Rationale and design of the Nephrotic Syndrome Study Network (NEPTUNE) Match in glomerular diseases: designing the right trial for the right patient, today.

Glomerular diseases are classified using a descriptive taxonomy that is not reflective of the heterogeneous underlying molecular drivers. This limits not only diagnostic and therapeutic patient management, but also impacts clinical trials evaluating targeted interventions. The Nephrotic Syndrome Study Network (NEPTUNE) is poised to address these challenges. The study has enrolled >850 pediatric and adult patients with proteinuric glomerular diseases who have contributed to deep clinical, histologic, genetic, and molecular profiles linked to long-term outcomes. The NEPTUNE Knowledge Network, comprising combined, multiscalar data sets, captures each participant's molecular disease processes at the time of kidney biopsy. In this editorial, we describe the design and implementation of NEPTUNE Match, which bridges a basic science discovery pipeline with targeted clinical trials. Noninvasive biomarkers have been developed for real-time pathway analyses. A Molecular Nephrology Board reviews the pathway maps together with clinical, laboratory, and histopathologic data assembled for each patient to compile a Match report that estimates the fit between the specific molecular disease pathway(s) identified in an individual patient and proposed clinical trials. The NEPTUNE Match report is communicated using established protocols to the patient and the attending nephrologist for use in their selection of available clinical trials. NEPTUNE Match represents the first application of precision medicine in nephrology with the aim of developing targeted therapies and providing the right medication for each patient with primary glomerular disease.

Effect of Incomplete Cryoablation and Matrix Metalloproteinase Inhibition on Intratumoral CD8+ T-Cell Infiltration in Murine Hepatocellular Carcinoma.

Background Image-guided tumor ablation is the first-line therapy for early-stage hepatocellular carcinoma (HCC), with ongoing investigations into its combination with immunotherapies. Matrix metalloproteinase (MMP) inhibition demonstrates immunomodulatory potential and reduces HCC tumor growth when combined with ablative treatment. Purpose To evaluate the effect of incomplete cryoablation with or without MMP inhibition on the local immune response in residual tumors in a murine HCC model. Materials and Methods Sixty 8- to 10-week-old female BALB/c mice underwent HCC induction with use of orthotopic implantation of syngeneic Tib-75 cells. After 7 days, mice with a single lesion were randomized into treatment groups: (a) no treatment, (b) MMP inhibitor, (c) incomplete cryoablation, and (d) incomplete cryoablation and MMP inhibitor. Macrophage and T-cell subsets were assessed in tissue samples with use of immunohistochemistry and immunofluorescence (cell averages calculated using five 1-µm2 fields of view [FOVs]). C-X-C motif chemokine receptor type 3 (CXCR3)- and interferon γ (IFNγ)-positive T cells were assessed using flow cytometry. Groups were compared using unpaired Student t tests, one-way analysis of variance with Tukey correction, and the Kruskal-Wallis test with Dunn correction. Results Mice treated with incomplete cryoablation (n = 6) showed greater infiltration of CD206+ tumor-associated macrophages (mean, 1.52 cells per FOV vs 0.64 cells per FOV; P = .03) and MMP9-expressing cells (mean, 0.89 cells per FOV vs 0.11 cells per FOV; P = .03) compared with untreated controls (n = 6). Incomplete cryoablation with MMP inhibition (n = 6) versus without (n = 6) led to greater CD8+ T-cell (mean, 15.8% vs 8.29%; P = .04), CXCR3+CD8+ T-cell (mean, 11.64% vs 8.47%; P = .004), and IFNγ+CD8+ T-cell infiltration (mean, 11.58% vs 5.18%; P = .02). Conclusion In a mouse model of HCC, incomplete cryoablation and systemic MMP inhibition showed increased cytotoxic CD8+ T-cell infiltration into the residual tumor compared with either treatment alone. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Gemmete in this issue.

A Machine Learning-Based Image Segmentation Method to Quantify In Vitro Osteoclast Culture Endpoints.

