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Post-concussion syndrome is common after head injury. It consists of a triad of physical, cognitive and psychological symptoms that occur after a head trauma and cause significant social and occupational disability. This article examines the clinical features, epidemiology, aetiology and treatment of the condition. [ABSTRACT FROM AUTHOR]

Objective: The neural basis for autistic spectrum disorders is unclear, but abnormalities in the development of limbic areas and of glutamate have been suggested. Proton magnetic resonance spectroscopy ((1)H-MRS) can be used to measure the concentration of brain metabolites. However, the concentration of glutamate/glutamine in brain regions implicated in autistic spectrum disorders has not yet been examined in vivo.Method: The authors used (1)H-MRS to investigate the neuronal integrity of the amygdala-hippocampal complex and a parietal control region in adults with autistic spectrum disorders and healthy subjects.Results: People with autistic spectrum disorders had a significantly higher concentration of glutamate/glutamine and creatine/phosphocreatine in the amygdala-hippocampal region but not in the parietal region.Conclusions: Abnormalities in glutamate/glutamine may partially underpin the pathophysiology of autistic spectrum disorders, and the authors confirm earlier reports that limbic areas are metabolically aberrant in these disorders. [ABSTRACT FROM AUTHOR]

Eighteen to 24 months after they adopted children in state custody, 159 parents were surveyed regarding their postadoption experiences. Most children remained with their new families, with parents reporting the adoption experience to be 'about as hard as expected,' and rating the past year of caring for the child as being more 'smooth' than 'stressful.' Parents saw how the child contributed positively to their lives, were less positive about available social supports, and expressed dissatisfaction with the speed of the adoption, the availability of community supports, and the ability to link with supports. Children's special needs (e.g., older age at adoption) were predictive of postplacement adjustment. [ABSTRACT FROM AUTHOR]

The MutSL mismatch repair (MMR) systems in bacteria and eukaryotes correct mismatches made at the replication fork to maintain genome stability. A novel MMR system is represented by the EndoMS/NucS endonuclease from Actinobacterium Corynebacterium glutamicum, which recognizes mismatched substrates in vitro and creates dsDNA breaks at the mismatch. In this report, a genetic analysis shows that an M. smegmatis ΔnucS strain could be complemented by expression of wild type NucS protein, but not by one deleted of its last five amino acids, a region predicted to be critical for binding to the β-clamp at the replication fork. Oligo-recombineering was then leveraged to deliver defined mismatches to a defective hygromycin resistance gene on the M. smegmatis chromosome. We find that NucS recognizes and repairs G-G, G-T, and T-T mismatches in vivo, consistent with the recognition of these same mismatches in C. glutamicum in vitro, as well as mutation accumulation studies done in M. smegmatis. Finally, an assay that employs an oligo that promotes the generation of two mismatches in close proximity on the chromosome shows that a NucS-promoted cut is processed by a 5'-3' exonuclease (or 5'-Flap endonuclease) and that NucS-promoted MMR is independent of both homologous recombination and non-homologous end-joining., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Successful tuberculosis therapy requires treatment with an unwieldy multidrug combination for several months. Thus, there is a growing need to identify novel genetic vulnerabilities that can be leveraged to develop new, more effective antitubercular drugs. Consequently, recent efforts to optimize TB therapy have exploited Mtb chemical genetics to identify pathways influencing antibiotic efficacy, novel mechanisms of antibiotic action, and new targets for TB drug discovery. However, the influence of the complex host environment on these interactions remains largely unknown, leaving the therapeutic potential of the identified targets unclear. In this study, we leveraged a library of conditional mutants targeting 467 essential Mtb genes to characterize the chemical-genetic interactions (CGIs) with TB drugs directly in the mouse infection model. We found that these in vivo CGIs differ significantly from those identified in vitro . Both drug-specific and drug-agnostic effects were identified, and many were preserved during treatment with a multidrug combination, suggesting numerous strategies for enhancing therapy. This work also elucidated the complex effects of pyrazinamide (PZA), a drug that relies on aspects of the infection environment for efficacy. Specifically, our work supports the importance of coenzyme A synthesis inhibition during infection, as well as the antagonistic effect of iron limitation on PZA activity. In addition, we found that inhibition of thiamine and purine synthesis increases PZA efficacy, suggesting novel therapeutically exploitable metabolic dependencies. Our findings present a map of the unique in vivo CGIs, characterizing the mechanism of PZA activity in vivo and identifying novel targets for TB drug development., Significance: The inevitable rise of multi-drug-resistant tuberculosis underscores the urgent need for new TB drugs and novel drug targets while prioritizing synergistic drug combinations. Chemical-genetic interaction (CGI) studies have delineated bacterial pathways influencing antibiotic efficacy and uncovered druggable pathways that synergize with TB drugs. However, most studies are conducted in vitro , limiting our understanding of how the host environment influences drug-mutant interactions. Using an inducible mutant library targeting essential Mtb genes to characterize CGIs during infection, this study reveals that CGIs are both drug-specific and drug-agnostic and differ significantly from those observed in vitro . Synergistic CGIs comprised distinct metabolic pathways mediating antibiotic efficacy, revealing novel drug mechanisms of action, and defining potential drug targets that would synergize with frontline antitubercular drugs.

