Re-appraising the role of T-cell derived interferon gamma in restriction of Mycobacterium tuberculosis in the murine lung: T-cell derived IFNγ is required to restrict pulmonary Mtb.

T cells producing interferon gamma (IFNγ) have long been considered a stalwart for immune protection against Mycobacterium tuberculosis (Mtb), but their relative importance to pulmonary immunity has been challenged by murine studies which achieved protection by adoptively transferred Mtb-specific IFNγ-/- T cells. Using IFNγ-/- T cell chimeric mice and adoptive transfer of IFNγ-/- T cells into TCRß-/-δ-/- mice, we demonstrate that control of lung Mtb burden is in fact dependent on T cell-derived IFNγ, and furthermore, mice selectively deficient in T cell-derived IFNγ develop exacerbated disease compared to T cell-deficient controls despite equivalent lung bacterial burdens. Deficiency in T cell-derived IFNγ skews infected and bystander monocyte-derived macrophages (MDMs) to an alternative M2 phenotype, and promotes neutrophil and eosinophil influx. Our studies support an important role for T cell-derived IFNγ in pulmonary immunity against TB.

TOLLIP inhibits lipid accumulation and the integrated stress response in alveolar macrophages to control Mycobacterium tuberculosis infection.

A polymorphism causing deficiencies in Toll-interacting protein (TOLLIP), an inhibitory adaptor protein affecting endosomal trafficking, is associated with increased tuberculosis (TB) risk. It is, however, unclear how TOLLIP affects TB pathogenesis. Here we show that TB severity is increased in Tollip-/- mice, characterized by macrophage- and T cell-driven inflammation, foam cell formation and lipid accumulation. Tollip-/- alveolar macrophages (AM) specifically accumulated lipid and underwent necrosis. Transcriptional and protein analyses of Mycobacterium tuberculosis (Mtb)-infected, Tollip-/- AM revealed increased EIF2 signalling and downstream upregulation of the integrated stress response (ISR). These phenotypes were linked, as incubation of the Mtb lipid mycolic acid with Mtb-infected Tollip-/- AM activated the ISR and increased Mtb replication. Correspondingly, the ISR inhibitor, ISRIB, reduced Mtb numbers in AM and improved Mtb control, overcoming the inflammatory phenotype. In conclusion, targeting the ISR offers a promising target for host-directed anti-TB therapy towards improved Mtb control and reduced immunopathology.

Improving the Timing of Acute Care Insulin Delivery.

LOCAL PROBLEM: Variations in nursing practice were observed across our hospital, a 520-bed acute care teaching facility in the northeast United States, regarding the timing and frequency of insulin administration in adult patients with diabetes. Chart audits noted that RNs administered insulin more than one hour after blood glucose results were obtained 97% of the time. In addition, insulin was given at bedtime only 37% of the time. PURPOSE: The purpose of this quality improvement (QI) project was to improve the care of inpatients requiring insulin by implementing protocols and adjusting practice to align with best practice recommendations. METHODS: The clinical nurse education specialist met with a team of staff nurses, providers, nurse leaders, and patient care technicians (PCTs) to formulate protocols and design interventions to ensure improvements in the quality of care for inpatients with diabetes. A sequence of education sessions and an online learning module were developed and assigned to nurses and PCTs to address knowledge gaps, specifically in the pharmacodynamics and safe administration of insulin, as well as how best to provide care to patients with diabetes. Monthly adherence data were disseminated to nurse leaders and educators and reviewed with clinical staff at daily safety huddles and staff meetings. Additional interventions to enhance nursing practice in caring for patients with diabetes included ensuring both bedtime insulin administration and timely insulin delivery. This project began in May 2017 and ended five years later. RESULTS: Two weeks after initial education sessions began in May and June 2017, the frequency of giving bedtime insulin based on the order set and according to the patient's blood glucose levels rose from 37% to 82%, and adherence to best practice protocols continued until final chart audits were performed in May 2022. The frequency of giving insulin less than one hour after obtaining blood glucose results improved from 3% to 64% between October and December 2019, and increased to a sustained level above the project's 92% goal two years later. CONCLUSION: Protocol development, targeted education, and audits with feedback led to improved care delivery for patients requiring insulin and increased nursing confidence.