Quantification of in vitro osteoclast cultures (e.g. cell number) often relies on manual counting methods. These approaches are labour intensive, time consuming and result in substantial inter- and intra-user variability. This study aimed to develop and validate an automated workflow to robustly quantify in vitro osteoclast cultures. Using ilastik, a machine learning-based image analysis software, images of tartrate resistant acid phosphatase-stained mouse osteoclasts cultured on dentine discs were used to train the ilastik-based algorithm. Assessment of algorithm training showed that osteoclast numbers strongly correlated between manual- and automatically quantified values (r = 0.87). Osteoclasts were consistently faithfully segmented by the model when visually compared to the original reflective light images. The ability of this method to detect changes in osteoclast number in response to different treatments was validated using zoledronate, ticagrelor, and co-culture with MCF7 breast cancer cells. Manual and automated counting methods detected a 70% reduction (p < 0.05) in osteoclast number, when cultured with 10 nM zoledronate and a dose-dependent decrease with 1-10 µM ticagrelor (p < 0.05). Co-culture with MCF7 cells increased osteoclast number by ≥ 50% irrespective of quantification method. Overall, an automated image segmentation and analysis workflow, which consistently and sensitively identified in vitro osteoclasts, was developed. Advantages of this workflow are (1) significantly reduction in user variability of endpoint measurements (93%) and analysis time (80%); (2) detection of osteoclasts cultured on different substrates from different species; and (3) easy to use and freely available to use along with tutorial resources.

Perspectives From Black and White Participants and Care Partners on Return of Amyloid and Tau PET Imaging and Other Research Results.

PURPOSE: Alzheimer disease (AD) biomarker testing is now common in research and approaching clinical translation. Disclosure protocols must be informed by diverse participants' perspectives on if/how the information would be useful. METHODS: This study utilized semistructured interviews assessing interest in receiving positron emission tomography (PET) amyloid and tau results, as well as perceived risks and benefits of hypothetical PET disclosure as a function of race and participant diagnosis. PARTICIPANTS: Participants [39% Black; 61% White; Mage =74.28 (5.98)] included 57 adults diagnosed as either cognitively healthy (58%) or with mild cognitive impairment (42%) and their respective care partners [33% Black; 67% White; Mage =66.93 (10.92)]. RESULTS: Most dyads endorsed strong interest in PET results (82.5% of both participants and partners) regardless of race or diagnosis. Black care partners were less interested in receiving the participant's results than White care partners ( χ2(4) =8.31, P =0.047). Reasons for disclosure were diverse and highly personalized, including access to treatments or clinical trials (23.2% participants; 29.8% partners), advance planning (14.3% participants; 17.5% partners), and improved health knowledge (12.5% participants; 15.8% partners). In contrast, over 80% of respondents denied any risks of disclosure. DISCUSSION: Results suggest that predisclosure education, decisional capacity assessment, and a flexible disclosure approach are needed.

Hyperammonemia syndrome in immunosuppressed individuals.

PURPOSE OF REVIEW: Hyperammonemia syndrome is an increasingly recognized and often fatal condition that occurs in immunosuppressed individuals, most commonly lung transplant recipients. Growing evidence suggests hyperammonemia syndrome is associated with systemic infections caused by urease-producing organisms, namely Ureaplasma spp., an organism unable to grow with routine culturing techniques. This review will summarize the epidemiology and clinical manifestations of hyperammonemia syndrome, as well as diagnostic and management strategies once hyperammonemia syndrome is suspected. RECENT FINDINGS: Hyperammonemia syndrome is being described in increasing frequency in the solid organ transplant population. Morbidity and mortality, even with treatment, is high once hyperammonemia syndrome occurs. Surveillance studies indicate the prevalence of lung donor colonization with Ureaplasma spp. is high, suggesting screening and treatment may be of benefit. Antibiotic resistance is common, and rapid diagnostics can facilitate appropriate antimicrobial therapy in the peri-transplant period. SUMMARY: Hyperammonemia syndrome is most commonly seen in lung transplant recipients and has a high mortality rate once it occurs. Screening for Ureaplasma spp. should be considered in all lung transplant donors.

An outbreak of SARS-CoV-2 on a transplant unit in the early vaccination era.

