Attention to novelty interferes with toddlers' emerging memory decision-making.

Memory decision-making in 26- to 32-month-olds was investigated using visual-paired comparison paradigms, requiring toddlers to select familiar stimuli (Active condition) or view familiar and novel stimuli (Passive condition). In Experiment 1 (N = 108, 54.6% female, 62% White; replication N = 98), toddlers with higher accuracy in the Active condition showed reduced novelty preference in that condition, but not in the Passive condition (d = -.11). In Experiment 2 (N = 78; 52.6% female; 70.5% White), a brief 5% increase in target size boosted gaze transitions across conditions (d = .50) and accuracy in the Active condition (d = .53). Overall, evidence suggests that better attentional distribution can support decision-making. Research was conducted between 2014 and 2020 in Northern California.

A transcriptome-wide association study implicates specific pre- and post-synaptic abnormalities in schizophrenia.

Schizophrenia is a complex highly heritable disorder. Genome-wide association studies (GWAS) have identified multiple loci that influence the risk of developing schizophrenia, although the causal variants driving these associations and their impacts on specific genes are largely unknown. We identify a significant correlation between schizophrenia risk and expression at 89 genes in the dorsolateral prefrontal cortex (P ≤ 9.43 × 10-6), including 20 novel genes. Genes whose expression correlate with schizophrenia were enriched for those involved in abnormal CNS synaptic transmission (PFDR = 0.02) and antigen processing and presentation of peptide antigen via MHC class I (PFDR = 0.02). Within the CNS synaptic transmission set, we identify individual significant candidate genes to which we assign direction of expression changes in schizophrenia. The findings provide strong candidates for experimentally probing the molecular basis of synaptic pathology in schizophrenia.

Targeted cancer treatment and fertility: effect of immunotherapy and small molecule inhibitors on female reproduction.

Targeted cancer therapy is rapidly evolving the landscape of personalized health care. Novel approaches to selectively impeding tumour growth carry significant potential to improve survival outcomes, particularly for reproductive-aged patients harbouring treatment refractory disease. Current agents fall within two classes: immunotherapy and small molecule inhibitors. These are collectively divided into the following subclasses: monoclonal antibodies; immunomodulators; adoptive cell therapy; treatment vaccines; kinase inhibitors; proteasome inhibitors; metalloproteinase and heat shock protein inhibitors; and promoters of apoptosis. The short- and long-term effects of these treatments on the female reproductive system are not well understood. As a result, clinicians are rendered unable to appropriately counsel women on downstream effects to their fertility. Data-driven consensus recommendations are desperately needed. This review aims to characterize the effect of targeted cancer therapy on the female hypothalamic-pituitary-ovary axis, direct ovarian function and conception.

Racial and ethnic disparities in surgical care for endometriosis across the United States.

BACKGROUND: Despite an estimated 10% prevalence of endometriosis among reproductive-age women, surgical population-based data are limited. OBJECTIVE: We sought to investigate racial and ethnic disparities in surgical interventions and complications among patients undergoing endometriosis surgery across the United States. STUDY DESIGN: We performed a retrospective cohort study of American College of Surgeons National Surgical Quality Improvement Program data from 2010 to 2018 identifying International Classification of Diseases, Ninth/Tenth Revision codes for endometriosis We compared procedures, surgical routes (laparoscopy vs laparotomy), and 30-day postoperative complications by race and ethnicity. RESULTS: We identified 11,936 patients who underwent surgery for endometriosis (65% White, 8.2% Hispanic, 7.3% Black or African American, 6.2% Asian, 1.0% Native Hawaiian or Pacific Islander, 0.6% American Indian or Alaska Native, and 11.5% of unknown race). Perioperative complications occurred in 9.6% of cases. After adjusting for confounders, being Hispanic (adjusted odds ratio, 1.31; 95% confidence interval, 1.06-1.64), Black or African American (adjusted odds ratio, 1.71; confidence interval, 1.39-2.10), Native Hawaiian or Pacific Islander (adjusted odds ratio, 2.08; confidence interval, 1.28-3.37), or American Indian or Alaska Native (adjusted odds ratio, 2.34; confidence interval, 1.32-4.17) was associated with surgical complications. Hysterectomies among Hispanic (adjusted odds ratio, 1.68; confidence interval, 1.38-2.06), Black or African American (adjusted odds ratio, 1.77; confidence interval, 1.43-2.18), Asian (adjusted odds ratio, 1.87; confidence interval, 1.43-2.46), Native Hawaiian or Pacific Islander (adjusted odds ratio, 4.16; confidence interval, 2.14-8.10), and patients of unknown race or ethnicity (adjusted odds ratio, 2.07; confidence interval, 1.75-2.47) were more likely to be open. Being Hispanic (adjusted odds ratio, 1.64; confidence interval, 1.16-2.30) or Black or African American (adjusted odds ratio, 2.64; confidence interval, 1.95-3.58) was also associated with receipt of laparotomy for nonhysterectomy procedures. The likelihood of undergoing oophorectomy was increased for Hispanic and Black women (adjusted odds ratio, 2.57; confidence interval, 1.96-3.37 and adjusted odds ratio, 2.06; confidence interval, 1.51-2.80, respectively), especially at younger ages. CONCLUSION: Race and ethnicity were independently associated with surgical care for endometriosis, with elevated complication rates experienced by Hispanic, Black or African American, Native Hawaiian or Pacific Islander, and American Indian or Alaska Native patients.