Pancreatic ductal adenocarcinoma (PDAC) has quickly risen to become the third leading cause of cancer-related death in the United States. This is in part because of its fibrotic tumor microenvironment (TME) that contributes to poor vascularization and immune infiltration and subsequent chemo- and immunotherapy failure. Here, we investigated an immunotherapy approach combining delivery of stimulator of interferon genes (STING) and Toll-like receptor 4 (TLR4) innate immune agonists by lipid-based nanoparticle (NP) coencapsulation with senescence-inducing RAS-targeted therapies, which can remodel the immune suppressive PDAC TME through the senescence-associated secretory phenotype. Treatment of transplanted and autochthonous PDAC mouse models with these regimens led to enhanced uptake of NPs by multiple cell types in the PDAC TME, induction of type I interferon and other proinflammatory signaling pathways, increased antigen presentation by tumor cells and antigen-presenting cells, and subsequent activation of both innate and adaptive immune responses. This two-pronged approach produced potent T cell-driven and type I interferon-mediated tumor regression and long-term survival in preclinical PDAC models dependent on both tumor and host STING activation. STING and TLR4-mediated type I interferon signaling was also associated with enhanced natural killer and CD8 + T cell immunity in human PDAC samples. Thus, combining localized immune agonist delivery with systemic tumor-targeted therapy can orchestrate a coordinated type I interferon-driven innate and adaptive immune response with durable antitumor efficacy against PDAC.

Patients with castration-resistant prostate cancer (CRPC) are generally unresponsive to tumor targeted and immunotherapies. Whether genetic alterations acquired during the evolution of CRPC impact immune and immunotherapy responses is largely unknown. Using our innovative electroporation-based mouse models, we generated distinct genetic subtypes of CRPC found in patients and uncovered unique immune microenvironments. Specifically, mouse and human prostate tumors with MYC amplification and p53 disruption had weak cytotoxic lymphocyte infiltration and an overall dismal prognosis. MYC and p53 cooperated to induce tumor intrinsic secretion of VEGF, which by signaling through VEGFR2 expressed on CD8 + T cells, could directly inhibit T cell activity. Targeting VEGF-VEGFR2 signaling in vivo led to CD8 + T cell-mediated tumor and metastasis growth suppression and significantly increased overall survival in MYC and p53 altered CPRC. VEGFR2 blockade also led to induction of PD-L1, and in combination with PD-L1 immune checkpoint blockade produced anti-tumor efficacy in multiple preclinical CRPC mouse models. Thus, our results identify a genetic mechanism of immune suppression through VEGF signaling in prostate cancer that can be targeted to reactivate immune and immunotherapy responses in an aggressive subtype of CRPC., Significance: Though immune checkpoint blockade (ICB) therapies can achieve curative responses in many treatment-refractory cancers, they have limited efficacy in CRPC. Here we identify a genetic mechanism by which VEGF contributes to T cell suppression, and demonstrate that VEGFR2 blockade can potentiate the effects of PD-L1 ICB to immunologically treat CRPC., Competing Interests: DECLARATION OF INTERESTS M.R. is a consultant for Boehringer Ingelheim.

