Immune restoration by TIGIT blockade is insufficient to control chronic SIV infection.

TIGIT is a negative immune checkpoint receptor associated with T cell exhaustion in cancer and HIV. TIGIT upregulation in virus-specific CD8+ T cells and NK cells during HIV/SIV infection results in dysfunctional effector capabilities. In vitro studies targeting TIGIT on CD8+ T cells suggest TIGIT blockade as a viable strategy to restore SIV-specific T cell responses. Here, we extend these studies in vivo using TIGIT blockage in nonhuman primates in an effort to reverse T cell and NK cell exhaustion in the setting of SIV infection. We demonstrate that in vivo administration of a humanized anti-TIGIT monoclonal antibody (mAb) is well tolerated in both cynomolgus macaques and rhesus macaques. Despite sustained plasma concentrations of anti-TIGIT mAb, we observed no consistent improvement in NK or T cell cytolytic capacity. TIGIT blockade minimally enhanced T cell proliferation and virus-specific T cell responses in both magnitude and breadth though plasma viral loads in treated animals remained stable indicating that anti-TIGIT mAb treatment alone was insufficient to increase anti-SIV CD8+ T cell function. The enhancement of virus-specific T cell proliferative responses observed in vitro with single or dual blockade of TIGIT and/or PD-1 highlights TIGIT as a potential target to reverse T cell dysfunction. Our studies, however, reveal that targeting the TIGIT pathway alone may be insufficient in the setting of viremia and that combining immune checkpoint blockade with other immunotherapeutics may be a future path forward for improved viral control or elimination of HIV.IMPORTANCEUpregulation of the immune checkpoint receptor TIGIT is associated with HIV-mediated T cell dysfunction and correlates with HIV disease progression. Compelling evidence exists for targeting immune checkpoint receptor pathways that would potentially enhance immunity and refocus effector cell efforts toward viral clearance. In this report, we investigate TIGIT blockade as an immunotherapeutic approach to reverse immune exhaustion during chronic SIV/SHIV infection in a nonhuman primate model of HIV infection. We show that interfering with the TIGIT signaling axis alone is insufficient to improve viral control despite modest improvement in T cell immunity. Our data substantiate the use of targeting multiple immune checkpoint receptors to promote synergy and ultimately eliminate HIV-infected cells.

Posterior reversible encephalopathy syndrome following uneventful clipping of an unruptured intracranial aneurysm: A case report.

BACKGROUND: Posterior reversible encephalopathy syndrome (PRES) is characterized mainly by occipital and parietal lobe involvement, which can be reversible within a few days. Herein, we report a rare case of PRES that developed after craniotomy for an unruptured intracranial aneurysm (UIA). CASE SUMMARY: A 59-year-old man underwent clipping surgery for the treatment of UIA arising from the left middle cerebral artery. Clipping surgery was performed uneventfully, and he regained consciousness quickly immediately after the surgery. At the 4th hour after surgery, he developed a disorder of consciousness and aphasia. Magnetic resonance imaging revealed cortical and subcortical T2/FLAIR hyperintensities in the parietal, occipital, and frontal lobes ipsilaterally, without restricted diffusion, consistent with unilateral PRES. With conservative treatment, his symptoms and radiological findings almost completely disappeared within weeks. In our case, the important causative factor of PRES was suspected to be a sudden increase in cerebral perfusion pressure associated with temporary M1 occlusion. CONCLUSION: Our unique case highlights that, to our knowledge, this is the second report of PRES developing after craniotomy for the treatment of UIA. Surgeons must keep PRES in mind as one of the causes of perioperative neurological abnormality following clipping of an UIA.

Allogeneic immunity clears latent virus following allogeneic stem cell transplantation in SIV-infected ART-suppressed macaques.

Allogeneic hematopoietic stem cell transplantation (alloHSCT) from donors lacking C-C chemokine receptor 5 (CCR5Δ32/Δ32) can cure HIV, yet mechanisms remain speculative. To define how alloHSCT mediates HIV cure, we performed MHC-matched alloHSCT in SIV+, anti-retroviral therapy (ART)-suppressed Mauritian cynomolgus macaques (MCMs) and demonstrated that allogeneic immunity was the major driver of reservoir clearance, occurring first in peripheral blood, then peripheral lymph nodes, and finally in mesenteric lymph nodes draining the gastrointestinal tract. While allogeneic immunity could extirpate the latent viral reservoir and did so in two alloHSCT-recipient MCMs that remained aviremic >2.5 years after stopping ART, in other cases, it was insufficient without protection of engrafting cells afforded by CCR5-deficiency, as CCR5-tropic virus spread to donor CD4+ T cells despite full ART suppression. These data demonstrate the individual contributions of allogeneic immunity and CCR5 deficiency to HIV cure and support defining targets of alloimmunity for curative strategies independent of HSCT.

