Fetal-placental antigens and the maternal immune system: Reproductive immunology comes of age.

Reproductive physiology and immunology as scientific disciplines each have rich, largely independent histories. The physicians and philosophers of ancient Greece made remarkable observations and inferences to explain regeneration as well as illness and immunity. The scientific enlightenment of the renaissance and the technological advances of the past century have led to the explosion of knowledge that we are experiencing today. Breakthroughs in transplantation, immunology, and reproduction eventually culminated with Medawar's discovery of acquired immunological tolerance, which helped to explain the transplantation success and failure. Medawar's musings also keenly pointed out that the fetus apparently breaks these newly discovered rules, and with this, the field of reproductive immunology was launched. As a result of having stemmed from transplantation immunology, scientist still analogizes the fetus to a successful allograft. Although we now know of the fundamental differences between the two, this analogy remains a useful tool to understand how the fetus thrives despite its immunological disparity with the mother. Here, we review the history of reproductive immunology, and how major and minor histocompatibility antigens, blood group antigens, and tissue-specific "self" antigens from the fetus and transplanted organs parallel and differ.

Cefiderocol For Injection: Compatibility Testing Using the MINI-BAG Plus Container System and the VIAL-MATE Adaptor.

Background: Cost-effective and convenient modalities are required to facilitate the administration of antibiotics in hospital and outpatient settings. Objective: This study investigated the physical compatibility of the MINI-BAG Plus Container System and VIAL-MATE Adaptor with the 1 g drug product vials used for cefiderocol. Methods: Qualitative testing of the MINI-BAG Plus Container System (50 and 100 mL of 5% dextrose injection or 0.9% sodium chloride injection), using empty vials and vials containing lyophilized cefiderocol powder, was conducted in triplicate on MINI-BAGs that were hung and observed over 3 hours. Connection security between empty vials and the VIAL-MATE Adaptor was assessed in triplicate. Results: All predefined physical compatibility criteria between cefiderocol 1 g vials and the MINI-BAG Plus Container System were met, including a secure connection, successful multiple transfers of solution between vial and bag, successful reconstitution of cefiderocol, and lack of leaking into the vial or from the connections. There was no particulate matter in the prepared solution and no precipitation or discoloration. Secure connections between the VIAL-MATE Adaptor and cefiderocol vials were demonstrated. Conclusion and Relevance: Use of these systems is relevant even where resources are limited and may increase the efficiency of cefiderocol administration in hospitals, outpatient settings, or long-term healthcare facilities.

Radiofrequency Ablation for Treating Headache.

PURPOSE OF REVIEW: Examining the efficacy of radiofrequency ablation in treating headache conditions. RECENT FINDINGS: The efficacy of radiofrequency ablation in treating headache conditions is not well studied. Chronic headache conditions can be difficult to treat with little consensus on management of headaches associated with pericranial neuralgias. In this retrospective study, we found that radiofrequency ablation is an effective and safe treatment for resistant headache conditions. This study is important as it describes a novel treatment for chronic headache which can benefit a large number of patients.

Safety and Efficacy of Radiofrequency Ablation of the Medial Branch Nerves with Preexisting Spinal Hardware. A Case Series and Review of Literature.

PURPOSE OF REVIEW: To explore the efficacy of radio frequency ablation in treating pain in patients with hardware at site of the procedure. RECENT FINDINGS: There is very limited data in literature about this topic. One study performed in 2016 indicated no complications when performing RFA close to hardware in patients with chronic pain conditions. Radiofrequency ablation can be safely and effectively performed close to hardware. While heating of the hardware can happen which can theoretically lead to tissue injury or decreased heat going to target nerve, this does not seem to be of clinical significance. More studies are needed to confirm this finding.

Immune response to a model shared placenta/tumor-associated antigen reduces cancer risk in parous mice.

During human pregnancy, paternally inherited antigens expressed by the fetal-placental unit can elicit expansion of antigen-specific CD8+ T cells. These cells can persist for years as memory T cells, but their effects on long-term maternal health are unknown. Shared placenta/tumor-associated antigens are expressed by placenta and tumors, but are minimally expressed or absent in normal adult tissues. We hypothesized that maternal T cells elicited against these antigens can alter risk of cancers expressing the same antigen after pregnancy, and tested this in mice using chicken ovalbumin (OVA) as a surrogate shared placenta/tumor antigen. Hemizygous OVA transgenic males were bred to wild-type C57BL/6 females (H2b haplotype) such that the fetuses inherited and expressed OVA. Maternal OVA/H2Kb-specific CD8+ T cells became detectable during gestation, and persisted in some animals for up to 24 weeks. To determine whether these cells might influence growth of OVA-expressing tumors in OVA-bred females, E.G7-OVA thymoma cells were inoculated subcutaneously in OVA-bred, wild-type bred, and virgin females, and monitored for growth. OVA-bred mice had prolonged survival as compared to virgin mice and the progression of tumors was delayed in comparison to wild-type bred and virgin females. Thus, paternally inherited OVA antigen elicited a CD8+ T cell response during pregnancy that was associated with delayed growth of OVA-expressing tumors following pregnancy. These data suggest a possible role of antigen-specific T cells in protecting parous females against tumors bearing shared placenta/tumor antigens.

