Genome-wide interaction study of dietary intake of fibre, fruits, and vegetables with risk of colorectal cancer.

BACKGROUND: Consumption of fibre, fruits and vegetables have been linked with lower colorectal cancer (CRC) risk. A genome-wide gene-environment (G × E) analysis was performed to test whether genetic variants modify these associations. METHODS: A pooled sample of 45 studies including up to 69,734 participants (cases: 29,896; controls: 39,838) of European ancestry were included. To identify G × E interactions, we used the traditional 1--degree-of-freedom (DF) G × E test and to improve power a 2-step procedure and a 3DF joint test that investigates the association between a genetic variant and dietary exposure, CRC risk and G × E interaction simultaneously. FINDINGS: The 3-DF joint test revealed two significant loci with p-value <5 × 10-8. Rs4730274 close to the SLC26A3 gene showed an association with fibre (p-value: 2.4 × 10-3) and G × fibre interaction with CRC (OR per quartile of fibre increase = 0.87, 0.80, and 0.75 for CC, TC, and TT genotype, respectively; G × E p-value: 1.8 × 10-7). Rs1620977 in the NEGR1 gene showed an association with fruit intake (p-value: 1.0 × 10-8) and G × fruit interaction with CRC (OR per quartile of fruit increase = 0.75, 0.65, and 0.56 for AA, AG, and GG genotype, respectively; G × E -p-value: 0.029). INTERPRETATION: We identified 2 loci associated with fibre and fruit intake that also modify the association of these dietary factors with CRC risk. Potential mechanisms include chronic inflammatory intestinal disorders, and gut function. However, further studies are needed for mechanistic validation and replication of findings. FUNDING: National Institutes of Health, National Cancer Institute. Full funding details for the individual consortia are provided in acknowledgments.

Two genome-wide interaction loci modify the association of nonsteroidal anti-inflammatory drugs with colorectal cancer.

Regular, long-term aspirin use may act synergistically with genetic variants, particularly those in mechanistically relevant pathways, to confer a protective effect on colorectal cancer (CRC) risk. We leveraged pooled data from 52 clinical trial, cohort, and case-control studies that included 30,806 CRC cases and 41,861 controls of European ancestry to conduct a genome-wide interaction scan between regular aspirin/nonsteroidal anti-inflammatory drug (NSAID) use and imputed genetic variants. After adjusting for multiple comparisons, we identified statistically significant interactions between regular aspirin/NSAID use and variants in 6q24.1 (top hit rs72833769), which has evidence of influencing expression of TBC1D7 (a subunit of the TSC1-TSC2 complex, a key regulator of MTOR activity), and variants in 5p13.1 (top hit rs350047), which is associated with expression of PTGER4 (codes a cell surface receptor directly involved in the mode of action of aspirin). Genetic variants with functional impact may modulate the chemopreventive effect of regular aspirin use, and our study identifies putative previously unidentified targets for additional mechanistic interrogation.

Profiling IOP-Responsive Genes in the Trabecular Meshwork and Optic Nerve Head in a Rat Model of Controlled Elevation of Intraocular Pressure.

Purpose: The rat controlled elevation of intraocular pressure (CEI) model allows study of in vivo responses to short-term exposure to defined intraocular pressures (IOP). In this study, we used NanoString technology to investigate in vivo IOP-related gene responses in the trabecular meshwork (TM) and optic nerve head (ONH) simultaneously from the same animals. Methods: Male and female rats (N = 35) were subjected to CEI for 8 hours at pressures simulating mean, daytime normotensive rat IOP (CEI-20), or 2.5× IOP (CEI-50). Naïve animals that received no anesthesia or surgical interventions served as controls. Immediately after CEI, TM and ONH tissues were dissected, RNA was isolated, and samples were analyzed with a NanoString panel containing 770 genes. Postprocessing, raw count data were uploaded to ROSALIND for differential gene expression analyses. Results: For the TM, 45 IOP-related genes were significant in the CEI-50 versus CEI-20 and CEI-50 versus naïve comparisons, with 15 genes common to both comparisons. Bioinformatics analysis identified Notch and transforming growth factor beta (TGFß) pathways to be the most up- and downregulated Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, respectively. For ONH, 22 significantly differentially regulated genes were identified in the CEI-50 versus naïve comparison. Pathway analysis identified defense response and immune response as two significantly upregulated biological process pathways. Conclusions: This study demonstrated the ability to assay short-term IOP-responsive genes in both TM and ONH tissues simultaneously. In the TM, downregulation of TGFß pathway genes suggests that TM responses may reduce TGFß-induced extracellular matrix synthesis. For ONH, the initial response to short-term elevated IOP may be protective.