Genetically engineered mouse models (GEMMs) allow for modeling of spontaneous tumorigenesis within its native microenvironment in mice and have provided invaluable insights into mechanisms of tumorigenesis and therapeutic strategies to treat human disease. However, as their generation requires germline manipulation and extensive animal breeding that is time-, labor-, and cost-intensive, traditional GEMMs are not accessible to most researchers, and fail to model the full breadth of cancer-associated genetic alterations and therapeutic targets. Recent advances in genome-editing technologies and their implementation in somatic tissues of mice have ushered in a new class of mouse models: non-germline GEMMs (nGEMMs). nGEMM approaches can be leveraged to generate somatic tumors de novo harboring virtually any individual or group of genetic alterations found in human cancer in a mouse through simple procedures that do not require breeding, greatly increasing the accessibility and speed and scale on which GEMMs can be produced. Here we describe the technologies and delivery systems used to create nGEMMs and highlight new biological insights derived from these models that have rapidly informed functional cancer genomics, precision medicine, and immune oncology., (Copyright © 2024 Cold Spring Harbor Laboratory Press; all rights reserved.)

Objectives: This study aimed to evaluate the proportion of Irish medical students exposed to 'badmouthing' of different specialities and to ascertain: the degree of criticism of specialities based on the seniority of clinical or academic members of staff; if 'badmouthing' influenced student career choice in psychiatry; and attitudes of medical students towards psychiatry as a speciality and career choice., Methods: Medical students in three Irish universities were invited to complete an online survey to determine the frequency and effect of non-constructive criticism on choice of medical specialty. The online questionnaire was distributed to Royal College of Surgeons in Ireland (RCSI), University of Galway (UoG) and University College Dublin (UCD) in the academic year 2020-2021., Results: General practice (69%), surgery (65%) and psychiatry (50%) were the most criticised specialties. Criticism was most likely to be heard from medical students. 46% of students reported reconsidering a career in psychiatry due to criticism from junior doctors. There was a positive perception of psychiatry with 27% of respondents considering psychiatry as a first-choice specialty., Conclusions: Criticism of psychiatry by doctors, academics and student peers negatively influences students' career choice, which could be contributing to recruitment difficulties in psychiatry.

Cellular senescence is a damage-induced condition characterized by enduring cell cycle arrest and a heightened secretory profile known as the senescence-associated secretory phenotype (SASP). The SASP consists not only of release of inflammatory cytokines and chemokines that attract and activate a diverse repertoire of innate and adaptive immune cells, but also the upregulation of immunomodulatory cell surface molecules that promote immune clearance of senescent cells. Natural Killer (NK) cells are particularly adept at sensing and eliminating senescent cells. In the setting of cancer, commonly administered cytotoxic and cytostatic therapies can elicit senescence and in turn reactivate NK cell immune surveillance against tumors. Here, we detail a series of in vivo, ex vivo, and in vitro assays to assess the impact of therapy-induced senescence on NK cell phenotypes, including their activation, exhaustion, migration, and killing capacity in the context of pancreatic cancer. Importantly, this methodology can be adapted to investigate NK cell biology across various disease states and treatment modalities and help inform NK cell-based immunotherapies for cancer., Competing Interests: Conflicts of interest M.R. has received a consulting honorarium from Boehringer Ingelheim. All other authors have no conflicts to declare., (Copyright © 2024 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