Bifidobacterium infantis associates with T cell immunity in human infants and is sufficient to enhance antigen-specific T cells in mice.

Bacille Calmette-Guerin (BCG) vaccine can elicit good TH1 responses in neonates. We hypothesized that the pioneer gut microbiota affects vaccine T cell responses. Infants who are HIV exposed but uninfected (iHEU) display an altered immunity to vaccination. BCG-specific immune responses were analyzed at 7 weeks of age in iHEU, and responses were categorized as high or low. Bifidobacterium longum subsp. infantis was enriched in the stools of high responders, while Bacteroides thetaiotaomicron was enriched in low responders at time of BCG vaccination. Neonatal germ-free or SPF mice orally gavaged with live B. infantis exhibited significantly higher BCG-specific T cells compared with pups gavaged with B. thetaiotaomicron. B. infantis and B. thetaiotaomicron differentially affected stool metabolome and colonic transcriptome. Human colonic epithelial cells stimulated with B. infantis induced a unique gene expression profile versus B. thetaiotaomicron. We thus identified a causal role of B. infantis in early-life antigen-specific immunity.

Assessing vaccine-mediated protection in an ultra-low dose Mycobacterium tuberculosis murine model.

Despite widespread immunization with Bacille-Calmette-Guérin (BCG), the only currently licensed tuberculosis (TB) vaccine, TB remains a leading cause of mortality globally. There are many TB vaccine candidates in the developmental pipeline, but the lack of a robust animal model to assess vaccine efficacy has hindered our ability to prioritize candidates for human clinical trials. Here we use a murine ultra-low dose (ULD) Mycobacterium tuberculosis (Mtb) challenge model to assess protection conferred by BCG vaccination. We show that BCG confers a reduction in lung bacterial burdens that is more durable than that observed after conventional dose challenge, curbs Mtb dissemination to the contralateral lung, and, in a small percentage of mice, prevents detectable infection. These findings are consistent with the ability of human BCG vaccination to mediate protection, particularly against disseminated disease, in specific human populations and clinical settings. Overall, our findings demonstrate that the ultra-low dose Mtb infection model can measure distinct parameters of immune protection that cannot be assessed in conventional dose murine infection models and could provide an improved platform for TB vaccine testing.

Predictors of SARS-CoV-2 Omicron breakthrough infection after receipt of AZD7442 (tixagevimab-cilgavimab) for pre-exposure prophylaxis among hematologic malignancy patients.

AZD7442 (tixagevimab-cilgavimab) is a combination of two human monoclonal antibodies for pre-exposure prophylaxis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among high-risk patients who do not mount a reliable vaccine response. Foremost among these are hematologic malignancy patients with limited clinical trial or realworld experience to assess the effectiveness of this combination treatment since the emergence of Omicron and its subvariants. We performed a retrospective study of 892 high-risk hematologic malignancy patients who received AZD7442 at Memorial Sloan Kettering Cancer Center in New York City from January 1, 2022 to July 31, 2022. We evaluated demographic, clinical, and laboratory characteristics and performed regression analyses to evaluate risk factors for breakthrough infection. We also evaluated the impact of updated AZD7442 dosing regimens on the risk of breakthrough infection. Among 892 patients, 98 (10.9%) had a breakthrough infection during the study period. A majority received early outpatient treatment (82%) and eventually eight (8.2%) required hospitalization for management of Coronavirus Disease 2019 (COVID-19), with a single instance of severe COVID-19 and death. Patients who received a repeat dose or a higher firsttime dose of AZD7442 had a lower incidence of breakthrough infection. Univariate analyses did not reveal any significant predictors of breakthrough infection. While AZD7442 is effective at reducing SARS-CoV-2 breakthrough infection in patients with hematologic malignancies, no risk factors reliably predicted risk of infection. Patients who received updated dosing regimens as per Food and Drug Administration guidelines had better protection against breakthrough infection.