Genetic risk impacts the association of menopausal hormone therapy with colorectal cancer risk.

BACKGROUND: Menopausal hormone therapy (MHT), a common treatment to relieve symptoms of menopause, is associated with a lower risk of colorectal cancer (CRC). To inform CRC risk prediction and MHT risk-benefit assessment, we aimed to evaluate the joint association of a polygenic risk score (PRS) for CRC and MHT on CRC risk. METHODS: We used data from 28,486 postmenopausal women (11,519 cases and 16,967 controls) of European descent. A PRS based on 141 CRC-associated genetic variants was modeled as a categorical variable in quartiles. Multiplicative interaction between PRS and MHT use was evaluated using logistic regression. Additive interaction was measured using the relative excess risk due to interaction (RERI). 30-year cumulative risks of CRC for 50-year-old women according to MHT use and PRS were calculated. RESULTS: The reduction in odds ratios by MHT use was larger in women within the highest quartile of PRS compared to that in women within the lowest quartile of PRS (p-value = 2.7 × 10-8). At the highest quartile of PRS, the 30-year CRC risk was statistically significantly lower for women taking any MHT than for women not taking any MHT, 3.7% (3.3%-4.0%) vs 6.1% (5.7%-6.5%) (difference 2.4%, P-value = 1.83 × 10-14); these differences were also statistically significant but smaller in magnitude in the lowest PRS quartile, 1.6% (1.4%-1.8%) vs 2.2% (1.9%-2.4%) (difference 0.6%, P-value = 1.01 × 10-3), indicating 4 times greater reduction in absolute risk associated with any MHT use in the highest compared to the lowest quartile of genetic CRC risk. CONCLUSIONS: MHT use has a greater impact on the reduction of CRC risk for women at higher genetic risk. These findings have implications for the development of risk prediction models for CRC and potentially for the consideration of genetic information in the risk-benefit assessment of MHT use.

Chronic SIV-Induced neuroinflammation disrupts CCR7+ CD4+ T cell immunosurveillance in the rhesus macaque brain.

CD4+ T cells survey and maintain immune homeostasis in the brain, yet their differentiation states and functional capabilities remain unclear. Our approach, combining single-cell transcriptomic analysis, ATAC-Seq, spatial transcriptomics, and flow cytometry, revealed a distinct subset of CCR7+ CD4+ T cells resembling lymph node central memory (TCM) cells. We observed chromatin accessibility at the CCR7, CD28, and BCL-6 loci, defining molecular features of TCM. Brain CCR7+ CD4+ T cells exhibited recall proliferation and interleukin-2 production ex vivo, showcasing their functional competence. We identified the skull bone marrow as a local niche for these cells alongside CNS border tissues. Sequestering TCM cells in lymph nodes using FTY720 led to reduced CCR7+ CD4+ T cell frequencies in the cerebrospinal fluid, accompanied by increased monocyte levels and soluble markers indicating immune activation. In macaques chronically infected with SIVCL757 and experiencing viral rebound due to cessation of antiretroviral therapy, a decrease in brain CCR7+ CD4+ T cells was observed, along with increased microglial activation and initiation of neurodegenerative pathways. Our findings highlight a role for CCR7+ CD4+ T cells in CNS immune surveillance, and their decline during chronic SIV highlights their responsiveness to neuroinflammation.

A Large-Scale Genome-Wide Study of Gene-Sleep Duration Interactions for Blood Pressure in 811,405 Individuals from Diverse Populations.