22q11.2 deletion syndrome (22q11DS) is the most frequently occurring microdeletion in humans. It is associated with a significant impact on brain structure, including prominent reductions in gray matter volume (GMV), and neuropsychiatric manifestations, including cognitive impairment and psychosis. It is unclear whether GMV alterations in 22q11DS occur according to distinct structural patterns. Then, 783 participants (470 with 22q11DS: 51% females, mean age [SD] 18.2 [9.2]; and 313 typically developing [TD] controls: 46% females, mean age 18.0 [8.6]) from 13 datasets were included in the present study. We segmented structural T1-weighted brain MRI scans and extracted GMV images, which were then utilized in a novel source-based morphometry (SBM) pipeline (SS-Detect) to generate structural brain patterns (SBPs) that capture co-varying GMV. We investigated the impact of the 22q11.2 deletion, deletion size, intelligence quotient, and psychosis on the SBPs. Seventeen GMV-SBPs were derived, which provided spatial patterns of GMV covariance associated with a quantitative metric (i.e., loading score) for analysis. Patterns of topographically widespread differences in GMV covariance, including the cerebellum, discriminated individuals with 22q11DS from healthy controls. The spatial extents of the SBPs that revealed disparities between individuals with 22q11DS and controls were consistent with the findings of the univariate voxel-based morphometry analysis. Larger deletion size was associated with significantly lower GMV in frontal and occipital SBPs; however, history of psychosis did not show a strong relationship with these covariance patterns. 22q11DS is associated with distinct structural abnormalities captured by topographical GMV covariance patterns that include the cerebellum. Findings indicate that structural anomalies in 22q11DS manifest in a nonrandom manner and in distinct covarying anatomical patterns, rather than a diffuse global process. These SBP abnormalities converge with previously reported cortical surface area abnormalities, suggesting disturbances of early neurodevelopment as the most likely underlying mechanism., (© 2024 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Background: Type 2 diabetes mellitus (T2DM) has been traditionally considered a chronic, progressive disease. Since 2017, guidelines from the US Department of Veterans Affairs and US Department of Defense have included low-carbohydrate (LC) dietary patterns in managing T2DM. Recently, carbohydrate reduction, including ketogenic diets, has gained renewed interest in the management and remission of T2DM., Observations: This narrative review examines the evidence behind carbohydrate reduction in T2DM and a practical guide for clinicians starting patients on therapeutic LC diets. We present an illustrative case and provide practical approaches to prescribing a very LC ketogenic (< 50 g), LC (50-100 g), or a moderate LC (101-150 g) dietary plan and discuss adverse effects and management of LC diets. We provide a medication management and deprescription approach and discuss strategies to consider in conjunction with LC diets. As patients adopt LC diets, glycemia improves, and medications are deprescribed, hemoglobin A 1c levels and fasting glucose may drop below the diagnostic threshold for T2DM. Remission of T2DM may occur with LC diets (hemoglobin A 1c < 6.5% for ≥ 3 months without T2DM medications). Finally, we describe barriers and limitations to applying therapeutic carbohydrate reduction in a federal health care system., Conclusions: The effective use of LC diets with close and intensive lifestyle counseling and a safe approach to medication management and deprescribing can improve glycemic control, reduce the overall need for insulin and medication and provide sustained weight loss. The efficacy and continuation of therapeutic carbohydrate reduction for patients with T2DM appears promising. Further research on LC diets, emerging strategies, and long-term effects on cardiometabolic risk factors, morbidity, and mortality will continue to inform practice., Competing Interests: Author disclosures: CM Jenks is married to an employee of Virta Medical, which provides care related to type 2 diabetes and ketogenic diets., (Copyright © 2024 Frontline Medical Communications Inc., Parsippany, NJ, USA.)

Objectives: To examine the impact of the first full year of the COVID-19 pandemic and its associated restrictions on the volume and nature of psychiatric presentations to an emergency department (ED) in a large academic hospital., Methods: Anonymised clinical data on psychiatric presentations to the ED were collected for the 52-week period from the start of the COVID-19 pandemic and compared with corresponding 1 year periods in 2019 and 2018., Results: There was a significant increase in psychiatric presentations overall to the ED during the first year of the COVID-19 pandemic compared to previous years, in contrast to a reduction in total presentations for all other specialties. There was a marked increase in psychiatric presentations of those below 18 years, and in the 30-39 years and 40-49 years age groups, but a decrease in the 18-29 years group. There was a significant increase in anxiety disorder presentations but a decrease in alcohol related presentations. There was no significant change observed in the rates of presentations for self-harm or suicidal ideation., Conclusions: Psychiatric presentations to the ED have increased during the first year of the COVID-19 pandemic in contrast to a decrease in presentations for other medical specialties, with this increase being driven by out-of-hours presentations. The fourfold increase in presentations of young people below the age of 18 years to the ED with mental health difficulties is an important finding and suggests a disproportionate burden of psychological strain placed on this group during the pandemic.