Population pharmacokinetics of meropenem administered as a prolonged infusion in children with cystic fibrosis.

OBJECTIVES: Meropenem is frequently used to treat pulmonary exacerbations in children with cystic fibrosis (CF) in the USA. Prolonged-infusion meropenem improves the time that free drug concentrations remain above the MIC (fT> MIC) in adults, but data in CF children are sparse. We describe the population pharmacokinetics, tolerability and treatment burden of prolonged-infusion meropenem in CF children. METHODS: Thirty children aged 6-17 years with a pulmonary exacerbation received 40 mg/kg meropenem every 8 h; each dose was administered as a 3 h infusion. Pharmacokinetics were determined using population methods in Pmetrics. Monte Carlo simulation was employed to compare 0.5 with 3 h infusions to estimate the probability of pharmacodynamic target attainment (PTA) at 40% fT> MIC. NCT#01429259. RESULTS: A two-compartment model fitted the data best with clearance and volume predicted by body weight. Clearance and volume of the central compartment were 0.41 ±â€Š0.23 L/h/kg and 0.30 ±â€Š0.17 L/kg, respectively. Half-life was 1.11 ±â€Š0.38 h. At MICs of 1, 2 and 4 mg/L, PTAs for the 0.5 h infusion were 87.6%, 70.1% and 35.4%, respectively. The prolonged infusion increased PTAs to >99% for these MICs and achieved 82.8% at 8 mg/L. Of the 30 children, 18 (60%) completed treatment with prolonged infusion; 5 did so at home without any reported burden. Nine patients were changed to a 0.5 h infusion when discharged home. CONCLUSIONS: In these CF children, meropenem clearance was greater compared with published values from non-CF children. Prolonged infusion provided an exposure benefit against pathogens with MICs ≥1 mg/L, was well tolerated and was feasible to administer in the hospital and home settings, the latter depending on perception and family schedule.

Antibiotic Stewardship Challenges in a Referral Neonatal Intensive Care Unit.

BACKGROUND: Antibiotic overuse in neonates is associated with adverse outcomes. Data are limited to guide antibiotic stewardship in the neonatal intensive care unit (NICU). Our objective was to identify areas for antibiotic stewardship improvement in a referral NICU. METHODS: Retrospective review of antibiotic use administered to infants admitted to a referral NICU compared with an inborn NICU. Antibiotic use was quantified by days of therapy (DOT) per 1,000 patient-days (PD). RESULTS: A total of 78% of referral NICU infants received ≥ 1 course of antibiotics. Infants in the referral NICU received more antibiotic DOT/1,000 PD than in the inborn NICU (558.9 vs. 343.2, p < 0.001), with a higher proportion of broad-spectrum therapy. For infants in the referral NICU, 39% of antibiotic courses were started at the transferring hospital; these were broader in spectrum (28 vs. 20%, p < 0.001) and less likely to be de-escalated or discontinued at 48 to 72 hours (58 vs. 87%, p < 0.001) than courses started after transfer. CONCLUSIONS: Compared with the inborn NICU, suspected sepsis in the referral NICU accounted for more antibiotic utilization, which was broad-spectrum and less likely to be de-escalated. Stewardship interventions should include reserving broad-spectrum therapy for infants with risk factors and de-escalating promptly once culture results become available.

Synthesis and chemical reactivity of a 6-Me-3,2-hydroxypyridinone dithiazolide with primary amines: a route to new hexadentate chelators for hard metal(III) ions.

A hydroxypyridinone building block, bifunctionalized with thiazoline, has been prepared from orthogonally protected 2-(3-(benzyloxy)-4-(ethoxycarbonyl)-6-methyl-2-oxopyridin-1(2H)-yl) acetic acid. The reactivity of the dithiazolide has been explored with two primary amines, leading to the synthesis and characterization of four new hexadentate ligands. Their complexes with selected hard trivalent ions pertinent to potential molecular imaging applications have been surveyed.