The Modified and Extended Hospital Elder Life Program: A remote model of care to expand delirium prevention.

BACKGROUND: Delirium is a common complication of hospitalization and is associated with poor outcomes. Multicomponent delirium prevention strategies such as the Hospital Elder Life Program (HELP) have proven effective but rely on face-to-face intervention protocols and volunteer staff, which was not possible due to restrictions during the COVID-19 pandemic. We developed the Modified and Extended Hospital Elder Life Program (HELP-ME), an innovative adaptation of HELP for remote and/or physically distanced applications. METHODS: HELP-ME protocols were adapted from well-established multicomponent delirium prevention strategies and were implemented at four expert HELP sites. Each site contributed to the protocol modifications and compilation of a HELP-ME Operations Manual with standardized protocols and training instructions during three expert panel working groups. Implementation was overseen and monitored during seven learning sessions plus four coaching sessions from January 8, 2021, through September 24, 2021. Feasibility of implementing HELP-ME was measured by protocol adherence rates. Focus groups were conducted to evaluate the acceptability, provide feedback, and identify facilitators and barriers to implementation. RESULTS: A total of 106 patients were enrolled across four sites, and data were collected for 214 patient-days. Overall adherence was 82% (1473 completed protocols/1798 patient-days), achieving our feasibility target of >75% overall adherence. Individual adherence rates ranged from 55% to 96% across sites for the individual protocols. Protocols with high adherence rates included the nursing delirium protocol (96%), nursing medication review (96%), vision (89%), hearing (87%), and orientation (88%), whereas lower adherence occurred with fluid repletion (64%) and range-of-motion exercises (55%). Focus group feedback was generally positive for acceptability, with recommendations that an optimal approach would be hybrid, balancing in-person and remote interventions for potency and long-term sustainability. CONCLUSIONS: HELP-ME was fully implemented at four HELP sites, demonstrating feasibility and acceptability. Testing hybrid approaches and evaluating effectiveness is recommended for future work.

Antibiotic Treatment during Gestation Enhances Susceptibility to Mycobacterium tuberculosis in Offspring.

Whether antibiotic treatment during gestation impacts T cell immunity to vaccination in offspring is unexplored. Dams treated with polymyxin B (PMB) during gestation (Mg) displayed altered microbial communities prior to delivery compared to control dams (Mc). Differences in microbiota were also evident in pups born to polymyxin B-treated dams (Pg) compared to control pups (Pc). When pups were immunized with Bacille Calmette-Guerin (BCG), we observed no difference in TB10.4-specific T cells between Pc and Pg 4 weeks postimmunization. Significantly fewer splenic CD4 T cells from BCG-vaccinated Pg produced interleukin-2 (IL-2) upon stimulation, suggesting a possible functional deficiency. There was no difference in purified protein derivative (PPD)-specific IgG between Pc and Pg at this time point. However, when infected with Mycobacterium tuberculosis, Pg displayed significantly higher bacterial burden in the lung than Pc. Our results show that maternal PMB treatment during gestation may not impact splenic antigen-specific T cell responses following BCG vaccination but alters susceptibility to M. tuberculosis in offspring. IMPORTANCE The composition of the pioneer microbiota that colonize the infant gut are determined by the mother. Polymyxin B-induced changes in the maternal microbiota during pregnancy impact the offspring gut microbiota but not vaccine-specific CD4 T cell response. However, when infected with Mycobacterium tuberculosis, offspring born to mothers with an altered gut microbiota are susceptible to infection compared to those born to mothers not exposed to antibiotics.

Longitudinal assessment of vascular calcification in generalized arterial calcification of infancy.