Uterine Transplantation: Recipient Patient Populations.

Uterine transplantation is an emerging treatment for patients with uterine factor infertility (UFI). In order to determine patient candidacy for transplant, it is imperative to understand how to identify, counsel and treat uterine transplant recipients. In this article, we focus on patient populations with UFI, whether congenital or acquired, including Mayer-Rokitansky-Kuster-Hauser, complete androgen insensitivity syndrome, hysterectomy, and other causes of nonabsolute UFI. Complete preoperative screening of recipients should be required to assess the candidacy of each individual prior to undergoing this extensive treatment option.

Fatal Respiratory Diphtheria Caused by ß-Lactam-Resistant Corynebacterium diphtheriae.

BACKGROUND: Diphtheria is a potentially fatal respiratory disease caused by toxigenic Corynebacterium diphtheriae. Although resistance to erythromycin has been recognized, ß-lactam resistance in toxigenic diphtheria has not been described. Here, we report a case of fatal respiratory diphtheria caused by toxigenic C. diphtheriae resistant to penicillin and all other ß-lactam antibiotics, and describe a novel mechanism of inducible carbapenem resistance associated with the acquisition of a mobile resistance element. METHODS: Long-read whole-genome sequencing was performed using Pacific Biosciences Single Molecule Real-Time sequencing to determine the genome sequence of C. diphtheriae BQ11 and the mechanism of ß-lactam resistance. To investigate the phenotypic inducibility of meropenem resistance, short-read sequencing was performed using an Illumina NextSeq500 sequencer on the strain both with and without exposure to meropenem. RESULTS: BQ11 demonstrated high-level resistance to penicillin (benzylpenicillin minimum inhibitory concentration [MIC] ≥ 256 µg/ml), ß-lactam/ß-lactamase inhibitors and cephalosporins (amoxicillin/clavulanic acid MIC ≥ 256 µg/mL; ceftriaxone MIC ≥ 8 µg/L). Genomic analysis of BQ11 identified acquisition of a novel transposon carrying the penicillin-binding protein (PBP) Pbp2c, responsible for resistance to penicillin and cephalosporins. When strain BQ11 was exposed to meropenem, selective pressure drove amplification of the transposon in a tandem array and led to a corresponding change from a low-level to a high-level meropenem-resistant phenotype. CONCLUSIONS: We have identified a novel mechanism of inducible antibiotic resistance whereby isolates that appear to be carbapenem susceptible on initial testing can develop in vivo resistance to carbapenems with repeated exposure. This phenomenon could have significant implications for the treatment of C. diphtheriae infection, and may lead to clinical failure.

Life underneath the VCA umbrella: Perspectives from the US Uterus Transplant Consortium.