Empiric Antibiotics for Serious Bacterial Infection in Young Infants: Opportunities for Stewardship.

OBJECTIVES: To evaluate the causative agents of serious bacterial infection (SBI) in young infants and the optimal approach to empiric antibiotic therapy for infants with SBI. METHODS: From May 1, 2011, to December 1, 2013, pertinent clinical data were collected on previously well infants 60 days or younger with SBI as defined by a positive bacterial culture from a sterile site. Infants were identified by prospective surveillance of admissions and daily review of microbiology records. RESULTS: Two hundred sixty-five infants with SBI were identified. Mean age was 32 days (SD ±16.6 days). Twenty-nine infants had meningitis, 66 had bacteremia (37 with concomitant urinary tract infection), and 170 had urinary tract infection alone. No methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus sp., or penicillin-resistant Streptococcus pneumoniae were identified. Four extended-spectrum ß-lactamase-producing gram-negative bacilli were seen. Empiric therapy was ampicillin and gentamicin (n = 116, 44%) or third-generation cephalosporin based (n = 149, 56%). Ampicillin and gentamicin, with third-generation cephalosporins reserved for cases where meningitis is suspected, would have provided effective coverage for 98.5% of infants and unnecessarily broad therapy for 4.3%. Third-generation cephalosporins with ampicillin would have been effective for 98.5% of infants and unnecessarily broad for 83.8%. Third-generation cephalosporin monotherapy was less effective than either combination (P < 0.001). Fifty-seven percent of broad spectrum empiric therapy was continued despite culture results allowing de-escalation. CONCLUSIONS: Ampicillin/gentamicin remains an effective empiric regimen for infants 60 days or younger with suspected SBI. Use of a third-generation cephalosporin for suspected meningitis is appropriate, but cerebrospinal fluid must be obtained promptly to guide appropriate therapy.

Probiotic-associated aspiration pneumonia due to Lactobacillus rhamnosus.

Lactobacilli are low-virulence, commensal organisms of the gastrointestinal and genitourinary tracts and are commonly used as "probiotic supplements." Herein, we describe an episode of respiratory syncytial virus (RSV) bronchiolitis with bacterial superinfection secondary to administration of Lactobacillus rhamnosus in an 11-month-old female with trisomy 21.

Isolation and screening of carboxydotrophs isolated from composts and their potential for butanol synthesis.

Carboxydotrophs are known for their ability to convert carbon monoxide (CO) to butanol through fermentation. Such a platform offers a promising alternative approach to biofuel production from synthesis gas feedstocks. In this study, carboxydotrophs were isolated from various manure compost. Out of 500 isolates, only 11 carboxydotrophs (7 mesophiles and 4 thermophiles) were found to utilize CO as the sole source of carbon and energy. To assess the biochemical basis for their ability to produce biofuel (butanol), the level of activities of CO dehydrogenase (CODH), hydrogenase and butanol dehydrogenase (BDH) enzymes for these isolates against the known carboxydotroph, Butyribacterium methylotrophicum was assessed. All isolates showed evidence of enzyme activities (0.16-2.20 micromol min(-1)), with the majority exhibiting higher activities compared with the known carboxydotroph, B. methylotrophicum (0.33-0.71 micromol min(-1)). The level of activities for CODH and BDH ranged from 0.163-3.59 micromolmin(-1) and 0.19-2.2 micromolmin(-1), respectively. Three isolates (M7-1, T2-22, and T3-14) demonstrated enzymatic activity three to seven times higher than B. methylotrophicum. Of these, T2-22 exhibited the highest BDH activity and shows great promise in the conversion of toxic CO into butanol more so than other carboxytotrophs known thus far. This study revealed some biochemical basis for butanol production from CO by carboxydotrophs. However, more research is needed to discover a direct biological route for butanol production from CO to strengthen their potential for synthesis gas bioprocessing. Follow-up work will focus on whole-genome sequencing of the promising isolate T2-22 to provide system-level insights into how carboxydotrophs utilize and regulate their molecular machineries for butanol production.

Right ventricular functional recovery assessment with stress echocardiography and cardiopulmonary exercise testing after pulmonary embolism: a pilot prospective multicentre study.