Cardiac Autotransplantation and Commando Operation for Complex Multivalvular Infective Endocarditis.

This report describes a patient with destructive multivalvular endocarditis with multiorgan dysfunction. Intraoperatively, severe unexpected adhesions due to pancarditis precluded the standard Commando operation. The approach of combining autotransplantation with a Commando operation was used to facilitate adequate débridement of infected tissues and reconstruction in a reasonable time and with satisfactory prosthetic valvular function. This approach may be considered in other cases of challenging destructive endocarditis with severe adhesions. We speculate that this approach may also be useful in redo surgeries.

Cesarean delivery rates and indications in pregnancies complicated by diabetes.

OBJECTIVE: Rates of pregestational (PGDM) and gestational diabetes (GDM), and their associated pregnancy complications, are rising. Pregnancies complicated by diabetes have increased cesarean delivery (CD) rates; however, there are limited data regarding the current rates of, and contributing factors to, these deliveries. The Robson Ten Group Classification System (TGCS) is a clinically relevant, standardized framework that can be used to evaluate and analyze cesarean rates. The objective of this study was to evaluate rates of, and indications for, intrapartum, unplanned CD among pregnancies complicated by diabetes, compared to normoglycemic (NG) pregnancies, in a large United States birth cohort. METHODS: This retrospective cohort study used chart-abstracted data on births between 24 and 42 weeks' gestation at 17 hospitals that contributed to the Obstetrical Care Outcome Assessment Program database between 01/2016 and 03/2019. The CD rate for NG pregnancies, and pregnancies complicated by gestational and PGDM was calculated and compared using the Robson TGCS. The indications for intrapartum CD in patients with term, singleton, vertex gestations without a prior cesarean were then analyzed. Univariate and multivariate logistic regression models were used to compare the cesarean rate and indications for CD, between the diabetic groups and the NG group. Results were adjusted for maternal age, BMI, neonatal birth weight, and insurance status, as well as clustering by hospital. RESULTS: A total of 86,381 pregnant people were included in the study cohort. Of these 76,272 (88.3%) were NG, 8591 (9.9%) had GDM, and 1518 (1.8%) had PGDM. Compared to NG patients, overall cesarean rates were higher in patients with GDM (40.3% vs. 29.7%; aOR 1.25, 95%CI 1.18-1.31) and PGDM (60.0% vs. 29.7%; aOR 2.53, 95%CI 2.04-3.13). This finding remained true when the cohort was restricted to term, singleton, vertex laboring patients without a prior cesarean; compared to NG patients, the cesarean rate was higher in patients with GDM (17.4% vs. 12.2%, aOR 1.37, 95%CI 1.29-1.45) and PGDM (26.0% vs. 12.2%, aOR 2.55, 95%CI 2.00-3.25). The cesarean rate for fetal indications was similar in the GDM (5.7%) and NG (4.4%) groups, while those patients with PGDM had a significantly higher rate (10.4%; aOR 2.01, 95%CI 1.43-2.83). Similarly, the rate of cesarean for labor dystocia in patients with PGDM was significantly higher than in NG patients (16.9% vs. 7.0%, and aOR 2.28, 95%CI 1.66-3.13) while patients with GDM had an intermediate rate (10.6% vs. 7.0%, aOR 1.49, 95%CI 1.40-1.57). CONCLUSIONS: The CD rate is significantly higher in pregnancies complicated by diabetes, particularly pregestational, compared to NG pregnancies. Despite controlling for maternal factors and birth weight, pregnancies complicated by diabetes are more likely to undergo an unplanned intrapartum cesarean secondary to labor dystocia than their NG counterparts, but only pregnancies complicated by PGDM have an increased risk of cesarean for fetal indications. More research is needed to understand whether this higher cesarean rate is due to factors intrinsic to diabetes in laboring patients or is due to a difference in the way clinicians manage diabetics in labor.