The parallel emergence of uterus transplantation (UTx) and other transplantation innovations including face and hand transplantation led to the categorization of the uterus as a vascular composite allograft (VCA). With >60 transplants and >20 births worldwide, UTx is transitioning rapidly from a research endeavor to an effective treatment option for women with uterine factor infertility. While it originally made sense to group the innovations under one umbrella, it is time to revisit the designation of UTx as a VCA. We describe how UTx needs unique policy, procedural codes, insurance contracts, and educational initiatives. We contend that separating UTx from VCAs may become necessary in the future to avoid hindering the growth and regulation of this field.

Memory-related hippocampal activation in the sleeping toddler.

Nonhuman research has implicated developmental processes within the hippocampus in the emergence and early development of episodic memory, but methodological challenges have hindered assessments of this possibility in humans. Here, we delivered a previously learned song and a novel song to 2-year-old toddlers during natural nocturnal sleep and, using functional magnetic resonance imaging, found that hippocampal activation was stronger for the learned song compared with the novel song. This was true regardless of whether the song was presented intact or backwards. Toddlers who remembered where and in the presence of which toy character they heard the song exhibited stronger hippocampal activation for the song. The results establish that hippocampal activation in toddlers reflects past experiences, persists despite some alteration of the stimulus, and is associated with behavior. This research sheds light on early hippocampal and memory functioning and offers an approach to interrogate the neural substrates of early memory.

Uterus transplantation: state of the art in 2021.

PURPOSE: To provide a comprehensive review of uterus transplantation in 2021, including a discussion of pregnancy outcomes of all reported births to date, the donor and recipient selection process, the organ procurement and transplant surgeries, reported complications, postoperative monitoring, preimplantation preparation, and ethical considerations. METHODS: Literature review and expert commentary. RESULTS: Reports of thirty-one live births following uterus transplantation have been published from both living and deceased donors. The proper selection of donors and recipients is a labor-intensive process that requires advanced planning. A multidisciplinary team is critical. Reported complications in the recipient include thrombosis, infection, vaginal stricture, antenatal complications, and graft failure. Graft rejection is a common occurrence but rarely leads to graft removal. While most embryo transfers are successful, recurrent implantation failures in uterus transplant patients have been reported. Rates of preterm delivery are high but appear to be declining; more data, including long-term outcome data, is needed. CONCLUSIONS: Uterus transplantation is an emerging therapy for absolute uterine factor infertility, a condition previously without direct treatment options. It is paramount that reproductive health care providers are familiar with the uterus transplantation process as more patients seek and receive this treatment.

Guidelines for standardized nomenclature and reporting in uterus transplantation: An opinion from the United States Uterus Transplant Consortium.

Uterus transplantation is a nascent but growing field. To support this growth, the United States Uterus Transplant Consortium proposes guidelines for nomenclature related to operative technique, vascular anatomy, and donor, recipient, and offspring outcomes. In terms of anatomy, the group recommends reporting donor arterial inflow and recipient anastomotic site delivering inflow to the graft and offers standardization of the names for the 4 veins originating from the uterus because of current inconsistency in this particular nomenclature. Seven progressive stages with milestones of success are defined for reporting on uterus transplantation outcomes: (1) technical, (2) menstruation, (3) embryo implantation, (4) pregnancy, (5) delivery, (6) graft removal, and (7) long-term follow-up. The 3 primary metrics for success are recipient survival (as reported for other organ transplant recipients), graft survival, and uterus transplant live birth rate (defined as live birth per transplanted recipient). A number of secondary outcomes should also be reported, most of which capture stage-specific milestones, as well as data on graft failure. Outcome metrics for living donors include patient survival, survival free of operative intervention, and data on complications and hospitalizations. Finally, we make specific recommendations on follow-up for offspring born from uterine grafts, which includes specialty surveillance as well as collection and reporting of routine pediatric outcomes. The goal of standardization in reporting is to create consistency and improve the quality of evidence available on the efficacy and value of the procedure.

Evolving ethical issues with advances in uterus transplantation.