BACKGROUND: Solid organ transplant recipients are at increased risk of COVID-19-associated morbidity and mortality. AIMS: We describe a nosocomial outbreak investigation on an immunocompromised inpatient unit. METHODS: Patients positive for SARS-CoV-2 were identified. An epidemiologic investigation was assisted with whole genome sequencing of positive samples. RESULTS: Two patients were identified as potential index cases; one presented with diarrhea and was initially not isolated, and the other developed hypoxemia on hospital day 18 before testing positive. Following identification of a SARS-CoV-2 cluster, the unit was closed and all patients and staff received surveillance testing revealing eight additional positive patients and staff members. Whole genome sequencing confirmed an outbreak. Enhanced infection prevention practices mitigated further spread. Asymptomatic patients with COVID-19 were successfully treated with bamlanivimab. DISCUSSION: Preventing SARS-CoV-2 outbreaks in transplant units poses unique challenges as patients may have atypical presentations of COVID-19. Immunocompromised patients who test positive for SARS-CoV-2 while asymptomatic may benefit from monoclonal antibody therapy to prevent disease progression. All hospital staff members working with immunocompromised patients should be promptly encouraged to follow infection prevention behaviors and receive SARS-CoV-2 vaccination. CONCLUSION: SARS-CoV-2 outbreaks on immunocompromised units can be mitigated through prompt identification of cases and robust infection prevention practices.

A single dose of self-transcribing and replicating RNA-based SARS-CoV-2 vaccine produces protective adaptive immunity in mice.

A self-transcribing and replicating RNA (STARR)-based vaccine (LUNAR-COV19) has been developed to prevent SARS-CoV-2 infection. The vaccine encodes an alphavirus-based replicon and the SARS-CoV-2 full-length spike glycoprotein. Translation of the replicon produces a replicase complex that amplifies and prolongs SARS-CoV-2 spike glycoprotein expression. A single prime vaccination in mice led to robust antibody responses, with neutralizing antibody titers increasing up to day 60. Activation of cell-mediated immunity produced a strong viral antigen-specific CD8+ T lymphocyte response. Assaying for intracellular cytokine staining for interferon (IFN)γ and interleukin-4 (IL-4)-positive CD4+ T helper (Th) lymphocytes as well as anti-spike glycoprotein immunoglobulin G (IgG)2a/IgG1 ratios supported a strong Th1-dominant immune response. Finally, single LUNAR-COV19 vaccination at both 2 µg and 10 µg doses completely protected human ACE2 transgenic mice from both mortality and even measurable infection following wild-type SARS-CoV-2 challenge. Our findings collectively suggest the potential of LUNAR-COV19 as a single-dose vaccine.

Disinfection of Virtual Reality Devices in Health Care Settings: In Vitro Assessment and Survey Study.

BACKGROUND: Virtual reality (VR) devices are increasingly used in health care settings. The use among patients has the potential to unintentionally transmit pathogens between patients and hospital staff. No standard operating procedure for disinfection exists to ensure safe use between patients. OBJECTIVE: This study aims to determine the efficacy of disinfectants on VR devices in order to ensure safe use in health care settings. METHODS: Three types of bacteria were inoculated onto porous and nonporous surfaces of 2 VR devices: the Meta Oculus Quest and Meta Oculus Quest 2. Disinfection was performed using either isopropyl alcohol or alcohol-free quaternary ammonium wipes. A quantitative culture was used to assess the adequacy of disinfection. A survey was separately sent out to VR device technicians at other pediatric health care institutes to compare the methods of disinfection and how they were established. RESULTS: Both products achieved adequate disinfection of the treated surfaces; however, a greater log-kill was achieved on nonporous surfaces than on the porous surfaces. Alcohol performed better than quaternary ammonium on porous surfaces. The survey respondents reported a wide variability in disinfection processes with only 1 person reporting an established standard operating procedure. CONCLUSIONS: Disinfection can be achieved through the use of either isopropyl alcohol or quaternary ammonium products. Porous surfaces showed lesser log-kill rates than the nonporous surfaces, indicating that the use of an added barrier may be of benefit and should be a point of future research. Given the variability in the disinfection process across health care systems, a standard operating procedure is proposed.

Role of Biliary Organoids in Cholestasis Research and Regenerative Medicine.