Cytomegalovirus-vaccine-induced unconventional T cell priming and control of SIV replication is conserved between primate species.

Strain 68-1 rhesus cytomegalovirus expressing simian immunodeficiency virus (SIV) antigens (RhCMV/SIV) primes MHC-E-restricted CD8+ T cells that control SIV replication in 50%-60% of the vaccinated rhesus macaques. Whether this unconventional SIV-specific immunity and protection is unique to rhesus macaques or RhCMV or is intrinsic to CMV remains unknown. Here, using cynomolgus CMV vectors expressing SIV antigens (CyCMV/SIV) and Mauritian cynomolgus macaques, we demonstrate that the induction of MHC-E-restricted CD8+ T cells requires matching CMV to its host species. RhCMV does not elicit MHC-E-restricted CD8+ T cells in cynomolgus macaques. However, cynomolgus macaques vaccinated with species-matched 68-1-like CyCMV/SIV mounted MHC-E-restricted CD8+ T cells, and half of the vaccinees stringently controlled SIV post-challenge. Protected animals manifested a vaccine-induced IL-15 transcriptomic signature that is associated with efficacy in rhesus macaques. These findings demonstrate that the ability of species-matched CMV vectors to elicit MHC-E-restricted CD8+ T cells that are required for anti-SIV efficacy is conserved in nonhuman primates, and these data support the development of HCMV/HIV for a prophylactic HIV vaccine.

Suppression of human and simian immunodeficiency virus replication with the CCR5-specific antibody Leronlimab in two species.

The CCR5-specific antibody Leronlimab is being investigated as a novel immunotherapy that can suppress HIV replication with minimal side effects. Here we studied the virological and immunological consequences of Leronlimab in chronically CCR5-tropic HIV-1 infected humans (n = 5) on suppressive antiretroviral therapy (ART) and in ART-naïve acutely CCR5-tropic SHIV infected rhesus macaques (n = 4). All five human participants transitioned from daily combination ART to self-administered weekly subcutaneous (SC) injections of 350 mg or 700 mg Leronlimab and to date all participants have sustained virologic suppression for over seven years. In all participants, Leronlimab fully occupied CCR5 receptors on peripheral blood CD4+ T cells and monocytes. In ART-naïve rhesus macaques acutely infected with CCR5-tropic SHIV, weekly SC injections of 50 mg/kg Leronlimab fully suppressed plasma viremia in half of the macaques. CCR5 receptor occupancy by Leronlimab occurred concomitant with rebound of CD4+ CCR5+ T-cells in peripheral blood, and full CCR5 receptor occupancy was found in multiple anatomical compartments. Our results demonstrate that weekly, self-administered Leronlimab was safe, well-tolerated, and efficacious for long-term virologic suppression and should be included in the arsenal of safe, easily administered, longer-acting antiretroviral treatments for people living with HIV-1. Trial Registration: ClinicalTrials.gov Identifiers: NCT02175680 and NCT02355184.

CCR5 Receptor Occupancy Analysis Reveals Increased Peripheral Blood CCR5+CD4+ T Cells Following Treatment With the Anti-CCR5 Antibody Leronlimab.

CCR5 plays a central role in infectious disease, host defense, and cancer progression, thereby making it an ideal target for therapeutic development. Notably, CCR5 is the major HIV entry co-receptor, where its surface density correlates with HIV plasma viremia. The level of CCR5 receptor occupancy (RO) achieved by a CCR5-targeting therapeutic is therefore a critical predictor of its efficacy. However, current methods to measure CCR5 RO lack sensitivity, resulting in high background and overcalculation. Here, we report on two independent, flow cytometric methods of calculating CCR5 RO using the anti-CCR5 antibody, Leronlimab. We show that both methods led to comparable CCR5 RO values, with low background on untreated CCR5+CD4+ T cells and sensitive measurements of occupancy on both blood and tissue-resident CD4+ T cells that correlated longitudinally with plasma concentrations in Leronlimab-treated macaques. Using these assays, we found that Leronlimab stabilized cell surface CCR5, leading to an increase in the levels of circulating and tissue-resident CCR5+CD4+ T cells in vivo in Leronlimab-treated macaques. Weekly Leronlimab treatment in a chronically SIV-infected macaque led to increased CCR5+CD4+ T cells levels and fully suppressed plasma viremia, both concomitant with full CCR5 RO on peripheral blood CD4+ T cells, demonstrating that CCR5+CD4+ T cells were protected from viral replication by Leronlimab binding. Finally, we extended these results to Leronlimab-treated humans and found that weekly 700 mg Leronlimab led to complete CCR5 RO on peripheral blood CD4+ T cells and a statistically significant increase in CCR5+CD4+ T cells in peripheral blood. Collectively, these results establish two RO calculation methods for longitudinal monitoring of anti-CCR5 therapeutic antibody blockade efficacy in both macaques and humans, demonstrate that CCR5+CD4+ T cell levels temporarily increase with Leronlimab treatment, and facilitate future detailed investigations into the immunological impacts of CCR5 inhibition in multiple pathophysiological processes.