While uterus transplantation was once considered only a theoretical possibility for patients with uterine factor infertility, researchers have now developed methods of transplantation that have led to successful pregnancies with multiple children born to date. Because of the unique and significant nature of this type of research, it has been undertaken with collaboration not only with scientists and physicians but also with bioethicists, who paved the initial path for research of uterus transplantation to take place. As the science of uterus transplantation continues to advance, so too must the public dialogue among obstetrician/gynecologists, transplant surgeons, bioethicists, and other key stakeholders in defining the continued direction of research in addition to planning for the clinical implementation of uterus transplantation as a therapeutic option. Given the rapid advances in this field, the time has come to revisit the fundamental questions raised at the inception of uterus transplantation and, looking forward, determine the future of this approach given emerging data on the procedure's impact on individuals, families, and society.

First birth from a deceased donor uterus in the United States: from severe graft rejection to successful cesarean delivery.

Uterus transplantation is the only known potential treatment for absolute uterine factor infertility. It offers a unique setting for the investigation of immunologic adaptations of pregnancy in the context of the pharmacologic-induced tolerance of solid organ transplants, thus providing valuable insights into the early maternal-fetal interface. Until recently, all live births resulting from uterus transplantation involved living donors, with only 1 prior birth from a deceased donor. The Cleveland Clinic clinical trial of uterus transplantation opened in 2015. In 2017, a 35 year old woman with congenital absence of the uterus was matched to a 24 year old parous deceased brain-dead donor. Transplantation of the uterus was performed with vaginal anastomosis and vascular anastomoses bilaterally from internal iliac vessels of the donor to the external iliac vessels of the recipient. Induction and maintenance immunosuppression were achieved and subsequently modified in anticipation of pregnancy 6 months after transplant. Prior to planned embryo transfer, ectocervical biopsy revealed ulceration and a significant diffuse, plasma cell-rich mixed inflammatory cell infiltrate, with histology interpreted as grade 3 rejection suspicious for an antibody-mediated component. Aggressive immunosuppressive regimen targeting both cellular and humoral rejection was initiated. After 3 months of treatment, there was no histologic evidence of rejection, and after 3 months from complete clearance of rejection, an uneventful embryo transfer was performed and a pregnancy was established. At 21 weeks, central placenta previa with accreta was diagnosed. A healthy neonate was delivered by cesarean hysterectomy at 34 weeks' gestation. In summary, this paper highlights the first live birth in North America resulting from a deceased donor uterus transplant. This achievement underscores the capacity of the transplanted uterus to recover from a severe, prolonged rejection and yet produce a viable neonate. This is the first delivery from our ongoing clinical trial in uterus transplantation, including the first reported incidence of severe mixed cellular/humoral rejection as well as the first reported placenta accreta.

Associative binding in early childhood: Evidence from a preferential looking paradigm.

Relational memory processes are responsible for forming representations that bind together the co-occurring elements of an experience. These processes provide a foundation of episodic memory, the capacity to remember specific events about one's past. In the present research, we used a visual comparison paradigm to determine whether toddlers can form memories for the relation between co-occurring items. In Experiment 1, 66 2-year-olds viewed pairs of cartoon faces (AB; CD) and did not show a significant novelty preference for the violated associations (i.e., did not look longer at AD rearranged pair than old AB pair when exposed to AD-AB). However, toddlers looked longest at the individual face (i.e., D) violating a studied pair, which appeared to be supported by visual preference for centrally located stimuli. In Experiment 2, 46 2-year-olds participated in a similar procedure, but faces violating the pair during test were located to the periphery (e.g., AB-AC). Under these conditions, toddlers looked longer at recombined pair AC. Overall, our results show that toddlers show some ability to make item-item associations but may need to overcome preferential looking biases to demonstrate this capacity. Furthermore, looking behaviors beyond overall novelty preference may be informative even when overall novelty preference is not found.

Characterizing the endometrial fluid cytokine profile in women with endometriosis.