BACKGROUND: Data on right ventricular (RV) exercise adaptation following acute intermediate and high-risk pulmonary embolism (PE) remain limited. This study aimed to evaluate the symptom burden, RV functional recovery during exercise and cardiopulmonary exercise parameters in survivors of intermediate and high-risk acute PE. METHODS: We prospectively recruited patients following acute intermediate and high-risk PE at four sites in Australia and UK. Study assessments included stress echocardiography, cardiopulmonary exercise testing (CPET) and ventilation-perfusion (VQ) scan at 3 months follow-up. RESULTS: Thirty patients were recruited and 24 (median age: 55 years, IQR: 22) completed follow-up. Reduced peak oxygen consumption (VO2) and workload was seen in 75.0% (n=18), with a persistent high symptom burden (mean PEmb-QoL Questionnaire 48.4±21.5 and emPHasis-10 score 22.4±8.8) reported at follow-up. All had improvement in RV-focused resting echocardiographic parameters. RV systolic dysfunction and RV to pulmonary artery (PA) uncoupling assessed by stress echocardiography was seen in 29.2% (n=7) patients and associated with increased ventilatory inefficiency (V̇E/V̇CO2 slope 47.6 vs 32.4, p=0.03), peak exercise oxygen desaturation (93.2% vs 98.4%, p=0.01) and reduced peak oxygen pulse (p=0.036) compared with controls. Five out of seven patients with RV-PA uncoupling demonstrated persistent bilateral perfusion defects on VQ scintigraphy consistent with chronic thromboembolic pulmonary vascular disease. CONCLUSION: In our cohort, impaired RV adaptation on exercise was seen in almost one-third of patients. Combined stress echocardiography and CPET may enable more accurate phenotyping of patients with persistent symptoms following acute PE to allow timely detection of long-term complications.

Nuclear Progesterone Receptor Expressed by the Cortical Thymic Epithelial Cells Dictates Thymus Involution in Murine Pregnancy.

Progesterone is a gonadal pro-gestational hormone that is absolutely necessary for the success of pregnancy. Most notable actions of progesterone are observed in the female reproductive organs, the uterus and the ovary. Acting through the nuclear progesterone receptor (PGR), progesterone prepares the endometrium for implantation of the embryo. Interestingly, the maternal thymus also is a known expressor of Pgr; its absence is associated with murine pregnancy complications. However, the localization of its expression and its functional importance were not known. Here, we used a transgenic dual fluorescent reporter mouse model and genetic deletion of Pgr in Foxn1+ thymic epithelial cells (TEC) to demonstrate TEC-specific Pgr expression in pregnancy, especially in the cortex where thymocyte maturation occurs. Using our TEC-specific Pgr deletion mouse model, we demonstrate that TEC-specific Pgr is necessary for pregnancy-induced thymic involution in pregnancy. Our investigation reveals that PGR expression is upregulated in the cortical thymic epithelial cells during pregnancy, and that PGR expression is important for thymic involution during murine pregnancy.

Corrigendum: Nuclear Progesterone Receptor Expressed by the Cortical Thymic Epithelial Cells Dictates Thymus Involution in Murine Pregnancy.

[This corrects the article DOI: 10.3389/fendo.2022.846226.].

Isolation and characterization of uterine leukocytes collected using a uterine swab technique.

PROBLEM: Leukocytes from the maternal-fetal interface are a valuable tool to study local changes in immune function during pregnancy; however, sampling can be challenging due to inadequate tissue availability and the invasive nature of placental bed biopsy. Here, we aim to purify and characterize leukocytes from paired peripheral and uterine blood samples to assess whether a less invasive method of uterine blood collection could yield a population of enriched uterine leukocytes suitable for ex vivo and in vitro analyses. METHOD OF STUDY: Human peripheral blood mononuclear cells (PBMC) and uterine blood mononuclear cells (UBMC) expressed from surgical gauze post C-section were isolated, and immunophenotypic information was acquired by multi-parameter flow cytometry. PBMC and UBMC were stained for markers used to define T and B lymphocytes, macrophages, regulatory T (TReg ) cells, and natural killer (NK) cells. Prime flow was performed to check expression and analysis of CD16- CD56++ and CD16- CD56++ NK transcripts in PBMC and UBMC samples. RESULTS: Immunophenotyping revealed that over 95% of both live PBMC and UBMC consisted of CD45+ leukocytes. Higher percentages of CD16- CD56++ , characterized as uterine NK (uNK) cells, were observed in UBMC samples as compared to PBMC samples (18.41% of CD45+ CD3- vs. 2.73%, respectively), suggesting that CD16- CD56++ cells were enriched in these samples. In UBMC, 49.64% of CD3-negative cells were of peripheral NK phenotype (CD16+ CD56++ ), suggesting infiltration of maternal peripheral NK (pNK) cell in the uterine interface. CONCLUSION: Intrauterine leukocytes, especially CD16- CD56++ NK cells, can be collected in sufficient numbers with increased purity by sampling the uterine cavity postdelivery with surgical gauze. Our results suggest that this non-invasive protocol is a useful sampling technique for isolating CD16- CD56++ cells, however, due to peripheral blood contamination, the NK cell yield could be lower compared to actual decidual or endometrial samples post-partum which is more invasive.

