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Genomic copy number variants (CNVs) are associated with a high risk of neurodevelopmental disorders. A growing body of genetic studies suggests that these high-risk genetic variants converge in common molecular pathways, and that common pathways also exist across clinically distinct disorders, such as schizophrenia and autism spectrum disorder. A key question is how common molecular mechanisms converge into similar clinical outcomes. We review emerging evidence for convergent cognitive and brain phenotypes across distinct CNVs. Multiple CNVs were shown to have similar effects on core sensory, cognitive and motor traits. Emerging data from multi-site neuroimaging studies have provided valuable information on how these CNVs affect brain structure and function. However, most of these studies examined one CNV at a time, making it difficult to fully understand the proportion of shared brain effects. Recent studies have started to combine neuroimaging data from multiple CNV carriers and identified similar brain effects across CNVs. Some early findings also support convergence in CNV animal models. Systems biology, through integration of multi-level data, provides new insights into convergent molecular mechanisms across genetic risk variants (e.g., altered synaptic activity). However, the link between such key molecular mechanisms and convergent psychiatric phenotypes is still unknown. In order to better understand this link, we need new approaches that integrate human molecular data with neuroimaging, cognitive, and animal models data, while taking into account critical developmental timepoints. Identifying risk mechanisms across genetic loci can elucidate the pathophysiology of neurodevelopmental disorders and identify new therapeutic targets for cross-disorder applications.

Post-traumatic stress disorder (PTSD) is prevalent in women; however, preclinical research on PTSD has predominantly been conducted in male animals. Using a predator scent stress (PSS) rodent model of PTSD, we sought to determine if stress-susceptible female rats show altered monoamine concentrations in brain regions associated with PTSD: the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), and dorsal (dHIPP) and ventral (vHIPP) hippocampus. Female Sprague–Dawley rats were exposed to a single, 10-min PSS exposure and tested for persistent anhedonia, fear, and anxiety-like behavior over four weeks. Rats were phenotyped as stress-Susceptible based on sucrose consumption in the sucrose preference task and time spent in the open arms of the elevated plus maze. Brain tissue was collected, and norepinephrine, dopamine, serotonin, and their metabolites were quantified using high-performance liquid chromatography. Stress-susceptibility in female rats was associated with increased dopamine and serotonin turnover in the mPFC. Susceptibility was also associated with elevated dopamine turnover in the NAc and increased norepinephrine in the vHIPP. Our findings suggest that stress-susceptibility after a single stress exposure is associated with long-term effects on monoamine function in female rats. These data suggest interventions that decrease monoamine turnover, such as MAOIs, may be effective in the treatment of PTSD in women.

Objective: To describe the association between objectively measurable imaging techniques and the resulting compression thickness and dose. Methods: The study included 80,495 routine screens from the South-West London Breast Screening Service between March 2013 and July 2017. Average compression force, paddle tilt and dose were calculated. The Volpara® DensityTM algorithm was used to estimate pressure, breast volume and density. Linear regression models, using generalized estimating equations (GEEs) to account for clustering by practitioner, assessed the strength of the associations between the imaging compression outcomes, (thickness, dose) and imaging techniques (force, pressure and paddle tilt), adjusting for the subject’s characteristics (age, ethnicity, breast volume and percent mammographic density). Results: Fully adjusted linear regression models showed that compression thickness decreased by ~1 mm (~2% of mean thickness) for every 1daN increase in force and decreased by ~0.8 mm with an increase of 1 kPa of pressure (at median pressure). Increasing pressure above 15 kPa resulted in minimal reduction in thickness. Dose increased with increased force but decreased by ~1% of mean dose with every increase in 1 kPa of pressure. For 1o increase in paddle tilt, the compression thickness increased by ~1.5 mm (~2.5%) and dose increased by ~2.5%, (Pt Conclusion: Differences in imaging technique are associated with imaging outcome measures (thickness and dose). A better understanding of the association between objective image acquisition parameters and tumour conspicuity could lead to clearer guidelines for practitioners. Advances in knowledge: Increased paddle tilt is associated with increased compression thickness and increased dose after adjustment for breast volume and force applied.