Although both short and long sleep duration are associated with elevated hypertension risk, our understanding of their interplay with biological pathways governing blood pressure remains limited. To address this, we carried out genome-wide cross-population gene-by-short-sleep and long-sleep duration interaction analyses for three blood pressure traits (systolic, diastolic, and pulse pressure) in 811,405 individuals from diverse population groups. We discover 22 novel gene-sleep duration interaction loci for blood pressure, mapped to genes involved in neurological, thyroidal, bone metabolism, and hematopoietic pathways. Non-overlap between short sleep (12) and long sleep (10) interactions underscores the plausibility of distinct influences of both sleep duration extremes in cardiovascular health. With several of our loci reflecting specificity towards population background or sex, our discovery sheds light on the importance of embracing granularity when addressing heterogeneity entangled in gene-environment interactions, and in therapeutic design approaches for blood pressure management.

Profiling IOP-responsive genes in anterior and posterior ocular tissues in the rat CEI glaucoma model.

Purpose: The rat Controlled Elevation of Intraocular pressure (CEI) model allows study of in vivo responses to defined intraocular pressures (IOP). In this study, we use Nanostring technology to investigate in vivo IOP-related gene responses in the trabecular meshwork (TM) and optic nerve head (ONH) simultaneously from the same animals. Methods: Male and female rats (N=35) were subject to CEI for 8-hours at pressures simulating mean, daytime normotensive rat IOP (CEI-20), or 2.5x IOP (CEI-50). Naïve animals, receiving no anesthesia or surgical interventions, served as controls. Immediately after CEI, TM and ONH tissues were dissected, RNA isolated, and samples were analyzed with a Nanostring panel containing 770 genes. Post-processing, raw count data were uploaded to Rosalind® for differential gene expression analyses. Results: For the TM, 45 IOP-related genes were significant in the "CEI-50 vs. CEI-20" and "CEI-50 vs. naïve" comparisons, with 15 genes common to both comparisons. Bioinformatics analysis identified Notch and TGFß pathways to be the most up- and down-regulated KEGG pathways, respectively. For ONH, 22 significantly regulated genes were identified in the "CEI-50 vs. naïve" comparison. Pathway analysis identified 'defense response' and 'immune response' as two significantly upregulated biological process pathways. Conclusions: This study demonstrates the ability to assay IOP-responsive genes in both TM and ONH tissues simultaneously. In the TM, downregulation of TGFß pathway genes suggest that TM responses may prevent TGFß-induced extracellular matrix synthesis. For ONH, the initial response to elevated IOP may be protective, with astrocytes playing a key role in these gene responses.

Performance of Febrile Infant Decision Tools on Hypothermic Infants Evaluated for Infection.

BACKGROUND: Given the lack of evidence-based guidelines for hypothermic infants, providers may be inclined to use febrile infant decision-making tools to guide management decisions. Our objective was to assess the diagnostic performance of febrile infant decision tools for identifying hypothermic infants at low risk of bacterial infection. METHODS: We conducted a secondary analysis of a retrospective cohort study of hypothermic (≤36.0 C) infants ≤90 days of age presenting to the emergency department or inpatient unit among 9 participating sites between September 1, 2016 and May 5, 2021. Well-appearing infants evaluated for bacterial infections via laboratory testing were included. Infants with complex chronic conditions or premature birth were excluded. Performance characteristics for detecting serious bacterial infection (SBI; urinary tract infection, bacteremia, bacterial meningitis) and invasive bacterial infection (IBI; bacteremia, bacterial meningitis) were calculated for each tool. RESULTS: Overall, 314 infants met the general inclusion criteria, including 14 cases of SBI (4.5%) and 7 cases of IBI (2.2%). The median age was 5 days, and 68.1% of the infants (214/314) underwent a full sepsis evaluation. The Philadelphia, Boston, IBI Score, and American Academy of Pediatrics Clinical Practice Guideline did not misclassify any SBI or IBI as low risk; however, they had low specificity and positive predictive value. Rochester and Pediatric Emergency Care Applied Research Network tools misclassified infants with bacterial infections. CONCLUSIONS: Several febrile infant decision tools were highly sensitive, minimizing missed SBIs and IBIs in hypothermic infants. However, the low specificity of these decision tools may lead to unnecessary testing, antimicrobial exposure, and hospitalization.