BACKGROUND: Generalized arterial calcification of infancy (GACI), also known as idiopathic infantile arterial calcification, is a very uncommon genetic disorder characterized by calcifications and stenoses of large- and medium-size arteries that can lead to end-organ damage. OBJECTIVE: To describe changes in imaging findings in 10 children with GACI at a single institution from 2010 to 2021. MATERIALS AND METHODS: In this retrospective study we reviewed initial and follow-up body imaging in children with genetic confirmation of GACI at our hospital. All initial images were analyzed for the presence and distribution of arterial calcifications, stenoses and wall thickening/irregularity within the chest, abdomen and pelvis. We compared available follow-up studies to the initial imaging findings. We extracted clinical information including prenatal and postnatal treatment from the children's medical records. RESULTS: We evaluated 10 children (five boys) with a diagnosis of GACI. Median age at first body imaging was 8 days (range: 1 day to 5 years). Six children were identified prenatally and four postnatally. Postnatal presentation included cardiac failure, seizures and hypertension. Images in newborns (n = 8) most commonly showed diffuse arterial calcifications (6/8; 75%), while stenoses were less common (2/8; 25%) during this period. Two children were diagnosed after the neonatal period - one in infancy and one during childhood. In total, half the children (5/10; 50%) had arterial stenoses - three cases visualized at first imaging and two identified on follow-up images during infancy. Stenoses had completely resolved in one child (1/5; 20%) at last follow-up. Eight children received prenatal or postnatal treatment or both. All children who received both prenatal and postnatal treatment (n = 4) had completely resolved calcifications at last follow-up. CONCLUSION: Children with GACI might have characteristic vascular calcifications at birth that raise the suspicion of this disease. Arterial calcifications decrease or disappear spontaneously or after treatment, but arterial stenoses usually persist. Calcifications and arterial stenoses can be easily identified and followed with non-contrast CT and CT angiography.

The Tuberculous Granuloma and Preexisting Immunity.

Pulmonary granulomas are widely considered the epicenters of the immune response to Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB). Recent animal studies have revealed factors that either promote or restrict TB immunity within granulomas. These models, however, typically ignore the impact of preexisting immunity on cellular organization and function, an important consideration because most TB probably occurs through reinfection of previously exposed individuals. Human postmortem research from the pre-antibiotic era showed that infections in Mtb-naïve individuals (primary TB) versus those with prior Mtb exposure (postprimary TB) have distinct pathologic features. We review recent animal findings in TB granuloma biology, which largely reflect primary TB. We also discuss our current understanding of postprimary TB lesions, about which much less is known. Many knowledge gaps remain, particularly regarding how preexisting immunity shapes granuloma structure and local immune responses at Mtb infection sites.

Pediatric chest wall masses: spectrum of benign findings on ultrasound.

A palpable finding along the chest wall is a frequent indication for pediatric US. Accurate identification of benign lesions can reassure families and appropriately triage children who need follow-up, cross-sectional imaging, or biopsy. In this pictorial essay, we review chest wall anatomy, illustrate US techniques and discuss key US imaging features of common benign lesions and normal variants.

Ultra-low Dose Aerosol Infection of Mice with Mycobacterium tuberculosis More Closely Models Human Tuberculosis.

Tuberculosis (TB) is a heterogeneous disease manifesting in a subset of individuals infected with aerosolized Mycobacterium tuberculosis (Mtb). Unlike human TB, murine infection results in uniformly high lung bacterial burdens and poorly organized granulomas. To develop a TB model that more closely resembles human disease, we infected mice with an ultra-low dose (ULD) of between 1-3 founding bacteria, reflecting a physiologic inoculum. ULD-infected mice exhibited highly heterogeneous bacterial burdens, well-circumscribed granulomas that shared features with human granulomas, and prolonged Mtb containment with unilateral pulmonary infection in some mice. We identified blood RNA signatures in mice infected with an ULD or a conventional Mtb dose (50-100 CFU) that correlated with lung bacterial burdens and predicted Mtb infection outcomes across species, including risk of progression to active TB in humans. Overall, these findings highlight the potential of the murine TB model and show that ULD infection recapitulates key features of human TB.

Protective efficacy of an attenuated Mtb ΔLprG vaccine in mice.