While the respiratory complications of COVID-19 infection are now well known, psychiatric manifestations are an emerging issue. We report a case of prolonged encephalopathy secondary to COVID-19 which was associated with prominent neuropsychiatric features. The patient went on to develop sub-clinical seizures, a rare but recognised complication of SARS-CoV-2.

Congenital heart disease (CHD) affecting the conotruncal region of the heart, occurs in 40-50% of patients with 22q11.2 deletion syndrome (22q11.2DS). This syndrome is a rare disorder with relative genetic homogeneity that can facilitate identification of genetic modifiers. Haploinsufficiency of TBX1, encoding a T-box transcription factor, is one of the main genes responsible for the etiology of the syndrome. We suggest that genetic modifiers of conotruncal defects in patients with 22q11.2DS may be in the TBX1 gene network. To identify genetic modifiers, we analyzed rare, predicted damaging variants in whole genome sequence of 456 cases with conotruncal defects and 537 controls, with 22q11.2DS. We then performed gene set approaches and identified chromatin regulatory genes as modifiers. Chromatin genes with recurrent damaging variants include EP400, KAT6A, KMT2C, KMT2D, NSD1, CHD7 and PHF21A. In total, we identified 37 chromatin regulatory genes, that may increase risk for conotruncal heart defects in 8.5% of 22q11.2DS cases. Many of these genes were identified as risk factors for sporadic CHD in the general population. These genes are co-expressed in cardiac progenitor cells with TBX1, suggesting that they may be in the same genetic network. The genes KAT6A, KMT2C, CHD7 and EZH2, have been previously shown to genetically interact with TBX1 in mouse models. Our findings indicate that disturbance of chromatin regulatory genes impact the TBX1 gene network serving as genetic modifiers of 22q11.2DS and sporadic CHD, suggesting that there are some shared mechanisms involving the TBX1 gene network in the etiology of CHD., (© 2023. The Author(s).)

Phase variation induced by insertions and deletions (INDELs) in genomic homopolymeric tracts (HT) can silence and regulate genes in pathogenic bacteria, but this process is not characterized in MTBC ( Mycobacterium tuberculosis complex) adaptation. We leverage 31,428 diverse clinical isolates to identify genomic regions including phase-variants under positive selection. Of 87,651 INDEL events that emerge repeatedly across the phylogeny, 12.4% are phase-variants within HTs (0.02% of the genome by length). We estimated the in-vitro frameshift rate in a neutral HT at 100× the neutral substitution rate at [Formula: see text] frameshifts/HT/year. Using neutral evolution simulations, we identified 4,098 substitutions and 45 phase-variants to be putatively adaptive to MTBC ( P < 0.002). We experimentally confirm that a putatively adaptive phase-variant alters the expression of espA, a critical mediator of ESX-1-dependent virulence. Our evidence supports the hypothesis that phase variation in the ESX-1 system of MTBC can act as a toggle between antigenicity and survival in the host.

Objectives: There is a high rate of psychiatric comorbidity in patients with epilepsy. However, the impact of surgical treatment of refractory epilepsy on psychopathology remains under investigation. We aimed to examine the impact of epilepsy surgery on psychopathology and quality of life at 1-year post-surgery in a population of patients with epilepsy refractory to medication., Methods: This study initially assessed 48 patients with refractory epilepsy using the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I), the Hospital Anxiety and Depression Scale (HADS) and the Quality of Life in Epilepsy Inventory 89 (QOLIE-89) on admission to an Epilepsy Monitoring Unit (EMU) as part of their pre-surgical assessment. These patients were again assessed using the SCID-I, QOLIE-89 and HADS at 1-year follow-up post-surgery., Results: There was a significant reduction in psychopathology, particularly psychosis, following surgery at 1-year follow-up ( p < 0.021). There were no new cases of de novo psychosis and surgery was also associated with a significant improvement in the quality of life scores ( p < 0.001)., Conclusions: This study demonstrates the impact of epilepsy surgery on psychopathology and quality of life in a patient population with refractory surgery. The presence of a psychiatric illness should not be a barrier to access surgical treatment.