Translational studies in human cholestatic diseases have for years been hindered by various challenges, including the rarity of the disorders, the difficulty in obtaining biliary tissue from across the spectrum of the disease stage, and the difficulty culturing and maintaining primary cholangiocytes. Organoid technology is increasingly being viewed as a technological breakthrough in translational medicine as it allows the culture and biobanking of self-organizing cells from various sources that facilitate the study of pathophysiology and therapeutics, including from individual patients in a personalized approach. This review describes current research using biliary organoids for the study of human cholestatic diseases and the emerging applications of organoids to regenerative medicine directed at the biliary tree. Challenges and possible solutions to the current hurdles in this emerging field, particularly the need for standardization of terminology and clarity on source materials and techniques, are also discussed.

Impact of Screening and Treatment of Ureaplasma species on Hyperammonemia Syndrome in Lung Transplant Recipients: A Single Center Experience.

BACKGROUND: Infection with Ureaplasma species (spp) has been linked to fatal hyperammonemia syndrome (HS) in lung transplant recipients. We sought to characterize the epidemiology of Ureaplasma spp in candidates and donors and describe outcomes of antimicrobial therapy in preventing and treating HS. METHODS: Candidate testing for Ureaplasma spp was performed with urine culture and polymerase chain reaction (PCR) pretransplant. Positive candidates were treated with levofloxacin. Donor testing was performed with bronchoalveolar lavage (BAL) culture and PCR intraoperatively. From 7/2014 to 2/2017 patients were treated according to results; from 2/2017 to 10/2018 recipients received empiric levofloxacin and azithromycin at transplant until testing returned negative. HS was defined as new onset altered mental status after transplant with ammonia > 200 µmol/L. RESULTS: In total, 60 patients who underwent lung transplant were included. And 80% (n = 48) of patients had negative screening tests in donor and candidate pre-lung transplant, 8.3% (n = 5) of recipients had positive Ureaplasma spp testing in urine pre-transplant, and 13.3% (n = 8) had positive donor BAL testing at the time of lung transplant. Three patients developed HS a median of 7 days posttransplant; 2 died of HS. Recipients of organs with Ureaplasma spp who received empiric therapy did not develop HS. Donors with Ureaplasma spp were younger and more sexually active. CONCLUSIONS: Donor-derived Ureaplasma spp in lung transplant was associated with HS. Screening lung donors for Ureaplasma spp might allow for targeted therapy to reduce risk for development of HS, but future confirmatory studies are needed.

Genetic Evaluation of Nosocomial Candida auris Transmission.

Whole-genome sequences of Candida auris isolates from nosocomial and nonnosocomial infections were compared. The average numbers of single nucleotide variations were different between the two groups. The small amount of genetic variability between intra- or interhost isolates suggests recovery of all colonizing or infecting genomes for comparison is required for outbreaks.

CD27 is a thymic determinant of the balance between interferon-gamma- and interleukin 17-producing gammadelta T cell subsets.

The production of cytokines such as interferon-gamma and interleukin 17 by alphabeta and gammadelta T cells influences the outcome of immune responses. Here we show that most gammadelta T lymphocytes expressed the tumor necrosis factor receptor family member CD27 and secreted interferon-gamma, whereas interleukin 17 production was restricted to CD27(-) gammadelta T cells. In contrast to the apparent plasticity of alphabeta T cells, the cytokine profiles of these distinct gammadelta T cell subsets were essentially stable, even during infection. These phenotypes were established during thymic development, when CD27 functions as a regulator of the differentiation of gammadelta T cells at least in part by inducing expression of the lymphotoxin-beta receptor and genes associated with trans-conditioning and interferon-gamma production. Thus, the cytokine profiles of peripheral gammadelta T cells are predetermined mainly by a mechanism involving CD27.

Effectiveness of Chlamydia trachomatis expedited partner therapy in pregnancy.