Frequency of Treatment Failure of UTIs in Children With Congenital Urinary Tract Anomalies.

OBJECTIVES: Children with certain congenital anomalies of the kidney and urinary tract and neurogenic bladder (CAKUT/NGB) are at higher risk of treatment failure for urinary tract infections (UTIs) than children with normal genitourinary anatomy, but the literature describing treatment and outcomes is limited. The objectives of this study were to describe the rate of treatment failure in children with CAKUT/NGB and compare duration of antibiotics between those with and without treatment failure. METHODS: Multicenter retrospective cohort of children 0 to 17 years old with CAKUT/NGB who presented to the emergency department with fever or hypothermia and were diagnosed with UTI between 2017 and 2018. The outcome of interest was treatment failure, defined as subsequent emergency department visit or hospitalization for UTI because of the same pathogen within 30 days of the index encounter. Descriptive statistics and univariates analyses were used to compare covariates between groups. RESULTS: Of the 2014 patient encounters identified, 482 were included. Twenty-nine (6.0%) of the 482 included encounters had treatment failure. There was no difference in the mean duration of intravenous antibiotics (3.4 ± 2.5 days, 3.5 ± 2.8 days, P = .87) or total antibiotics between children with and without treatment failure (10.2 ± 3.8 days, 10.8 ± 4.0 days, P = .39) Of note, there was a higher rate of bacteremia in children with treatment failure (P = .04). CONCLUSIONS: In children with CAKUT/NGB and UTI, 6.0% of encounters had treatment failure. Duration of antibiotics was not associated with treatment failure. Larger studies are needed to assess whether bacteremia modifies the risk of treatment failure.

Noninvasive Respiratory Support for Pediatric Critical Asthma: A Multicenter Cohort Study.

BACKGROUND: Noninvasive respiratory support (NRS) for pediatric critical asthma includes CPAP; bi-level positive airway pressure (BPAP); and heated, humidified, high-flow nasal cannula (HFNC). We used the Virtual Pediatric System database to estimate NRS by prescribing rates for pediatric critical asthma and characterize patient clinical features and in-patient outcomes by the initial NRS device applied. METHODS: We performed a retrospective cohort study from 125 participating pediatric ICUs among children 2-17 years of age hospitalized for critical asthma and prescribed NRS from 2017 through 2021. The primary outcomes were NRS modality prescribing rates and trends. Secondary outcomes were descriptive and included demographics, comorbidities, severity of illness indices, and NRS failure rates (defined as escalation from the initial NRS modality to invasive ventilation, HFNC to BPAP or CPAP, or CPAP to BPAP). RESULTS: Of the 10,083 encounters studied, the initial NRS modalities prescribed varied widely by hospital center (HFNC: 69.7 ± 29.6%; BPAP: 27.2 ± 7.1%; CPAP: 3.1 ± 5.9%). The mean rates of HFNC use increased from 59.7% in 2017 to 71.9% in 2021 (+2.5%/y). In contrast, BPAP (-1.6%/y) and CPAP (-0.8%/y) utilization declined throughout the study period. Older children who were obese and with a higher Pediatric Risk of Mortality III-Probability of Mortality score were more frequently prescribed BPAP and CPAP compared with HFNC. Those children on HFNC experienced higher noninvasive respiratory support failure rates versus BPAP (7.3% vs 2.4%; P < .001) but a lower subsequent invasive ventilation rate versus BPAP (0.8% vs 2.4%; P < .001). CONCLUSIONS: In this multi-center cohort study, we observed that children with critical asthma are increasingly exposed to HFNC compared with BPAP and CPAP. Rates of HFNC failure were greater than those of BPAP failure, but a majority were transitioned to BPAP without subsequent invasive ventilation. The next steps include prospective trials, including practical end points such as patient comfort and optimal delivery of nebulized treatments to distinguish device superiority and suitable NRS utilization.

Time to Positive Blood and Cerebrospinal Fluid Cultures in Hypothermic Young Infants.