PURPOSE: To compare growth factor and cytokine profiles in the endometrial secretions of patients with and without endometriosis to determine whether a particular protein profile is predictive of the disease. METHODS: Patients undergoing laparoscopic gynecologic surgery for benign indications were recruited for this prospective cohort study. Prior to surgery, endometrial fluid was aspirated and multiplex immunoassay was used to quantify 7 cytokines and growth factors. During surgery, each patient was staged according to the ASRM staging system for endometriosis. Cytokines and growth factors were evaluated using the Mann-Whitney and Kruskal-Wallis tests. Combinations of cytokines were evaluated using logistic regression analysis, and ROC curves were generated to evaluate the predictive capacity of the assay. RESULTS: Endometrial secretions were analyzed from 60 patients. Nineteen had stage 3-4 endometriosis, 19 had stage 1-2 disease, and 22 had no endometriosis. There were no significant differences between controls and stage 1-2 endometriosis; however, levels of IL-1α and IL-6 were significantly increased in women with moderate-to-severe disease. A combination of IL-1α, IL-1ß, and IL-6 in endometrial secretions predicts stage 3-4 endometriosis with an AUC of 0.78. A threshold value of 118 pg/mL yields a sensitivity of 75% and specificity of 70%. CONCLUSION: Aspiration of endometrial fluid is a safe and effective approach for evaluating the endometrial profile of women with endometriosis. Women with moderate-to-severe endometriosis demonstrate a distinct cytokine profile compared to controls. A combination of IL-1α, IL-1ß, and IL-6 in the endometrial secretions is predictive of stage 3-4 endometriosis, but is not predictive of minimal-to-mild disease.

Cryptococcal infections over a 15 year period at a tertiary facility & impact of guideline management.

Cryptococcosis is an invasive fungal infection caused primarily by Cryptococcus neoformans and Cryptococcus gattii species, presenting predominantly as meningoencephalitis. The aim of this study is to assess all cryptococcal infections managed at our facility from 2001 to 2015 to determine incidence, risk factors, and comparison of outcomes prior to and following introduction of the 2010 Infectious Disease Society of America (IDSA) guidelines. Retrospective analysis of all patients diagnosed and treated for cryptococcal infection occurring between January 2001 and December 2015. Of 102 patients diagnosed with cryptococcal infection, 97 were eligible for study inclusion. There appears to be an overall increased incidence of cryptococcosis in both transplant and non-transplant cohorts with a peak in 2015 of 6 transplant and 13 non-transplant cases. In the meningitis cohort, 38/52 (73%) of identified isolates were C. neoformans, and 14/52 (27%) were C. gattii. Notably, 14/14 (100%) of C. gattii isolates were associated with meningitis, as compared to only 38/64 (59%) C. neoformans associated with meningitis (P: .003). It appears that patients presenting with cough are less likely to have meningitis, 17/27 (63%), (P: .005). When stratifying for culture positive meningitis lumbar puncture opening pressure, the median in the culture positive cohort was 31.5 cm H2 O compared with 15.5 cm H2 O (P: .036).Multiple admissions were required prior to diagnosis in the majority of cases with only 18/72 (25%) diagnosed on 1st presentation. Postguideline mortality has improved from 15% to 6.1% (P: .046). Cryptococcal infection remains relatively uncommon, but there appears to be an increasing trend in incidence. Overall mortality is relatively low and has improved since introduction of the 2010 IDSA guidelines.

Birth outcomes of singleton vaginal deliveries to ART-treated, subfertile, and fertile primiparous women.

PURPOSE: To determine whether differences in birth outcomes among assisted reproductive technology (ART)-treated, subfertile, and fertile women exist in primiparous women with, singleton, vaginal deliveries. METHODS: Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) data were linked to Massachusetts vital records and hospital discharges for deliveries between July 2004 and December 2010. Primiparous women with in-state vaginal deliveries, adequate prenatal care, and singleton birth at ≥ 20 weeks (n = 117,779) were classified as ART-treated (linked to ART data from SART CORS, n = 3138); subfertile (not ART-treated but with indicators of subfertility, n = 1507); or fertile (neither ART-treated nor subfertile, n = 113,134). Outcomes of prematurity (< 37 weeks), low birthweight (< 2500 g), perinatal death (death at ≥ 20 weeks to ≤ 7 days), and maternal prolonged length of hospital stay (LOS > 3 days) were compared using multivariable logistic regression. RESULTS: Compared to fertile, higher odds were found for prematurity among ART-treated (adjusted odds ratio [AOR] 1.40, 95% confidence interval [CI] 1.25-1.50) and subfertile (AOR 1.25, 95% CI 1.03-1.50) women, low birthweight among ART-treated (AOR 1.41, 95% CI 1.23-1.62) and subfertile (AOR 1.40, 95% CI 1.15-1.71) women, perinatal death among subfertile (AOR 2.64, 95% CI 1.72-4.05), and prolonged LOS among ART-treated (AOR 1.33, 95% CI 1.19-1.48) women. Differences remained despite stratification by young age and absence of pregnancy/delivery complications. CONCLUSIONS: Greater odds of prematurity and low birthweight in ART-treated and subfertile, and perinatal death in subfertile deliveries are evident among singleton vaginal deliveries. The data suggest that even low-risk pregnancies to ART-treated and subfertile women be managed for adverse outcomes.