Objectives: Over 50% of inpatients with neurological disorders may present with a co-morbid psychiatric illness. Delirium has a reported point prevalence of 20% in hospital inpatients and is frequently undetected. We aimed to (1) examine inpatient referrals to a Liaison Neuropsychiatry service and (2) review the diagnosis and management of delirium before and after an educational intervention., Methods: An initial 6-month audit of referrals to the inpatient Liaison Neuropsychiatry service was conducted in 2018. We then undertook a psychoeducational intervention to raise awareness of the diagnosis and management of delirium. We conducted a re-audit of referrals to the service in 2019., Results: On initial audit, of 84 referrals, the most common referral was for mood (38%; n = 32). Just 4% ( n = 3) had a specific delirium query. Following assessment by Neuropsychiatry, organic disorders (43%; n = 32), including delirium (33%; n = 25), were the most common diagnoses. On re-audit, of 86 referrals, mood assessment remained the most common reason for referral (38%; n = 33) and 2% ( n = 2) were referred for possible delirium. Organic disorders remained the most common diagnoses (53%; n = 45) including delirium (38%; n = 32). We found a significant increase in the use of the delirium protocol from 12% ( n = 3) on initial audit to 47% ( n = 15); p < 0.01 on re-audit despite no increase in the number of specific delirium queries., Conclusions: A psychoeducational intervention improves the management of delirium by Neurologists and Neurosurgeons in patients with brain disorders.

Immunotherapies that produce durable responses in some malignancies have failed in pancreatic ductal adenocarcinoma (PDAC) due to rampant immune suppression and poor tumor immunogenicity. We and others have demonstrated that induction of the senescence-associated secretory phenotype (SASP) can be an effective approach to activate anti-tumor natural killer (NK) cell and T cell immunity. In the present study, we found that the pancreas tumor microenvironment suppresses NK cell and T cell surveillance after therapy-induced senescence through enhancer of zeste homolog 2 (EZH2)-mediated epigenetic repression of proinflammatory SASP genes. EZH2 blockade stimulated production of SASP chemokines CCL2 and CXCL9/10, leading to enhanced NK cell and T cell infiltration and PDAC eradication in mouse models. EZH2 activity was also associated with suppression of chemokine signaling and cytotoxic lymphocytes and reduced survival in patients with PDAC. These results demonstrate that EZH2 represses the proinflammatory SASP and that EZH2 inhibition combined with senescence-inducing therapy could be a powerful means to achieve immune-mediated tumor control in PDAC., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Cancer prevention has a profound impact on cancer-associated mortality and morbidity. We previously identified TGFβ signaling as a candidate regulator of mammary epithelial cells associated with breast cancer risk. Here, we show that short-term TGFBR inhibitor (TGFBRi) treatment of peripubertal ACI inbred and Sprague Dawley outbred rats induces lasting changes and prevents estrogen- and carcinogen-induced mammary tumors, respectively. We identify TGFBRi-responsive cell populations by single cell RNA-sequencing, including a unique epithelial subpopulation designated secretory basal cells (SBCs) with progenitor features. We detect SBCs in normal human breast tissues and find them to be associated with breast cancer risk. Interactome analysis identifies SBCs as the most interactive cell population and the main source of insulin-IGF signaling. Accordingly, inhibition of TGFBR and IGF1R decrease proliferation of organoid cultures. Our results reveal a critical role for TGFβ in regulating mammary epithelial cells relevant to breast cancer and serve as a proof-of-principle cancer prevention strategy., (© 2022. The Author(s).)