BACKGROUND: Expedited partner therapy for Chlamydia trachomatis has had mixed efficacy in different populations, but limited data exist on the efficacy of the therapy in a pregnant population. OBJECTIVE: This study aimed to evaluate the real-world effectiveness of establishing a prenatal expedited partner therapy program in eradicating chlamydia before delivery and to examine the maternal and neonatal outcomes between women who received expedited partner therapy for chlamydia and women who received standard partner referral testing and treatment during pregnancy. STUDY DESIGN: An expedited partner therapy program was implemented on August 21, 2019, at a public hospital in a county with high chlamydia prevalence. Pregnant women were provided with single-dose packets of azithromycin to treat partners following a diagnosis of chlamydia infection. We prospectively observed pregnant women treated in the expedited partner therapy program who delivered at our institution in the same year and compared the outcomes with a historic cohort from the previous year that had traditional partner referral testing and treatment. We excluded women with concurrent gonorrhea, HIV, syphilis, or current intimate partner violence. The primary outcome was chlamydia reinfection or no-cure rates at repeat testing in 4 to 6 weeks following treatment or at the 36-week prenatal care screening. Secondary outcomes included obstetrical, maternal, and neonatal outcomes, including premature rupture of membranes, chorioamnionitis, endometritis, neonatal intensive care unit admission, neonatal sepsis, pneumonia, and conjunctivitis. RESULTS: The rate of chlamydia infection was 3.6% over a 2-year period in our delivered population. In the year following the implementation of the expedited partner therapy, compared with 419 women (mean±standard deviation, 23.4±5.5 years) who were diagnosed with chlamydia infection in the previous year, 471 women (mean±standard deviation age, 23.8±5.3 years) who delivered at our institution were diagnosed with chlamydia infection. There was no difference in race, parity, prenatal care attendance, or concomitant sexually transmitted infections. Compared with the pre-expedited partner therapy group, the rate of reinfection in the post-expedited partner therapy group was not statistically different (60/471 [13%] vs 61/419 [15%]; odds ratio, 0.86 [95% confidence interval 0.58-1.26]). In a per-protocol analysis, 72 women (17%) in the pre-expedited partner therapy group and 389 women (83%) in post-expedited partner therapy group received expedited partner therapy; reinfection was not statistically different between groups (P=.47). There was no difference in secondary outcomes, although a trend toward improved rates of endometritis was noted in the post-expedited partner therapy group (odds ratio, 0.13; 95% confidence interval, 0.02-1.02). CONCLUSION: The implementation of a prenatal expedited partner therapy program did not affect the rate of chlamydia reinfection before delivery. Treatment of chlamydia in an inner-city population has multiple factors that lead to successful treatment. Future efforts to reduce sexually transmitted infection and chlamydia reinfection rates in an at-risk population should include exploring patient education and safe sex practices beyond expedited partner therapy alone during pregnancy.

Acoustic measurement and statistical characterization of direct-printed, variable-porosity aluminum foams.

Additive manufacturing has expanded greatly in recent years with the promise of being able to create complex and custom structures at will. Enhanced control over the microstructure properties, such as percent porosity, is valuable to the acoustic design of materials. In this work, aluminum foams are fabricated using a modified powder bed fusion method, which enables voxel-by-voxel printing of structures ranging from fully dense to approximately 50% porosity. To understand the acoustic response, samples are measured in an acoustic impedance tube and characterized with the Johnson-Champoux-Allard-Lafarge model for rigid-frame foams. Bayesian statistical inversion of the model parameters is performed to assess the applicability of commonly employed measurement and modeling methods for traditional foams to the additively manufactured, low porosity aluminum foams. This preliminary characterization provides insights into how emerging voxel-by-voxel additive manufacturing approaches could be used to fabricate acoustic metal foams and what could be learned about the microstructure using traditional measurement and analysis techniques.

Acute upregulation of an NKG2D ligand promotes rapid reorganization of a local immune compartment with pleiotropic effects on carcinogenesis.

The self-encoded ligands MICA (human) and Rae-1 (mouse) for the cytotoxic lymphocyte activating receptor NKG2D are highly expressed in carcinomas and inflammatory lesions and have been linked to immunosurveillance and graft rejection. However, whether NKG2D ligands have an intrinsic ability to acutely regulate tissue-associated immune compartments is not known. Here we show that epidermis-specific upregulation of Rae-1 induced rapid, coincident and reversible changes in the organization of tissue-resident V(gamma)5V(delta)1 TCRgammadelta+ intraepithelial T cells and Langerhans cells, swiftly followed by epithelial infiltration by unconventional alphabeta T cells. Whereas local V(gamma)5V(delta)1+ T cells limited carcinogenesis, Langerhans cells unexpectedly promoted it. These results provide unique insight into the early phases of tissue immunosurveillance and indicate that acute changes in NKG2D ligands may alone initiate a rapid, multifaceted immunosurveillance response in vivo.

