory for socially transmitted food preferences (STFP). In Experiment 1 we found that 2-4 month-old F2 C57Bl/6x129sv male and female mice demonstrated a STFP after a 5min exposure to an anesthetized demonstrator mouse when tested 24h later. In Experiment 2, observer mice anesthetized with Sagatal (60 mg/kg) prior to the "social interaction" preferentially avoided the cued food when tested 24h later. This aversion was not due to any overt aversive effects of this dose of Sagatal because mice that ate the food and were then anesthetized, or could only smell the food for 5 min while anesthetized, showed no preference or aversion. In a third experiment we found that the Sagatal-induced aversion was not a general property of anesthesia because there were varied results produced by observer mice treated with anesthetic drugs with different mechanisms of action. Vetalar (200mg/kg) and Rompun (10 mg/kg) treated animals ate similar amounts of cued and non-cued food at test, indicating an absence of learning. Hypnorm (0.5 ml/kg) treated animals showed a preference for the cued food whereas those treated with Hypnovel (2.5 ml/kg) showed an aversion to the cued food. These results show that the food aversion observed with Sagatal is not a general property of anesthetic agents, but appears to be restricted to those acting primarily on the GABAergic system. Thus, we have shown that under certain conditions it is possible for an anesthetized observer mouse to learn a preference or aversion of a socially-linked olfactory cue.

Preparing healthcare facilities to operate safely and effectively during the COVID-19 pandemic: The missing piece in the puzzle.

The stated objective of the COVID-19 lockdown was to allow time to prepare healthcare facilities. Preparation must include administrative and environmental measures, which when combined with personal protective equipment, minimise the risk of the spread of infection to patients and healthcare workers (HCWs) in facilities, allowing HCWs to safely provide essential services during the pandemic and limit the indirect effects of COVID-19 caused by healthcare disruption. We present our model for facility preparation based on colour-coded zones, social distancing, hand hygiene, rapid triage and separate management of symptomatic patients, and attention to infection transmission prevention between HCWs in communal staff areas. This model specifically addresses the challenges in preparing a facility for COVID-19 in a low-resource setting and in rural areas. In addition, we include links to resources to allow workers in low-resource settings to prepare their facilities adequately.

Cyanobacteria as regulators of methylmercury production in periphyton.

Biotic mercury (Hg) methylation appears to depend on factors such as microbial activity and the concentration and bioavailability of Hg2+ to the Hg-methylating organisms. Recently, the presence of cyanobacteria has been linked with high methylmercury (MeHg) concentrations. The aim of this work was to test MeHg production in microcosms, in relation to the amount of periphytic cyanobacteria, dissolved organic matter (DOM) and phosphorus concentrations, as well as periphytic primary production rates. Water and periphyton samples were collected for cultivation and isolation of cyanobacteria from the Guaporé River floodplain, Brazil. We cultivated the periphyton in microcosms with different concentrations of cyanobacteria, total phosphorus and DOM. The highest net MeHg production (6.8 to 24.6% of added Hg d-1) occurred in the microcosm with added cyanobacteria, followed by microcosms with added phosphorus (6.1 to 11.4%) and added DOM (6.4 to 9.1%). Positive correlations were found between MeHg production, addition of cyanobacteria, phosphorus and DOM and periphytic primary productivity. Our results bring the first direct experimental evidence of the relevance of cyanobacteria and primary production as regulators of MeHg production in periphyton. These findings have numerous implications for the management of natural and engineered wetlands.

Seasonal changes in peryphytic microbial metabolism determining mercury methylation in a tropical wetland.

Mercury (Hg) methylation, a key process in the biogeochemical cycle of Hg, is mainly attributed to sulfate-reducing bacteria and methanogenic Archaea. However, environmental regulation by these groups has not yet been ascertained in tropical environments, especially in respect to the seasonal flood flooding. This work evaluated the variation of net methylmercury production potential in relation to biological characteristics of the periphyton, environmental factors, and flood pulse seasons. Our results indicate that there is a seasonal change between metabolic groups as main Hg methylators, sulfate-reducing bacteria in the dry season and methanogenic Archaea in the flood season. In addition, there was a positive relationship between dissolved organic carbon (DOC), phosphorus, cyanobacteria biovolume, and periphytic Hg methylation potential. These results shed a new light on MeHg production plasticity, mediated by landscape and flood pulses in tropical wetlands, as well as on ecological relationships within the periphyton.