To measure associations between surgeons' examination performance and obtaining American Board of Surgery certification with the likelihood of having medical malpractice payments.Further research is needed to establish a broader understanding of the association of board certification and patient and practice outcomes.Retrospective analysis using propensity score-matched surgeons who attempted to obtain American Board of Surgery certification. Surgeons who completed residency between 2000 and 2019 (n=910) and attempted to become certified were categorized as certified or failing to obtain certification. In addition, groups were categorized as either passing or failing their first attempt on the qualifying and certifying examinations. Malpractice payment reports were dichotomized for surgeons who either had a payment report or not.The hazard rate (HR) of malpractice payment reports was significantly greater for surgeons who attempted and failed to obtain certification [HR=1.87; 95% confidence interval (CI), 1.28-2.74] than for surgeons who were certified. Moreover, surgeons who failed either the qualifying (HR=1.64; 95% CI, 1.14-2.37) or certifying examination (HR=1.72; 95% CI, 1.14-2.60) had significantly higher malpractice payment HRs than those who passed the examinations on their first attempt.Failing to obtain board certification was associated with a higher rate of medical malpractice payments. In addition, failing examinations in the certification examination process on the first attempt was also associated with higher rates of medical malpractice payments. This study provides further evidence that board certification is linked to potential indicators for patient outcomes and practice quality.

Background. Post-menopausal hormone therapy (HT) may elevate the risk of venous thromboembolism (VTE), while statin therapy may lower risk. Purpose. To estimate VTE risk from HT exposure with/without statin therapy in women 50-64 years of age. Methods. A case-control study in a large commercially-insured database matched cases of VTE diagnoses (1:10) to controls without VTE on age +/- 2 yrs. Conditional logistic regression estimated odds ratios (ORs) for recent HT exposure (any estrogen and/or progestogen within 60 days) and current statin therapy (>90 days continuous exposure) controlling for VTE risk factors, comorbidities, and coronary artery disease. Results. In a comparison of cases (n=20,359) and matched controls (n=203,590), 9% (n=19,558) had recent HT exposure and 16% (n=36,238) had current/continuous statin exposure. After adjustment for all covariates, the OR for any recent HT exposure (regardless of statin exposure) was 1.51 (95% CI: 1.43, 1.60) compared to no HT exposure. The OR for current statin therapy (regardless of HT exposure) was 0.88 (95% CI: 0.84, 0.93). For those with HT exposure without statin therapy the OR was 1.53 (95% CI: 1.44, 1.63), for those with HT exposure with statin therapy the OR was 1.25 (95% CI: 1.10, 1.43), and for those exposed to statin therapy without HT exposure the OR was 0.89 (95% CI: 0.85, 0.94), compared those not exposed to either statin or HT. HT with statin therapy had a 18% significantly lower odds ratio than HT without statin therapy (OR=0.82, 95% CI: 0.71, 0.94). High intensity statin therapy showed greater risk reduction. Conclusion. Statin therapy may reduce VTE risk associated with HT.

Patients presenting for thyroidectomy may have an unrecognized pre-existing vocal cord palsy (VCP). This raises the danger of bilateral VCP if a patient sustains an injury to the RLN on the sole functioning side. Part of the rationale for routine preoperative laryngoscopy is to eliminate such a risk. This paper endeavours to quantify the relevant potential risk.Patients who underwent laryngoscopy prior to thyroid or parathyroid surgery in an endocrine surgical unit over a 5 year period were identified. Literature review revealed four papers in which VCP prevalence in patients without risk factors was reported. Using our data, combined with that of these other authors, the background rate of pre-existing VCP was ascertained, and the subsequent risk of bilateral VCP estimated.Of our 632 patients who underwent preoperative laryngoscopy, there were four patients (0.63%) who were found to have a unilateral VCP, but all had voice symptoms or previous neck surgery. When patients with these risk factors are excluded, our data combined with the published data provides a pre-existing VCP rate of 0.2%. Calculations estimate that if preoperative laryngoscopy is omitted in patients with no risk factors, the risk of bilateral VCP, due to the nerve on the sole functioning side being injured, would be between 1/50000 and 1/150000, depending on an individual surgeon's level of experience.Selective use of laryngoscopy prior to thyroidectomy would result in an acceptably low statistical risk of bilateral VCP. Routine laryngoscopy for all patients is not necessary.