Bile-Derived Organoids From Patients With Primary Sclerosing Cholangitis Recapitulate Their Inflammatory Immune Profile.

Primary sclerosing cholangitis (PSC) is a heterogeneous and progressive fibroinflammatory cholangiopathy with no known etiology or effective treatment. Studies of PSC are limited due to difficulty in accessing the cholangiocyte, the small percentage of these cells in the liver, instability of in vitro culture systems, and reliance on samples from end-stage disease. Here, we demonstrate that stem cells can be isolated from the bile of PSC patients undergoing endoscopic retrograde cholangiopancreatography earlier in their clinical course and maintained long term in vitro as three-dimensional (3D) organoids that express a biliary genetic phenotype. Additionally, bile-derived organoids (BDOs) can be biobanked and samples obtained longitudinally over the course of the disease. These BDOs express known cholangiocyte markers including gamma glutamyl transferase, cytokeratin 19, epithelial cellular adhesion molecule, cystic fibrosis transmembrane conductance regulator, and anion exchanger 2. RNA sequence analysis identified 39 genes whose expression differed in organoids from PSC patients compared to non-PSC controls, including human leukocyte antigen DM alpha chain and chemokine (C-C motif) ligand 20 (CCL20), immune-related genes previously described in genome-wide association studies of PSC. Incubation of these BDOs with interleukin 17A or tumor necrosis factor alpha led to an immune-reactive phenotype with a significant increase in secretion of proinflammatory mediators, including CCL20, a T-cell chemoattractant. Conclusion: This study demonstrates that bile can be used as a source of biliary-like cells that can be maintained long term in vitro as 3D organoids; these BDOs retain features of cholangiopathies, including the ability to react to inflammatory stimuli by secreting chemokines and propagating an immune-reactive phenotype reflective of the pathogenesis of these diseases; thus, BDOs represent a platform for the study of the pathogenesis and therapy of cholangiopathies, particularly PSC.

Mapping human serum-induced gene networks as a basis for the creation of biomimetic periosteum for bone repair.

BACKGROUND: The periosteum is a highly vascularized, collagen-rich tissue that plays a crucial role in directing bone repair. This is orchestrated primarily by its resident progenitor cell population. Indeed, preservation of periosteum integrity is critical for bone healing. Cells extracted from the periosteum retain their osteochondrogenic properties and as such are a promising basis for tissue engineering strategies for the repair of bone defects. However, the culture expansion conditions and the way in which the cells are reintroduced to the defect site are critical aspects of successful translation. Indeed, expansion in human serum and implantation on biomimetic materials has previously been shown to improve in vivo bone formation. AIM: This study aimed to develop a protocol to allow for the expansion of human periosteum derived cells (hPDCs) in a biomimetic periosteal-like environment. METHODS: The expansion conditions were defined through the investigation of the bioactive cues involved in augmenting hPDC proliferative and multipotency characteristics, based on transcriptomic analysis of cells cultured in human serum. RESULTS: Master regulators of transcriptional networks were identified, and an optimized periosteum-derived growth factor cocktail (PD-GFC; containing ß-estradiol, FGF2, TNFα, TGFß, IGF-1 and PDGF-BB) was generated. Expansion of hPDCs in PD-GFC resulted in serum mimicry with regard to the cell morphology, proliferative capacity and chondrogenic differentiation. When incorporated into a three-dimensional collagen type 1 matrix and cultured in PD-GFC, the hPDCs migrated to the surface that represented the matrix topography of the periosteum cambium layer. Furthermore, gene expression analysis revealed a down-regulated WNT and TGFß signature and an up-regulation of CREB, which may indicate the hPDCs are recreating their progenitor cell signature. CONCLUSION: This study highlights the first stage in the development of a biomimetic periosteum, which may have applications in bone repair.

Macrophage migration inhibitory factor regulates innate γδ T-cell responses via IL-17 expression.