On the hunt for a cure: A guide to Huntington disease.

ABSTRACT: Huntington disease is a rare genetic disorder characterized by motor, cognitive, and psychiatric impairments. Although the typical patient has a positive family history and initially presents with chorea between ages 30 and 50 years, some patients do not have a typical presentation. Healthcare providers should know when to refer patients to neurology for testing for Huntington disease. The earlier the diagnosis is made, the earlier the patient and patient's family can receive education about the expected disease trajectory. A multidisciplinary approach is required to mitigate symptoms as the disease progresses. Although no cure exists, ongoing research is targeting genotypic abnormalities in hopes of finding a permanent treatment for Huntington disease.

Higher severe acute respiratory syndrome coronavirus 2 infection rate in pregnant patients.

BACKGROUND: During the early months of the coronavirus disease 2019 pandemic, risks associated with severe acute respiratory syndrome coronavirus 2 in pregnancy were uncertain. Pregnant patients can serve as a model for the success of clinical and public health responses during public health emergencies as they are typically in frequent contact with the medical system. Population-based estimates of severe acute respiratory syndrome coronavirus 2 infections in pregnancy are unknown because of incomplete ascertainment of pregnancy status or inclusion of only single centers or hospitalized cases. Whether pregnant women were protected by the public health response or through their interactions with obstetrical providers in the early months of pandemic is not clearly understood. OBJECTIVE: This study aimed to estimate the severe acute respiratory syndrome coronavirus 2 infection rate in pregnancy and to examine the disparities by race and ethnicity and English language proficiency in Washington State. STUDY DESIGN: Pregnant patients with a polymerase chain reaction-confirmed severe acute respiratory syndrome coronavirus 2 infection diagnosed between March 1, 2020, and June 30, 2020 were identified within 35 hospitals and clinics, capturing 61% of annual deliveries in Washington State. Infection rates in pregnancy were estimated overall and by Washington State Accountable Community of Health region and cross-sectionally compared with severe acute respiratory syndrome coronavirus 2 infection rates in similarly aged adults in Washington State. Race and ethnicity and language used for medical care of pregnant patients were compared with recent data from Washington State. RESULTS: A total of 240 pregnant patients with severe acute respiratory syndrome coronavirus 2 infections were identified during the study period with 70.7% from minority racial and ethnic groups. The principal findings in our study were as follows: (1) the severe acute respiratory syndrome coronavirus 2 infection rate was 13.9 per 1000 deliveries in pregnant patients (95% confidence interval, 8.3-23.2) compared with 7.3 per 1000 (95% confidence interval, 7.2-7.4) in adults aged 20 to 39 years in Washington State (rate ratio, 1.7; 95% confidence interval, 1.3-2.3); (2) the severe acute respiratory syndrome coronavirus 2 infection rate reduced to 11.3 per 1000 deliveries (95% confidence interval, 6.3-20.3) when excluding 45 cases of severe acute respiratory syndrome coronavirus disease 2 detected through asymptomatic screening (rate ratio, 1.3; 95% confidence interval, 0.96-1.9); (3) the proportion of pregnant patients in non-White racial and ethnic groups with severe acute respiratory syndrome coronavirus disease 2 infection was 2- to 4-fold higher than the race and ethnicity distribution of women in Washington State who delivered live births in 2018; and (4) the proportion of pregnant patients with severe acute respiratory syndrome coronavirus 2 infection receiving medical care in a non-English language was higher than estimates of pregnant patients receiving care with limited English proficiency in Washington State (30.4% vs 7.6%). CONCLUSION: The severe acute respiratory syndrome coronavirus 2 infection rate in pregnant people was 70% higher than similarly aged adults in Washington State, which could not be completely explained by universal screening at delivery. Pregnant patients from nearly all racial and ethnic minority groups and patients receiving medical care in a non-English language were overrepresented. Pregnant women were not protected from severe acute respiratory syndrome coronavirus 2 infection in the early months of the pandemic. Moreover, the greatest burden of infections occurred in nearly all racial and ethnic minority groups. These data coupled with a broader recognition that pregnancy is a risk factor for severe illness and maternal mortality strongly suggested that pregnant people should be broadly prioritized for coronavirus disease 2019 vaccine allocation in the United States similar to some states.