Bacille Calmette-Guerin (BCG), an attenuated whole cell vaccine based on Mycobacterium bovis, is the only licensed vaccine against Mycobacterium tuberculosis (Mtb), but its efficacy is suboptimal and it fails to protect against pulmonary tuberculosis. We previously reported that Mtb lacking the virulence genes lprG and rv1410c (ΔLprG) was highly attenuated in immune deficient mice. In this study, we show that attenuated ΔLprG Mtb protects C57BL/6J, Balb/cJ, and C3HeB/FeJ mice against Mtb challenge and is as attenuated as BCG in SCID mice. In C3HeB/FeJ mice, ΔLprG vaccination resulted in innate peripheral cytokine production and induced high polyclonal PPD-specific cytokine-secreting CD4+ T lymphocytes in peripheral blood. The ΔLprG vaccine afforded protective efficacy in the lungs of C3H/FeJ mice following both H37Rv and Erdman aerosolized Mtb challenges. Vaccine efficacy correlated with antigen-specific PD-1-negative CD4+ T lymphocytes as well as with serum IL-17 levels after vaccination. We hypothesize that induction of Th17 cells in lung is critical for vaccine protection, and we show a serum cytokine biomarker for IL-17 shortly after vaccination may predict protective efficacy.

MRI Findings of Infectious Sacroiliitis in Children: Are There Age-Dependent Differences?

OBJECTIVE. The purpose of this study was to investigate the prevalence of various MRI findings of infectious sacroiliitis in children and with respect to age. MATERIALS AND METHODS. This institutional review board-approved, HIPAA-compliant retrospective study included children with infectious sacroiliitis who underwent MRI examination between December 1, 2002, and September 30, 2018. Two radiologists blinded to the clinical outcome reviewed each MRI examination to determine the presence or absence of periarticular marrow edema, erosions, capsular bulge, extracapsular edema, and soft-tissue abscess. If available, pelvic radiographs were retrospectively reviewed by a third radiologist. Mann-Whitney U, chi-square, and Fisher exact tests were used to compare MRI findings between younger and older children. RESULTS. The study included 40 children (19 boys and 21 girls; mean age, 8.6 ± 6.2 [SD] years). Sixteen children presented at or below 5 years of age (mean age, 1.7 ± 1.4 years) and 24 children presented at or above 8 years of age (mean age, 13.3 + 2.6 years). Periarticular marrow edema and anterior extracapsular edema were present in all children. Posterior extracapsular edema (p = 0.01) was statistically significantly more common in younger children when compared with older children. There was no significant difference in the presence of erosions (p = 0.60), capsule bulge (p = 0.63), or abscess (p = 0.34) between younger and older children. Pelvic radiographs (n = 28; obtained 1.6 days ± 1.7 from MRI) allowed the correct identification of the abnormal joint in only 50% of the studies. CONCLUSION. MRI findings of infectious sacroiliitis are common in children of all ages with posterior extracapsular edema statistically significantly more prevalent in younger children.

Imaging Musculoskeletal Manifestations of Pediatric Hematologic Malignancies.

OBJECTIVE. The purpose of this article is to describe imaging findings of common and uncommon musculoskeletal manifestations, posttreatment changes, and complications of pediatric hematologic malignancies. CONCLUSION. Many pediatric patients with leukemia and lymphoma present with or experience musculoskeletal symptoms over the course of the disease. Imaging can depict bone and soft-tissue signs of pediatric hematologic malignancies and plays an important role in the diagnosis of complications and treatment-related changes.

Imaging of developmental dysplasia of the hip: ultrasound, radiography and magnetic resonance imaging.

Developmental dysplasia of the hip (DDH) describes a broad spectrum of developmental abnormalities of the hip joint that are traditionally diagnosed during infancy. Because the development of the hip joint is a dynamic process, optimal treatment depends not only on the severity of the dysplasia, but also on the age of the child. Various imaging modalities are routinely used to confirm suspected diagnosis, to assess severity, and to monitor treatment response. For infants younger than 4 months, screening hip ultrasound (US) is recommended only for those with risk factors, equivocal or positive exam findings, whereas for infants older than 4-6 months, pelvis radiography is preferred. Following surgical hip reduction, magnetic resonance (MR) imaging is preferred over computed tomography (CT) because MR can not only confirm concentric hip joint reduction, but also identify the presence of soft-tissue barriers to reduction and any unexpected postoperative complications. The routine use of contrast-enhanced MR remains controversial because of the relative paucity of well-powered and validated literature. The main objectives of this article are to review the normal and abnormal developmental anatomy of the hip joint, to discuss the rationale behind the current recommendations on the most appropriate selection of imaging modalities for screening and diagnosis, and to review routine and uncommon findings that can be identified on post-reduction MR, using an evidence-based approach. A basic understanding of the physiology and the pathophysiology can help ensure the selection of optimal imaging modality and reduce equivocal diagnoses that can lead to unnecessary treatment.