T cells expressing invariant γδ antigen receptors (γδ T cells) bridge innate and adaptive immunity and facilitate barrier responses to pathogens. Macrophage migration inhibitory factor (MIF) is an upstream mediator of host defense that up-regulates the expression of pattern recognition receptors and sustains inflammatory responses by inhibiting activation-induced apoptosis in monocytes and macrophages. Surprisingly, Mif-/- γδ T cells, when compared with wild type, were observed to produce >10-fold higher levels of the proinflammatory cytokine IL-17 after stimulation with gram-positive exotoxins. High-IL-17 expression was associated with the characteristic features of IL-17-producing γδ T (γδ17) cells, including expression of IL-23R, IL-1R1, and the transcription factors RORγt and Sox13. In the gram-positive model of shock mediated by toxic shock syndrome toxin (TSST-1), Mif-/- mice succumbed to death more quickly with increased pulmonary neutrophil accumulation and higher production of cytokines, including IL-1ß and IL-23. Mif-/- γδ T cells also produced high levels of IL-17 in response to Mycobacterium lipomannan, and depletion of γδ T cells improved survival from acutely lethal Mycobacterium infection or TSST-1 administration. These data indicate that MIF deficiency is associated with a compensatory amplification of γδ17 cell responses, with implications for innate immunity and IL-17-mediated pathology in situations such as gram-positive toxic shock or Mycobacterium infection.-Kim, H. K., Garcia, A. B., Siu, E., Tilstam, P., Das, R., Roberts, S., Leng, L., Bucala, R. Macrophage migration inhibitory factor regulates innate γδ T-cell responses via IL-17 expression.

Syphilis Immunoassay Signal Strength Correlates with Active Infection in Pregnant Women.

OBJECTIVE: This study aimed to evaluate the association of ARCHITECT chemiluminescent immunoassay (CIA) signal strength (signal-to-cutoff [S/CO] ratio), with maternal syphilis stage, rapid plasma reagin (RPR) reactivity, and congenital syphilis. STUDY DESIGN: A prospective observational study of reverse syphilis screening was conducted. Pregnant women were screened with CIA. Reactive CIA was reflexed to RPR; particle agglutination test (Treponema pallidum particle agglutination [TPPA]) was performed for CIA+/RPR- results. Clinical staging with history and physical was performed, and disease stage was determined. Prior treatment was confirmed. We compared S/CO ratio and neonatal outcomes among the following groups: Group 1: CIA+/RPR+/TPPA+ or CIA+/RPR-/TPPA+ with active syphilis; Group 2: CIA+/RPR-/TPPA+ or CIA+/serofast RPR/TPPA+, previously treated; Group 3: CIA+/RPR-/TPPA+, no history of treatment or active disease; Group 4: CIA+/RPR-/TPPA-, false-positive CIA. RESULTS: A total of 144 women delivered with reactive CIA: 38 (26%) in Group 1, 69 (48%) in Group 2, 20 (14%) in Group 3, and 17 (12%) in Group 4. Mean (±standard deviation) S/CO ratio was 18.3 ± 5.4, 12.1 ± 5.3, 9.1 ± 4.6, and 1.9 ± 0.8, respectively (p < 0.001). Neonates with overt congenital syphilis occurred exclusively in Group 1. CONCLUSION: Women with active syphilis based on treatment history, clinical staging, and laboratory indices have higher CIA S/CO ratio and are more likely to deliver neonates with overt evidence of congenital syphilis.

Cutaneous manifestations of Campylobacter jejuni infection: A case report and review of the literature.

A 51 year old man with active follicular lymphoma presented with several days of erythematous skin nodules on all extremities two weeks after a self-limited diarrheal illness. All serum immunoglobulin levels were found to be low. Blood cultures grew Campylobacter jejuni. The patient was given one week of azithromycin with complete resolution of his skin nodules. The literature of skin manifestations seen in active Campylobacter jejuni infection are reviewed. The majority of cases occur in immunocompromised hosts, many with low or no serum immunoglobulin levels. Postulated mechanisms include a lack of secretory IgA in intestinal mucosa predisposing susceptible patients to translocated enteric pathogens however the precise pathogenesis underlying cutaneous manifestations are unknown.