Disease severity, pregnancy outcomes, and maternal deaths among pregnant patients with severe acute respiratory syndrome coronavirus 2 infection in Washington State.

BACKGROUND: Evidence is accumulating that coronavirus disease 2019 increases the risk of hospitalization and mechanical ventilation in pregnant patients and for preterm delivery. However, the impact on maternal mortality and whether morbidity is differentially affected by disease severity at delivery and trimester of infection are unknown. OBJECTIVE: This study aimed to describe disease severity and outcomes of severe acute respiratory syndrome coronavirus 2 infections in pregnancy across the Washington State, including pregnancy complications and outcomes, hospitalization, and case fatality. STUDY DESIGN: Pregnant patients with a polymerase chain reaction-confirmed severe acute respiratory syndrome coronavirus 2 infection between March 1, 2020, and June 30, 2020, were identified in a multicenter retrospective cohort study from 35 sites in Washington State. Sites captured 61% of annual state deliveries. Case-fatality rates in pregnancy were compared with coronavirus disease 2019 fatality rates in similarly aged adults in Washington State using rate ratios and rate differences. Maternal and neonatal outcomes were compared by trimester of infection and disease severity at the time of delivery. RESULTS: The principal study findings were as follows: (1) among 240 pregnant patients in Washington State with severe acute respiratory syndrome coronavirus 2 infections, 1 in 11 developed severe or critical disease, 1 in 10 were hospitalized for coronavirus disease 2019, and 1 in 80 died; (2) the coronavirus disease 2019-associated hospitalization rate was 3.5-fold higher than in similarly aged adults in Washington State (10.0% vs 2.8%; rate ratio, 3.5; 95% confidence interval, 2.3-5.3); (3) pregnant patients hospitalized for a respiratory concern were more likely to have a comorbidity or underlying conditions including asthma, hypertension, type 2 diabetes mellitus, autoimmune disease, and class III obesity; (4) 3 maternal deaths (1.3%) were attributed to coronavirus disease 2019 for a maternal mortality rate of 1250 of 100,000 pregnancies (95% confidence interval, 257-3653); (5) the coronavirus disease 2019 case fatality in pregnancy was a significant 13.6-fold (95% confidence interval, 2.7-43.6) higher in pregnant patients than in similarly aged individuals in Washington State with an absolute difference in mortality rate of 1.2% (95% confidence interval, -0.3 to 2.6); and (6) preterm birth was significantly higher among women with severe or critical coronavirus disease 2019 at delivery than for women who had recovered from coronavirus disease 2019 (45.4% severe or critical coronavirus disease 2019 vs 5.2% mild coronavirus disease 2019; P<.001). CONCLUSION: Coronavirus disease 2019 hospitalization and case-fatality rates in pregnant patients were significantly higher than in similarly aged adults in Washington State. These data indicate that pregnant patients are at risk of severe or critical disease and mortality compared to nonpregnant adults, and also at risk for preterm birth.

Clinical characteristics of 46 pregnant women with a severe acute respiratory syndrome coronavirus 2 infection in Washington State.