BACKGROUND AND OBJECTIVE: Hypothermia in young infants may be secondary to an invasive bacterial infection. No studies have explored culture time-to-positivity (TTP) in hypothermic infants. Our objective was to compare TTP of blood and cerebrospinal fluid (CSF) cultures between pathogenic and contaminant bacteria in hypothermic infants ≤90 days of age. METHODS: Secondary analysis of a retrospective cohort of 9 children's hospitals. Infants ≤90 days of age presenting to the emergency department or inpatient setting with hypothermia from September 1, 2017, to May 5, 2021, with positive blood or CSF cultures were included. Differences in continuous variables between pathogenic and contaminant organism groups were tested using a 2-sample t test and 95% confidence intervals for the mean differences reported. RESULTS: Seventy-seven infants met inclusion criteria. Seventy-one blood cultures were positive, with 20 (28.2%) treated as pathogenic organisms. Five (50%) of 10 positive CSF cultures were treated as pathogenic. The median (interquartile range [IQR]) TTP for pathogenic blood cultures was 16.8 (IQR 12.7-19.2) hours compared with 26.11 (IQR 20.5-48.1) hours for contaminant organisms (P < .001). The median TTP for pathogenic organisms on CSF cultures was 34.3 (IQR 2.0-53.7) hours, compared with 58.1 (IQR 52-72) hours for contaminant CSF organisms (P < .186). CONCLUSIONS: Our study is the first to compare the TTP of blood and CSF cultures between pathogenic and contaminant bacteria in hypothermic infants. All pathogenic bacteria in the blood grew within 36 hours. No difference in TTP of CSF cultures between pathogenic and contaminant bacteria was detected.

Genome-Wide Gene-Environment Interaction Analyses to Understand the Relationship between Red Meat and Processed Meat Intake and Colorectal Cancer Risk.

BACKGROUND: High red meat and/or processed meat consumption are established colorectal cancer risk factors. We conducted a genome-wide gene-environment (GxE) interaction analysis to identify genetic variants that may modify these associations. METHODS: A pooled sample of 29,842 colorectal cancer cases and 39,635 controls of European ancestry from 27 studies were included. Quantiles for red meat and processed meat intake were constructed from harmonized questionnaire data. Genotyping arrays were imputed to the Haplotype Reference Consortium. Two-step EDGE and joint tests of GxE interaction were utilized in our genome-wide scan. RESULTS: Meta-analyses confirmed positive associations between increased consumption of red meat and processed meat with colorectal cancer risk [per quartile red meat OR = 1.30; 95% confidence interval (CI) = 1.21-1.41; processed meat OR = 1.40; 95% CI = 1.20-1.63]. Two significant genome-wide GxE interactions for red meat consumption were found. Joint GxE tests revealed the rs4871179 SNP in chromosome 8 (downstream of HAS2); greater than median of consumption ORs = 1.38 (95% CI = 1.29-1.46), 1.20 (95% CI = 1.12-1.27), and 1.07 (95% CI = 0.95-1.19) for CC, CG, and GG, respectively. The two-step EDGE method identified the rs35352860 SNP in chromosome 18 (SMAD7 intron); greater than median of consumption ORs = 1.18 (95% CI = 1.11-1.24), 1.35 (95% CI = 1.26-1.44), and 1.46 (95% CI = 1.26-1.69) for CC, CT, and TT, respectively. CONCLUSIONS: We propose two novel biomarkers that support the role of meat consumption with an increased risk of colorectal cancer. IMPACT: The reported GxE interactions may explain the increased risk of colorectal cancer in certain population subgroups.

Deep analysis of CD4 T cells in the rhesus CNS during SIV infection.