Cutting Edge: Bacillus Calmette-Guérin-Induced T Cells Shape Mycobacterium tuberculosis Infection before Reducing the Bacterial Burden.

Growing evidence suggests the outcome of Mycobacterium tuberculosis infection is established rapidly after exposure, but how the current tuberculosis vaccine, bacillus Calmette-Guérin (BCG), impacts early immunity is poorly understood. In this study, we found that murine BCG immunization promotes a dramatic shift in infected cell types. Although alveolar macrophages are the major infected cell for the first 2 weeks in unimmunized animals, BCG promotes the accelerated recruitment and infection of lung-infiltrating phagocytes. Interestingly, this shift is dependent on CD4 T cells, yet does not require intrinsic recognition of Ag presented by infected alveolar macrophages. M. tuberculosis-specific T cells are first activated in lung regions devoid of infected cells, and these events precede vaccine-induced reduction of the bacterial burden, which occurs only after the colocalization of T cells and infected cells. Understanding how BCG alters early immune responses to M. tuberculosis provides new avenues to improve upon the immunity it confers.

American Joint Committee on Cancer's Staging System for Breast Cancer, Eighth Edition: What the Radiologist Needs to Know.

The TNM staging system for cancer was developed by Pierre Denoix in France in the 1940s and 1950s. The North American effort to standardize the TNM system for cancer staging was first organized in 1959 as the American Joint Committee for Cancer Staging and End-Results Reporting, which is now the American Joint Committee on Cancer (AJCC). The most recent edition of the AJCC Cancer Staging Manual, the eighth edition, was globally adopted on January 1, 2018. Previous editions of the manual have relied on anatomic methods of staging alone, which used population-based survival data to predict clinical outcomes. In the era of precision medicine, the major change in the eighth edition is the incorporation of prognostic biomarkers to more accurately predict clinical outcomes and treatment response on an individual basis, without relying solely on the anatomic extent of disease. Factors such as tumor grade, hormone receptor and oncogene expression, and multigene panel recurrence scores are now integrated with anatomic information to yield a final prognostic stage group, which will provide better stratification of patient prognosis. The purpose of this article is to review the major changes in the AJCC eighth edition for breast cancer staging, review anatomic TNM staging, familiarize the radiologist with prognostic biomarkers and prognostic staging, and identify key sites of disease that may alter clinical management. ©RSNA, 2018.

Alveolar Macrophages Provide an Early Mycobacterium tuberculosis Niche and Initiate Dissemination.

Mycobacterium tuberculosis (Mtb) infection is initiated in the distal airways, but the bacteria ultimately disseminate to the lung interstitium. Although various cell types, including alveolar macrophages (AM), neutrophils, and permissive monocytes, are known to be infected with Mtb, the initially infected cells as well as those that mediate dissemination from the alveoli to the lung interstitium are unknown. In this study, using a murine infection model, we reveal that early, productive Mtb infection occurs almost exclusively within airway-resident AM. Thereafter Mtb-infected, but not uninfected, AM localize to the lung interstitium through mechanisms requiring an intact Mtb ESX-1 secretion system. Relocalization of infected AM precedes Mtb uptake by recruited monocyte-derived macrophages and neutrophils. This dissemination process is driven by non-hematopoietic host MyD88/interleukin-1 receptor inflammasome signaling. Thus, interleukin-1-mediated crosstalk between Mtb-infected AM and non-hematopoietic cells promotes pulmonary Mtb infection by enabling infected cells to disseminate from the alveoli to the lung interstitium.