BACKGROUND: The impact of coronavirus disease 2019 on pregnant women is incompletely understood, but early data from case series suggest a variable course of illness from asymptomatic or mild disease to maternal death. It is unclear whether pregnant women manifest enhanced disease similar to influenza viral infection or whether specific risk factors might predispose to severe disease. OBJECTIVE: To describe maternal disease and obstetrical outcomes associated with coronavirus disease 2019 in pregnancy to rapidly inform clinical care. STUDY DESIGN: This is a retrospective study of pregnant patients with a laboratory-confirmed severe acute respiratory syndrome coronavirus 2 infection from 6 hospital systems in Washington State between Jan. 21, 2020, and April 17, 2020. Demographics, medical and obstetrical history, and coronavirus disease 2019 encounter data were abstracted from medical records. RESULTS: A total of 46 pregnant patients with a severe acute respiratory syndrome coronavirus 2 infection were identified from hospital systems capturing 40% of births in Washington State. Nearly all pregnant individuals with a severe acute respiratory syndrome coronavirus 2 infection were symptomatic (93.5%, n=43) and the majority were in their second or third trimester (43.5% [n=20] and 50.0% [n=23], respectively). Symptoms resolved in a median of 24 days (interquartile range, 13-37). Notably, 7 women were hospitalized (16%) including 1 admitted to the intensive care unit. A total of 6 cases (15%) were categorized as severe coronavirus disease 2019 with nearly all patients being either overweight or obese before pregnancy or with asthma or other comorbidities. Of the 8 deliveries that occurred during the study period, there was 1 preterm birth at 33 weeks' gestation to improve pulmonary status in a woman with class III obesity, and 1 stillbirth of unknown etiology. CONCLUSION: Severe coronavirus disease 2019 developed in approximately 15% of pregnant patients and occurred primarily in overweight or obese women with underlying conditions. Obesity and coronavirus disease 2019 may synergistically increase risk for a medically indicated preterm birth to improve maternal pulmonary status in late pregnancy. These findings support categorizing pregnant patients as a higher-risk group, particularly those with chronic comorbidities.

Multivisceral Transplant, The Prince Charles Hospital Experience.

BACKGROUND: Multi-visceral organ transplant is uncommon. As a result of the rarity of these surgeries, there are limited studies, making it difficult to interpret outcomes and identify specific patient complications. We aim to assess the indications for multi-organ transplant, the time on the wait-list and evaluate outcomes including patient survival, graft survival and postoperative complications in an Australian context. METHODS: Patients undergoing multi-organ transplant from 1993 to 2018 at The Prince Charles Hospital, Brisbane, Australia were retrospectively reviewed, looking at baseline characteristics and post-transplant morbidity, mortality and graft survival. RESULTS: A total of 37 patients were included in the study, comprising 22 heart-lung transplants, eight heart-kidney transplants and seven heart-lung-liver transplants. There were six domino heart transplants performed, all in the heart-lung-liver transplant group. The mean age at transplant was 37 years and the mean wait-list time was 10 months. One patient, receiving a heart-lung transplant, required re-transplantation (bilateral lung) at 3 years. One-year (1-year) survival was 91% for heart-lung transplants, 86% for heart-lung-liver transplants and 87.5% for heart-kidney transplants. Five- and ten-year (5- and 10-year) survival was 79% for both in heart-lung transplant, 43% and 29% for heart-lung-liver transplant and 87.5% for both in heart-kidney transplant. CONCLUSION: Patients undergoing multi-organ transplant at our unit had long-term survival and organ function comparable to international data. In addition, waitlist time for multi-organ transplant was not found to be excessive.

Validation of the Eighth Edition TNM Lung Cancer Staging System.

INTRODUCTION: We performed a validation study at our institution, the International Union Against Cancer (Union for International Cancer Control latest version of TNM Classification of Malignant Tumors Eighth Edition). METHODS: Data were collected from the Queensland Oncology Online registry of NSCLC or SCLC cases between 2000 and 2015 and validated against the Queensland Integrated Lung Cancer Outcomes Project registry using case identification number, first name, last name, and date of birth. Where data were available, cases were classified according to the Union for International Cancer Control TNM seventh edition stage groupings and then compared with the eighth edition groupings. Kaplan-Meier curves were plotted, and the log-rank test of survival differences was performed with SPSS version 25 (IBM Corp, Armonk, NY). RESULTS: Of the 3636 cases, 3352 and 1031 had complete clinical and pathologic staging, respectively. Median survival time was found to reduce with increasing clinical stage: seventh edition (IA: 88, IB: 44, IIA: 31, IIB: 18, IIIA: 15, IIIB: 8, and IV: 5 mo) versus eighth edition TNM stage (IA1: not reached, IA2: 88, IA3: 53, IB: 56, IIA: 36, IIB: 22, IIIA: 14, IIIB: 9, IIIC: 8, IVA: 6, and IVB: 3 mo). A similar overall pattern was reflected in the pathologic stage: seventh edition (IA: 124, IB: 110, IIA: 48, IIB: 42, IIIA: 26, IIIB: 31, and IV: 27 mo) versus eighth edition (IA1: not reached, IA2: 122, IA3: 125, IB: 144, IIA: 98, IIB: 57, IIIA: 31, IIIB: 24, and IVA: 7 mo). The log-rank test for survival curves was significant at p < 0.001. CONCLUSIONS: Our external validation study confirms the prognostic accuracy of the eighth edition TNM lung cancer classification. Our analyses also indicated that IIIB, IIIC, and IVA stage groups had similar survival outcomes and suggest further research for refinement.