Using data to make the case for program resources and sustainability: the BEST action inventory case study.

Career development programs are a valuable part of any student's experience, and increasingly is an expected part of graduate school training. While such programs are commonly available to undergraduates, there is a growing need for career support to be offered to graduate students. Making the case for resources can be a challenge in this domain, however. Research on the impact of career services for graduate students and post-doctoral scholars is a growing scholarly concern. However, there remains a need to better understand what level of intervention is most appropriate: What kind of activities, how much time, and what resources would best serve the professional development needs of graduate students and post-doctoral scholars? And to answer these questions, a more foundational one: what activities are drawing the attention of graduate students and post doctoral trainees, and in what activities are they spending their time? In this manuscript, we describe how Our University approached this research question by developing an online data tracking system to capture graduate and post-doctoral trainee participation in one co-curricular professional development program. We demonstrate how this data tracking system can be used to advocate for institutional resources in career development programming, for research, and for practical purposes such as advocating for institutional support and for program design and assessment.

Integrins mediate placental extracellular vesicle trafficking to lung and liver in vivo.

Membrane-bound extracellular vesicles (EVs) mediate intercellular communication in all organisms, and those produced by placental mammals have become increasingly recognized as significant mediators of fetal-maternal communication. Here, we aimed to identify maternal cells targeted by placental EVs and elucidate the mechanisms by which they traffic to these cells. Exogenously administered pregnancy-associated EVs traffic specifically to the lung; further, placental EVs associate with lung interstitial macrophages and liver Kupffer cells in an integrin-dependent manner. Localization of EV to maternal lungs was confirmed in unmanipulated pregnancy using a transgenic reporter mouse model, which also provided in situ and in vitro evidence that fetally-derived EVs, rarely, may cause genetic alteration of maternal cells. These results provide for the first time direct in vivo evidence that placental EVs target maternal immune cells, and further, that EVs can alter cellular phenotype.

Bioorthogonal chemistry.

Bioorthogonal chemistry represents a class of high-yielding chemical reactions that proceed rapidly and selectively in biological environments without side reactions towards endogenous functional groups. Rooted in the principles of physical organic chemistry, bioorthogonal reactions are intrinsically selective transformations not commonly found in biology. Key reactions include native chemical ligation and the Staudinger ligation, copper-catalysed azide-alkyne cycloaddition, strain-promoted [3 + 2] reactions, tetrazine ligation, metal-catalysed coupling reactions, oxime and hydrazone ligations as well as photoinducible bioorthogonal reactions. Bioorthogonal chemistry has significant overlap with the broader field of 'click chemistry' - high-yielding reactions that are wide in scope and simple to perform, as recently exemplified by sulfuryl fluoride exchange chemistry. The underlying mechanisms of these transformations and their optimal conditions are described in this Primer, followed by discussion of how bioorthogonal chemistry has become essential to the fields of biomedical imaging, medicinal chemistry, protein synthesis, polymer science, materials science and surface science. The applications of bioorthogonal chemistry are diverse and include genetic code expansion and metabolic engineering, drug target identification, antibody-drug conjugation and drug delivery. This Primer describes standards for reproducibility and data deposition, outlines how current limitations are driving new research directions and discusses new opportunities for applying bioorthogonal chemistry to emerging problems in biology and biomedicine.

Developing bioorthogonal probes to span a spectrum of reactivities.

Bioorthogonal chemistries enable researchers to interrogate biomolecules in living systems. These reactions are highly selective and biocompatible and can be performed in many complex environments. However, like any organic transformation, there is no perfect bioorthogonal reaction. Choosing the "best fit" for a desired application is critical. Correspondingly, there must be a variety of chemistries-spanning a spectrum of rates and other features-to choose from. Over the past few years, significant strides have been made towards not only expanding the number of bioorthogonal chemistries, but also fine-tuning existing reactions for particular applications. In this Review, we highlight recent advances in bioorthogonal reaction development, focusing on how physical organic chemistry principles have guided probe design. The continued expansion of this toolset will provide more precisely tuned reagents for manipulating bonds in distinct environments.