Animal models are critical for the preclinical validation of cancer immunotherapies. Unfortunately, mouse breast cancer models do not faithfully reproduce the molecular subtypes and immune environment of the human disease. In particular, there are no good murine models of estrogen receptor-positive (ER+) breast cancer, the predominant subtype in patients. Here, we show that Nitroso-N-methylurea-induced mammary tumors in outbred Sprague-Dawley rats recapitulate the heterogeneity for mutational profiles, ER expression, and immune evasive mechanisms observed in human breast cancer. We demonstrate the utility of this model for preclinical studies by dissecting mechanisms of response to immunotherapy using combination TGFBR inhibition and PD-L1 blockade. Short-term treatment of early-stage tumors induced durable responses. Gene expression profiling and spatial mapping classified tumors as inflammatory and noninflammatory, and identified IFNγ, T-cell receptor (TCR), and B-cell receptor (BCR) signaling, CD74/MHC II, and epithelium-interacting CD8+ T cells as markers of response, whereas the complement system, M2 macrophage phenotype, and translation in mitochondria were associated with resistance. We found that the expression of CD74 correlated with leukocyte fraction and TCR diversity in human breast cancer. We identified a subset of rat ER+ tumors marked by expression of antigen-processing genes that had an active immune environment and responded to treatment. A gene signature characteristic of these tumors predicted disease-free survival in patients with ER+ Luminal A breast cancer and overall survival in patients with metastatic breast cancer receiving anti-PD-L1 therapy. We demonstrate the usefulness of this preclinical model for immunotherapy and suggest examination to expand immunotherapy to a subset of patients with ER+ disease. See related Spotlight by Roussos Torres, p. 672., (©2022 The Authors; Published by the American Association for Cancer Research.)

Current chemotherapy against Mycobacterium tuberculosis (Mtb), an important human pathogen, requires a multidrug regimen lasting several months. While efforts have been made to optimize therapy by exploiting drug–drug synergies, testing new drug combinations in relevant host environments remains arduous. In particular, host environments profoundly affect the bacterial metabolic state and drug efficacy, limiting the accuracy of predictions based on in vitro assays alone. In this study, we utilized conditional Mtb knockdown mutants of essential genes as an experimentally tractable surrogate for drug treatment and probe the relationship between Mtb carbon metabolism and chemical–genetic interactions (CGIs). We examined the antitubercular drugs isoniazid, rifampicin, and moxifloxacin and found that CGIs are differentially responsive to the metabolic state, defining both environment-independent and -dependent interactions. Specifically, growth on the in vivo–relevant carbon source, cholesterol, reduced rifampicin efficacy by altering mycobacterial cell surface lipid composition. We report that a variety of perturbations in cell wall synthesis pathways restore rifampicin efficacy during growth on cholesterol, and that both environment-independent and cholesterol-dependent in vitro CGIs could be leveraged to enhance bacterial clearance in the mouse infection model. Our findings present an atlas of chemical–genetic–environmental interactions that can be used to optimize drug–drug interactions, as well as provide a framework for understanding in vitro correlates of in vivo efficacy.

Schizophrenia has a heritability of 60-80% 1 , much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

The outcome of an encounter with Mycobacterium tuberculosis ( Mtb ) depends on the pathogen's ability to adapt to the variable immune pressures exerted by the host. Understanding this interplay has proven difficult, largely because experimentally tractable animal models do not recapitulate the heterogeneity of tuberculosis disease. We leveraged the genetically diverse Collaborative Cross (CC) mouse panel in conjunction with a library of Mtb mutants to create a resource for associating bacterial genetic requirements with host genetics and immunity. We report that CC strains vary dramatically in their susceptibility to infection and produce qualitatively distinct immune states. Global analysis of Mtb transposon mutant fitness (TnSeq) across the CC panel revealed that many virulence pathways are only required in specific host microenvironments, identifying a large fraction of the pathogen's genome that has been maintained to ensure fitness in a diverse population. Both immunological and bacterial traits can be associated with genetic variants distributed across the mouse genome, making the CC a unique population for identifying specific host-pathogen genetic interactions that influence pathogenesis., Competing Interests: CS, RB, MP, BM, JL, SP, HL, MK, MB, AO, KM, KP, FB, CR, RM, BH, CL, GS, PH, TB, SE, DS, FP, MF, TI, CS No competing interests declared, (© 2022, Smith et al.)