Perforation During Gynecological Procedures.

This article in the Women's Health series discusses uterine perforation occurring during gynecological procedures, including prevention, identification of risk factors, recognition, management, and long-term outcomes.

Cryptococcal infections in solid organ transplant recipients over a 15-year period at a state transplant center.

BACKGROUND: The aim of this research paper was to determine the incidence, risk factors, and clinical outcome of solid organ transplant (SOT) recipients diagnosed and treated for cryptococcosis at our institution. METHODS: Retrospective analysis of all patients with SOT diagnosed and treated for cryptococcal infection occurring between January 2001 and December 2015. RESULTS: Of 102 patients diagnosed with cryptococcal infection, 23 were SOT recipients. Renal transplant accounted for 22/23 cases, of which 13 had meningitis. The annual incidence of infection has risen significantly, and is now greater than 2/1000 prevalent renal transplant recipients. As expected, biochemical factors associated with meningitis include lower glucose on cerebrospinal fluid (CSF) analysis, median 2.4 vs 4.5 mmol/L (P=.02); CSF white blood cell median 50 vs 1/µL (P<.001); CSF protein, median 950 vs 335 mg/L (P=.04). Serum cryptococcal antigen titers were higher in the meningitis cohort, median 512 vs 32 (P=.03). Clinically, headache on admission (odds ratio: 9 [1.29-63.03], P=.03) and a prolonged length of stay (median of 36 vs 13 days) in the meningitis cohort (P=.02) were significant. CONCLUSION: Cryptococcal infection in SOT recipients remains rare; however, there has been a marked increase in cases since 2014. This study reveals a need for increased vigilance for a potential emerging infectious disease. It furthermore highlights the need for ongoing research to further aid early diagnosis, prognostication, management, and screening cost-effectiveness.

ADVERSE EVENT REPORTING IN PATIENTS TREATED WITH THYROID HORMONE EXTRACT.

OBJECTIVE: Thyroid hormone extract is used for the treatment of thyroid disorders, but limited data exist on adverse events commonly noted by the physicians associated with this use. The purpose of this survey was to report adverse events observed by expert physicians managing patients treated for thyroid disease with thyroid hormones. METHODS: Members of the American Thyroid Association, The Endocrine Society, and the American Association of Clinical Endocrinologists developed a survey instrument modeled on the U.S. Food and Drug Administration (FDA)'s reported adverse events for levothyroxine that would effectively assess the clinical experience of frequent prescribers of thyroid hormone. Survey links were emailed to physicians, and the websites of each society provided links to the data collection form. RESULTS: A total of 174 reports of adverse events occurring in patients on thyroid hormone extract were received. Ninety-one of these reports were accompanied by alterations in thyrotropin values and were further analyzed. Of these, 62 (68%) subjects had developed new symptoms associated with altered thyroid-stimulating hormone (TSH). A majority of TSH changes and symptoms described were consistent with thyrotoxicosis (65%), and 2 patients had developed arrhythmias. Reporters noted difficulty in dose adjustment by primary care providers due to confusion in interpreting thyroid function test results while on thyroid extract, which often necessitated subspecialty referrals. CONCLUSION: These adverse event reports should stimulate consideration by the FDA to regulate and monitor thyroid hormone extract use and consider standardizing these extracts to meet current standards of manufacture, hormone content, availability, and shelf-life, like the rigor with which preparations such as levothyroxine are monitored. ABBREVIATIONS: AE = adverse event ATA = American Thyroid Association FDA = Food and Drug Administration LT3 = liothyronine LT4 = levothyroxine PTF = Pharmacovigilance Task Force T3 = triiodothyronine TSH = thyroid-stimulating hormone.