Virologic suppression with antiretroviral therapy (ART) has significantly improved health outcomes for people living with HIV, yet challenges related to chronic inflammation in the central nervous system (CNS)-known as Neuro-HIV- persist. As primary targets for HIV-1 with the ability to survey and populate the CNS and interact with myeloid cells to co-ordinate neuroinflammation, CD4 T cells are pivotal in Neuro-HIV. Despite their importance, our understanding of CD4 T cell distribution in virus-targeted CNS tissues, their response to infection, and potential recovery following initiation of ART remain limited. To address these gaps, we studied ten SIVmac251-infected rhesus macaques using an ART regimen simulating suboptimal adherence. We evaluated four macaques during the acute phase pre-ART and six during the chronic phase. Our data revealed that HIV target CCR5+ CD4 T cells inhabit both the brain parenchyma and adjacent CNS tissues, encompassing choroid plexus stroma, dura mater, and the skull bone marrow. Aligning with the known susceptibility of CCR5+ CD4 T cells to viral infection and their presence within the CNS, high levels of viral RNA were detected in the brain parenchyma and its border tissues during acute SIV infection. Single-cell RNA sequencing of CD45+ cells from the brain revealed colocalization of viral transcripts within CD4 clusters and significant activation of antiviral molecules and specific effector programs within T cells, indicating CNS CD4 T cell engagement during infection. Acute infection led to marked imbalance in the CNS CD4/CD8 ratio which persisted into the chronic phase. These observations underscore the functional involvement of CD4 T cells within the CNS during SIV infection, enhancing our understanding of their role in establishing CNS viral presence. Our findings offer insights for potential T cell-focused interventions while underscoring the challenges in eradicating HIV from the CNS, particularly in the context of sub-optimal ART.

Directional microwave emission from femtosecond-laser illuminated linear arrays of superconducting rings.

We examine the electromagnetic emission from two photo-illuminated linear arrays composed of inductively charged superconducting ring elements. The arrays are illuminated by an ultrafast infrared laser that triggers microwave broadband emission detected in the 1-26 GHz range. Based on constructive interference from the arrays a narrowing of the forward radiation lobe is observed with increasing element count and frequency demonstrating directed GHz emission. Results suggest that higher frequencies and a larger number of elements are achievable leading to a unique pulsed array emitter concept that can span frequencies from the microwave to the terahertz (THz) regime.

CD4 T cell Responses in the CNS during SIV infection.

Virologic suppression with antiretroviral therapy (ART) has significantly improved health outcomes for people living with HIV, yet challenges related to chronic inflammation in the central nervous system (CNS) - known as Neuro-HIV- persist. As primary targets for HIV-1 with the ability to survey and populate the CNS and interact with myeloid cells to co-ordinate neuroinflammation, CD4 T cells are pivotal in Neuro-HIV. Despite their importance, our understanding of CD4 T cell distribution in virus-targeted CNS tissues, their response to infection, and potential recovery following initiation of ART remain limited. To address these gaps, we studied ten SIVmac251-infected rhesus macaques using an ART regimen simulating suboptimal adherence. We evaluated four macaques during the acute phase pre-ART and six during the chronic phase. Our data revealed that HIV target CCR5+ CD4 T cells inhabit both the brain parenchyma and adjacent CNS tissues, encompassing choroid plexus stroma, dura mater, and the skull bone marrow. Aligning with the known susceptibility of CCR5+ CD4 T cells to viral infection and their presence within the CNS, high levels of viral RNA were detected in the brain parenchyma and its border tissues during acute SIV infection. Single-cell RNA sequencing of CD45+ cells from the brain revealed colocalization of viral transcripts within CD4 clusters and significant activation of antiviral molecules and specific effector programs within T cells, indicating CNS CD4 T cell engagement during infection. Despite viral suppression with ART, acute infection led to significant depletion of CNS CD4 T cells, persisting into the chronic phase. These findings underscore the functional involvement of CD4 T cells within the CNS during SIV infection, enhancing our understanding of their role in establishing CNS viral presence. Our results offer insights for potential T cell-focused interventions while also underscoring the challenges in eradicating HIV from the CNS, even with effective ART.

CCR7+ CD4 T Cell Immunosurveillance Disrupted in Chronic SIV-Induced Neuroinflammation in Rhesus Brain.