Schizophrenia occurs in about one in four individuals with 22q11.2 deletion syndrome (22q11.2DS). The aim of this International Brain and Behavior 22q11.2DS Consortium (IBBC) study was to identify genetic factors that contribute to schizophrenia, in addition to the ~20-fold increased risk conveyed by the 22q11.2 deletion. Using whole-genome sequencing data from 519 unrelated individuals with 22q11.2DS, we conducted genome-wide comparisons of common and rare variants between those with schizophrenia and those with no psychotic disorder at age ≥25 years. Available microarray data enabled direct comparison of polygenic risk for schizophrenia between 22q11.2DS and independent population samples with no 22q11.2 deletion, with and without schizophrenia (total n = 35,182). Polygenic risk for schizophrenia within 22q11.2DS was significantly greater for those with schizophrenia (p adj  = 6.73 × 10 -6 ). Novel reciprocal case-control comparisons between the 22q11.2DS and population-based cohorts showed that polygenic risk score was significantly greater in individuals with psychotic illness, regardless of the presence of the 22q11.2 deletion. Within the 22q11.2DS cohort, results of gene-set analyses showed some support for rare variants affecting synaptic genes. No common or rare variants within the 22q11.2 deletion region were significantly associated with schizophrenia. These findings suggest that in addition to the deletion conferring a greatly increased risk to schizophrenia, the risk is higher when the 22q11.2 deletion and common polygenic risk factors that contribute to schizophrenia in the general population are both present., (© 2020. The Author(s), under exclusive licence to Springer Nature Limited.)

Despite the availability of multiple human epidermal growth factor receptor 2-targeted (HER2-targeted) treatments, therapeutic resistance in HER2+ breast cancer remains a clinical challenge. Intratumor heterogeneity for HER2 and resistance-conferring mutations in the PIK3CA gene (encoding PI3K catalytic subunit α) have been investigated in response and resistance to HER2-targeting agents, while the role of divergent cellular phenotypes and tumor epithelial-stromal cell interactions is less well understood. Here, we assessed the effect of intratumor cellular genetic heterogeneity for ERBB2 (encoding HER2) copy number and PIK3CA mutation on different types of neoadjuvant HER2-targeting therapies and clinical outcome in HER2+ breast cancer. We found that the frequency of cells lacking HER2 was a better predictor of response to HER2-targeted treatment than intratumor heterogeneity. We also compared the efficacy of different therapies in the same tumor using patient-derived xenograft models of heterogeneous HER2+ breast cancer and single-cell approaches. Stromal determinants were better predictors of response than tumor epithelial cells, and we identified alveolar epithelial and fibroblastic reticular cells as well as lymphatic vessel endothelial hyaluronan receptor 1-positive (Lyve1+) macrophages as putative drivers of therapeutic resistance. Our results demonstrate that both preexisting and acquired resistance to HER2-targeting agents involve multiple mechanisms including the tumor microenvironment. Furthermore, our data suggest that intratumor heterogeneity for HER2 should be incorporated into treatment design.

Objectives: To determine if the initial COVID-19 societal restrictions, introduced in Ireland in March 2020, impacted on the number and nature of psychiatry presentations to the emergency department (ED) of a large academic teaching hospital., Methods: We examined anonymised clinical data of psychiatry presentations to the ED during the initial 8-week period of COVID-19 restrictions. Data from corresponding 8-week periods in 2018 and 2019 were also extracted for comparison., Results: Psychiatry presentations to ED reduced by 21% during the COVID-19 restrictions, from 24/week to 19/week when compared with corresponding periods in 2018/2019 (Poisson's Rate Test estimate of difference -5.2/week, 95% CI 1.3-9.1, p = 0.012). Numbers attending for out-of-hours assessment remained unchanged (81 v. 80), but numbers seeking assessment during normal hours decreased (71 v. 114). We observed increased presentations from the <18 age group, but decreased presentations from the 18 to 29 age group (Pearson's Chi-Square 20.363, df = 6, p = 0.002). We recorded an increase in anxiety disorders during the initial COVID-19 restrictions (31 v. 23), and a reduction in alcohol disorders (28 v. 52). The proportion of presentations with suicidal ideation (SI) or self-harm as factors remained unchanged., Conclusions: Rates of emergency presentation with mental illness reduced during the initial COVID-19 restrictions. This may represent an unmet burden of mental health needs. Younger people may be experiencing greater distress and mental illness during the current crisis. More people sought help for anxiety disorders during the COVID-19 restrictions compared with corresponding data from 2018 and 2019.