Quantitation of low abundant soluble biomarkers using high sensitivity Single Molecule Counting technology.

Quantitation of biomarkers in biofluids plays a central role in basic research to management of patient care and is routinely used in clinical laboratories and academic institutions. Standard immunoassays, such as an enzyme-linked immunosorbent assay (ELISA), have provided understanding of both normal and pathological processes for many decades. However, in more recent decades, new immunoassay technologies have uncovered numerous analytes in blood that were once undetectable using traditional ELISAs. To meet this new challenge for quantifying low abundant proteins in biofluids, Single Molecule Counting (SMC™) technology was developed. This new technology is a combination of improvements to both the immunoassay procedure as well as the instrument. The aim of this article is to introduce the new SMCxPRO™ instrument, xPRO Acquisition and Analysis software, and the high sensitivity immunoassay kits validated on this instrument for the detection of low abundant proteins in biofluids, such as serum and plasma. Using this new technology platform, biomarkers that were once unquantifiable can now be quantitated in both normal and diseased biofluids.

Maternal microbiome - A pathway to preterm birth.

Despite great medical advances in preventing maternal and infant mortality in the past century, one issue remains unresolved: why do so many women give birth prematurely? A major new field of human microbiome studies has begun to shed light on the impact of microbes (of both the commensal and pathogen varieties) on pregnancy outcomes. Recent advances in next-generation sequencing and metagenomic analysis have revealed that maternal microbiomes at a variety of niches including the oral, vaginal, gut, cervical, and even the placenta itself govern pregnancy outcomes. In this review, we describe how alterations in the microbial biomasses impact preterm birth and we discuss the major research questions concerning the cause and/or interdependent relationships between microbiome, infection, and preterm delivery.

Progesterone interactions with the cervix: translational implications for term and preterm birth.

The uterine cervix plays a vital role in maintaining pregnancy and an equally important role in allowing parturition to occur. Progesterone, either endogenously produced or supplied exogenously, supports the function of the cervix in sustaining intrauterine pregnancy, and the withdrawal of progesterone, either through natural processes or pharmacologic intervention, leads to delivery which underscores the importance of the progesterone's biological activities manifest in normal gestation and pregnancy that ends prematurely. Research crossing many scientific disciplines has demonstrated that progesterone is a pleotropic compound that affects the cervix through cytoplasmic and membrane receptors with profound effects on cellular and molecular functions that influence inflammatory cascades and extracellular matrix, both of which have consequences for parturition. Beyond the local cell and molecular biology of progesterone, it has systemic effects of relevance to pregnancy as well. This paper examines the biology of the cervix from its gross to cellular structure and biological activities of its cell and molecular processes that may be affected by progesterone. The implications of these processes for preterm birth are explored, and direction of current research is in relation to translational medicine implications for diagnostic, prognostic, and therapeutic approaches to threatened preterm birth.

Mycoplasma, Ureaplasma, and adverse pregnancy outcomes: a fresh look.

Recent work on the Molicutes that associate with genital tract tissues focuses on four species that may be of interest in potential maternal, fetal, and neonatal infection and in contributing to adverse pregnancy outcomes. Mycoplasma hominis and Ureaplasma urealyticum have historically been the subject of attention, but Mycoplasma genitalis which causes male urethritis in addition to colonizing the female genital tract and the division of Ureaplasma into two species, urealyticum and parvum, has also added new taxonomic clarity. The role of these genital tract inhabitants in infection during pregnancy and their ability to invade and infect placental and fetal tissue is discussed. In particular, the role of some of these organisms in prematurity may be mechanistically related to their ability to induce inflammatory cytokines, thereby triggering pathways leading to preterm labor. A review of this intensifying exploration of the mycoplasmas in relation to pregnancy yields several questions which will be important to examine in future research.