CD4 T cells survey and maintain immune homeostasis in the brain, yet their differentiation states and functional capabilities remain unclear. Our approach, combining single-cell transcriptomic analysis, ATAC-seq, spatial transcriptomics, and flow cytometry, revealed a distinct subset of CCR7+ CD4 T cells resembling lymph node central memory (T CM ) cells. We observed chromatin accessibility at the CCR7, CD28, and BCL-6 loci, defining molecular features of T CM . Brain CCR7+ CD4 T cells exhibited recall proliferation and interleukin-2 production ex vivo, showcasing their functional competence. We identified the skull bone marrow as a local niche for these cells alongside other CNS border tissues. Sequestering T CM cells in lymph nodes using FTY720 led to reduced CCR7+ CD4 T cell frequencies in the cerebrospinal fluid, accompanied by increased monocyte levels and soluble markers indicating immune activation. In macaques chronically infected with SIVCL57 and experiencing viral rebound due to cessation of antiretroviral therapy, a decrease in brain CCR7+ CD4 T cells was observed, along with increased microglial activation and initiation of neurodegenerative pathways. Our findings highlight a role for CCR7+ CD4 T cells in CNS immune surveillance and their decline during chronic SIV-induced neuroinflammation highlights their responsiveness to neuroinflammatory processes. In Brief: Utilizing single-cell and spatial transcriptomics on adult rhesus brain, we uncover a unique CCR7+ CD4 T cell subset resembling central memory T cells (T CM ) within brain and border tissues, including skull bone marrow. Our findings show decreased frequencies of this subset during SIV- induced chronic neuroinflammation, emphasizing responsiveness of CCR7+ CD4 T cells to CNS disruptions. Highlights: CCR7+ CD4 T cells survey border and parenchymal CNS compartments during homeostasis; reduced presence of CCR7+ CD4 T cells in cerebrospinal fluid leads to immune activation, implying a role in neuroimmune homeostasis. CNS CCR7+ CD4 T cells exhibit phenotypic and functional features of central memory T cells (T CM ) including production of interleukin 2 and the capacity for rapid recall proliferation. Furthermore, CCR7+ CD4 T cells reside in the skull bone marrow. CCR7+ CD4 T cells are markedly decreased within the brain parenchyma during chronic viral neuroinflammation.

Fetal anomaly diagnosis and termination of pregnancy in Ireland: a service evaluation following implementation of abortion services in 2019.

BACKGROUND: Approximately 3% of pregnancies are diagnosed with a fetal anomaly, of which a proportion is fatal or life-limiting. The introduction of legislation for termination of pregnancy in Ireland in 2019 for conditions "likely to lead to the death of the fetus" made termination of pregnancy for "fatal fetal anomaly" an option for pregnant women in Ireland. OBJECTIVE: This study examined all cases of termination of pregnancy performed for major fetal anomaly over the first 3 years of service implementation, including cases that did not meet the legal criteria, resulting in women traveling outside Ireland for abortion care. STUDY DESIGN: A retrospective service evaluation of tertiary fetal medicine clinics in 2 tertiary maternity hospitals between 2019 and 2021 was undertaken. We compared pregnancies of patients diagnosed with fatal fetal anomaly who underwent termination of pregnancy in Ireland with those of patients who did not meet the legal criteria and hence traveled outside Ireland for termination of pregnancy. RESULTS: Overall, 139 pregnancies met the inclusion criteria; 83 (59.7%) patients had termination of pregnancy in the tertiary maternity hospital (local), and 56 (40.3%) traveled abroad, mainly to the United Kingdom. Demographic characteristics were similar between the 2 groups, as was gestation at diagnosis and delivery. All cases where termination of pregnancy was local were discussed at fetal medicine multidisciplinary meetings, as opposed to 34% of cases of patients who ultimately traveled outside Ireland for termination of pregnancy. The most common indication (25/83; 30.1%) for local termination of pregnancy was trisomy 18, followed by anencephaly. Traveling to obtain abortion care was mainly due to diagnosis of trisomy 21 (30/56; 53.6%), followed by other multiple structural anomalies/syndromes deemed locally as not meeting the legal criteria. CONCLUSION: Legislation for termination of pregnancy for fetal anomaly, restricted to fatal diagnoses, is difficult to implement, requires significant multidisciplinary input, and can lead to limited services for pregnancies diagnosed with major fetal anomalies. Our findings emphasize the impact of legislative barriers to abortion care for fetal anomaly and the need for policies and services that support women's access to termination of pregnancy for fetal anomaly.