Chimeric antigen receptor (CAR) T cell therapy in glioblastoma faces many challenges including insufficient CAR T cell abundance and antigen-negative tumor cells evading targeting. Unfortunately, preclinical studies evaluating CAR T cells in glioblastoma focus on tumor models that express a single antigen, use immunocompromised animals, and/or pre-treat with lymphodepleting agents. While lymphodepletion enhances CAR T cell efficacy, it diminishes the endogenous immune system that has the potential for tumor eradication. Here, we engineered CAR T cells to express IL7 and/or Flt3L in 50% EGFRvIII-positive and -negative orthotopic tumors pre-conditioned with non-lymphodepleting irradiation. IL7 and IL7 Flt3L CAR T cells increased intratumoral CAR T cell abundance seven days after treatment. IL7 co-expression with Flt3L modestly increased conventional dendritic cells as well as the CD103+XCR1+ population known to have migratory and antigen cross-presenting capabilities. Treatment with IL7 or IL7 Flt3L CAR T cells improved overall survival to 67% and 50%, respectively, compared to 9% survival with conventional or Flt3L CAR T cells. We concluded that CAR T cells modified to express IL7 enhanced CAR T cell abundance and improved overall survival in EGFRvIII heterogeneous tumors pre-conditioned with non-lymphodepleting irradiation. Potentially IL7 or IL7 Flt3L CAR T cells can provide new opportunities to combine CAR T cells with other immunotherapies for the treatment of glioblastoma.

Coherent laser arrays compatible with silicon photonics are demonstrated in a waveguide geometry in epitaxially grown semiconductor membrane quantum well lasers transferred on substrates of silicon carbide and oxidised silicon; we record lasing thresholds as low as 60 mW of pump power. We study the emission of single lasers and arrays of lasers in the sub-mm range. We are able to create waveguide laser arrays with modal widths of approximately 5 − 10 µm separated by 10 − 20 µm, using real and reciprocal space imaging we study their emission characteristics and find that they maintain their mutual coherence while operating on either single or multiple longitudinal modes per lasing cavity.

An analytical theoretical model for the waveguide grating coupler is developed and applicable to practical deep gratings. The grating-assisted input coupling efficiency is calculated by considering the reciprocal out-coupling problem. The deep grating structure is modelled as an optical layer filled with polarization dipole sources, and the scattered fields are then calculated using the associated Green’s functions and taking into account the multiple reflections and interference from the adjacent layers. The joint loss between the grating region and the waveguide is also considered. Comparison with numerical simulations shows very good agreement and validates the accuracy of the analytical model. The model explicitly describes the importance of multilayer interference of the scattered fields and guided-mode joint loss on the total grating-assisted coupling efficiency and can be used for practical waveguide grating coupler design with negligible computation workload.

Post-traumatic stress disorder (PTSD) develops in a subset of individuals exposed to a trauma with core features being increased anxiety and impaired fear extinction. To model the heterogeneity of PTSD behavioral responses, we exposed male Sprague-Dawley rats to predator scent stress once for 10 min and then assessed anxiety-like behavior 7 days later using the elevated plus maze and acoustic startle response. Rats displaying anxiety-like behavior in both tasks were classified as stress Susceptible, and rats exhibiting behavior no different from un-exposed Controls were classified as stress Resilient. In Resilient rats, we previously found increased mRNA expression of mGlu5 in the amygdala and prefrontal cortex (PFC) and CB1 in the amygdala. Here, we performed fluorescent in situ hybridization (FISH) to determine the subregion and cell-type-specific expression of these genes in Resilient rats 3 weeks after TMT exposure. Resilient rats displayed increased mGlu5 mRNA expression in the basolateral amygdala (BLA) and the infralimbic and prelimbic regions of the PFC and increased BLA CB1 mRNA. These increases were limited to glutamatergic cells. To test the necessity of mGlu5 for attenuating TMT-conditioned contextual fear 3 weeks after TMT conditioning, intra-BLA infusions of the mGlu5 negative allosteric modulator MTEP were administered prior to context re-exposure. In TMT-exposed Resilient rats, but not Controls, MTEP increased freezing on the day of administration, which extinguished over two additional un-drugged sessions. These results suggest that increased mGlu5 expression in BLA glutamate neurons contributes to the behavioral flexibility observed in stress-Resilient animals by facilitating a capacity for extinguishing contextual fear associations.

Funder: Policy Research Unit in Cancer Awareness, Screening and early Diagnosis, PR-PRU-1217-21601, Funder: American Cancer Society NHPDCSGBR-GBRLONG Policy Research Unit in Cancer Awareness, Screening and early Diagnosis, PR-PRU-1217-21601, BACKGROUND: This study investigates whether quantitative breast density (BD) serves as an imaging biomarker for more intensive breast cancer screening by predicting interval, and node-positive cancers. METHODS: This case-control study of 1204 women aged 47-73 includes 599 cancer cases (302 screen-detected, 297 interval; 239 node-positive, 360 node-negative) and 605 controls. Automated BD software calculated fibroglandular volume (FGV), volumetric breast density (VBD) and density grade (DG). A radiologist assessed BD using a visual analogue scale (VAS) from 0 to 100. Logistic regression and area under the receiver operating characteristic curves (AUC) determined whether BD could predict mode of detection (screen-detected or interval); node-negative cancers; node-positive cancers, and all cancers vs. controls. RESULTS: FGV, VBD, VAS, and DG all discriminated interval cancers (all p < 0.01) from controls. Only FGV-quartile discriminated screen-detected cancers (p < 0.01). Based on AUC, FGV discriminated all cancer types better than VBD or VAS. FGV showed a significantly greater discrimination of interval cancers, AUC = 0.65, than of screen-detected cancers, AUC = 0.61 (p < 0.01) as did VBD (0.63 and 0.53, respectively, p < 0.001). CONCLUSION: FGV, VBD, VAS and DG discriminate interval cancers from controls, reflecting some masking risk. Only FGV discriminates screen-detected cancers perhaps adding a unique component of breast cancer risk.

Comparative analyses of bats indicate that hibernation is associated with increased longevity among species. However, it is not yet known if hibernation affects biological ageing of individuals. Here, we use DNA methylation (DNAm) as an epigenetic biomarker of ageing to determine the effect of hibernation on the big brown bat, Eptesicus fuscus . First, we compare epigenetic age, as predicted by a multi-species epigenetic clock, between hibernating and non-hibernating animals and find that hibernation is associated with epigenetic age. Second, we identify genomic sites that exhibit hibernation-associated change in DNAm, independent of age, by comparing samples taken from the same individual in hibernating and active seasons. This paired comparison identified over 3000 differentially methylated positions (DMPs) in the genome. Genome-wide association comparisons to tissue-specific functional elements reveals that DMPs with elevated DNAm during winter occur at sites enriched for quiescent chromatin states, whereas DMPs with reduced DNAm during winter occur at sites enriched for transcription enhancers. Furthermore, genes nearest DMPs are involved in regulation of metabolic processes and innate immunity. Finally, significant overlap exists between genes nearest hibernation DMPs and genes nearest previously identified longevity DMPs. Taken together, these results are consistent with hibernation influencing ageing and longevity in bats.

Background:Genetic variations indicating loss of function in theDLG2gene have been associated with markedly increased risk for schizophrenia, autism spectrum disorder, and intellectual disability.DLG2encodes the postsynaptic scaffolding protein DLG2 (PSD93) that interacts with NMDA receptors, potassium channels, and cytoskeletal regulators but the net impact of these interactions on synaptic plasticity, likely underpinning cognitive impairments associated with these conditions, remains unclear.Methods:Hippocampal CA1 neuronal excitability and synaptic function were investigated in a novel clinically relevant heterozygousDlg2+/−rat model usingex vivopatch-clamp electrophysiology, pharmacology, and computational modelling.Results:Dlg2+/−rats had increased NMDA receptor-mediated synaptic currents and, conversely, impaired associative long-term potentiation. This impairment resulted from an increase in potassium channel function leading to a decrease in input resistance and reduced supra-linear dendritic integration during induction of associative long-term potentiation. Enhancement of dendritic excitability by blockade of potassium channels or activation of muscarinic M1 receptors with selective allosteric agonist 77-LH-28-1 reduced the threshold for dendritic integration and 77-LH-28-1 rescued the associative long-term potentiation impairment in theDlg2+/−rats.Conclusions:Despite increasing synaptic NMDA receptor currents, the combined impact of reduced DLG2 impairs synaptic integration in dendrites resulting in disrupted associative synaptic plasticity. This biological phenotype can be reversed by compound classes used clinically such as muscarinic M1 receptor agonists and is therefore a potential target for therapeutic intervention.

Globally, extreme weather events are occurring more often, with increased intensity due to anthropogenic climate change. For example, in July 2022, monthly average temperature in Spain was 2.7 C above average, and UK has recorded temperatures above 40 degrees for the first time. It has been proven that implementation of green spaces in cities helps to address environmental, social, and even economic problems by providing ecological services, reducing temperature, and attenuating the heat island effect, providing aesthetic enjoyment, recreational opportunities and decreased stress levels. However, green infrastructure is rarely prioritised by developers. It has been argued that, due to space constraints, green infrastructures are an inefficient land use, costly to maintain, and that there is uncertainty if green infrastructures are valued by the market. This paper reports on results from a study examining the attractiveness and the effect of green spaces on housing market customer’ perceptions. To analyse the impact of green spaces, we worked with landscape architects and residential housing developers designing a multi apartment building with a courtyard. The courtyard area was designed accordance to The Green Area Factor resulting in five courtyard designs, each with a different level of greenery. All five designs were presented in dynamic virtual views and embedded in a survey questionnaire. Maintenance costs of all five green spaces were calculated. The findings shows that greenery does effect the perceived attractiveness of residential development. Maintenance costs for the courtyards, with lowest and highest level of greenery, differ by approximately 10 percent of the total maintenance costs. These findings are applicable in the context of new housing construction and renovation projects.

Hearing loss is a hallmark of aging, typically initially affecting the higher frequencies. In echolocating bats, the ability to discern high frequencies is essential. However, nothing is known about age-related hearing loss in bats, and they are often assumed to be immune to it. We tested the hearing of 47 wild Egyptian fruit bats by recording their auditory brainstem response and cochlear microphonics, and we also assessed the cochlear histology in four of these bats. We used the bats’ DNA methylation profile to evaluate their age and found that bats exhibit age-related hearing loss, with more prominent deterioration at the higher frequencies. The rate of the deterioration was ∼1 dB per year, comparable to the hearing loss observed in humans. Assessing the noise in the fruit bat roost revealed that these bats are exposed to continuous immense noise—mostly of social vocalizations—supporting the assumption that bats might be partially resistant to loud noise. Thus, in contrast to previous assumptions, our results suggest that bats constitute a model animal for the study of age-related hearing loss.

Background The presence of cefoxitin and oxacillin resistance in Staphylococcus aureus isolates is suggestive of methicillin resistance (MRSA) with molecular detection of the mecA or mecC genes providing confirmation. The UK SMI and EUCAST guidelines for MRSA detection describe a subset of strains that exhibit reduced susceptibility to oxacillin and cefoxitin, though negative for mecA and mecC genes—frequently named borderline oxacillin-resistant S. aureus (BORSA). Local data noted a number of S. aureus isolates that matched the above phenotype leading to laboratory, clinical and epidemiological questions. Methods Routine samples were collected between August 2020 and April 2021 at West Midlands Health Security Agency Laboratory, Birmingham. If provisional results suggested an MRSA isolate, the following confirmatory tests were undertaken. Locally, clinical samples underwent susceptibility testing with cefoxitin disc diffusion and oxacillin gradient diffusion (MRSA screens) or Vitek 2 (non-MRSA screens). Isolates with discrepant results [susceptible to cefoxitin; resistant to oxacillin (MIC >2 mg/L) or vice versa] were sent to the reference laboratory at Colindale, UK for further testing, which included mecA or mecC gene detection by PCR and serotyping with Illumina sequencing for all isolates. Results In total, 53 isolates were sent to the reference lab of which 22 were confirmed to have an ST97 serotype. All 53 were negative by PCR for mecA and mecC genes. For the 22 isolates of ST97, local oxacillin MIC values ranged from 2 to 6 mg/L. Cefoxitin susceptibility was confirmed locally in all isolates. The 22 isolates were from 15 patients; wound swabs (n = 18); blood culture (n = 1), sputum (n = 1) and MRSA screen (n = 2). Median patient age was 48 years (IQR 38–59) with 5 being female and 10 male. A history of injecting drug use was documented in 53% (8/15). Conclusions BORSA remains a problem from a laboratory, clinical and infection control perspective. This work raises two important questions: what is the most appropriate local laboratory testing pathway and what is the clinical relevance of these isolates (i.e. can flucloxacillin be relied upon in treatment)? The ST97 serotype appears to be associated with skin and soft tissue infection and may be linked to people who inject drugs.

Large-scale genomic studies of schizophrenia implicate genes involved in the epigenetic regulation of transcription by histone methylation and genes encoding components of the synapse. However, the interactions between these pathways in conferring risk to psychiatric illness are unknown. Loss-of-function (LoF) mutations in the gene encoding histone methyltransferase, SETD1A, confer substantial risk to schizophrenia. Among several roles, SETD1A is thought to be involved in the development and function of neuronal circuits. Here, we employed a multi-omics approach to study the effects of heterozygous Setd1a LoF on gene expression and synaptic composition in mouse cortex across five developmental timepoints from embryonic day 14 to postnatal day 70. Using RNA sequencing, we observed that Setd1a LoF resulted in the consistent downregulation of genes enriched for mitochondrial pathways. This effect extended to the synaptosome, in which we found age-specific disruption to both mitochondrial and synaptic proteins. Using large-scale patient genomics data, we observed no enrichment for genetic association with schizophrenia within differentially expressed transcripts or proteins, suggesting they derive from a distinct mechanism of risk from that implicated by genomic studies. This study highlights biological pathways through which SETD1A LOF may confer risk to schizophrenia. Further work is required to determine whether the effects observed in this model reflect human pathology.