Prostaglandin E2 activates melanin-concentrating hormone neurons to drive diet-induced obesity.

Hypothalamic inflammation reduces appetite and body weight during inflammatory diseases, while promoting weight gain when induced by high-fat diet (HFD). How hypothalamic inflammation can induce opposite energy balance outcomes remains unclear. We found that prostaglandin E2 (PGE2), a key hypothalamic inflammatory mediator of sickness, also mediates diet-induced obesity (DIO) by activating appetite-promoting melanin-concentrating hormone (MCH) neurons in the hypothalamus in rats and mice. The effect of PGE2 on MCH neurons is excitatory at low concentrations while inhibitory at high concentrations, indicating that these neurons can bidirectionally respond to varying levels of inflammation. During prolonged HFD, endogenous PGE2 depolarizes MCH neurons through an EP2 receptor-mediated inhibition of the electrogenic Na+/K+-ATPase. Disrupting this mechanism by genetic deletion of EP2 receptors on MCH neurons is protective against DIO and liver steatosis in male and female mice. Thus, an inflammatory mediator can directly stimulate appetite-promoting neurons to exacerbate DIO and fatty liver.

Acute assessment services for patient flow assistance in hospital emergency departments.

BACKGROUND: Emergency departments (EDs) are facing serious and significant issues in the delivery of effective and efficient care to patients. Acute assessment services have been implemented at many hospitals internationally to assist in maintaining patient flow for identified groups of patients attending the ED. Identifying the risks and benefits, and optimal configurations of these services may be beneficial to those wishing to utilise an acute assessment service to improve patient flow. OBJECTIVES: To assess the effects of acute assessment services on patient flow following attendance at a hospital ED. SEARCH METHODS: We searched MEDLINE, CENTRAL, Embase and two trials registers on 24 September 2022 to identify studies. No restrictions were imposed on publication year, publication type, or publication language. SELECTION CRITERIA: Studies eligible for inclusion were randomised trials and cluster-randomised trials with at least two intervention and two control sites. Participants were adults (as defined by study authors) receiving care either in the ED or the acute assessment service, where both were based in the hospital setting. The comparison was hospital-based acute assessment services with usual, ED-only care. The outcomes of this review were mortality at time point closest to 30 days, length of stay in the service (in minutes), and waiting time to see a doctor (in minutes). DATA COLLECTION AND ANALYSIS: We followed the standard procedures of Cochrane Effective Practice and Organisation of Care for this review (https://epoc.cochrane.org/resources). MAIN RESULTS: We identified a total of 5754 records in the search. Following assessment of 3609 de-duplicated records, none were found to be eligible for inclusion in this review. AUTHORS' CONCLUSIONS: At present there are no randomised controlled trials exploring the effects of acute assessment services on patient flow in hospital-based emergency departments compared to usual, ED-only care.

Enhancement of Antibody-Dependent Cellular Cytotoxicity and Phagocytosis in Anti-HIV-1 Human-Bovine Chimeric Broadly Neutralizing Antibodies.

No prophylactic vaccine has provided robust protection against human immunodeficiency virus type 1 (HIV-1). Vaccine-induced broadly neutralizing antibodies (bNAbs) have not been achieved in humans and most animals; however, cows vaccinated with HIV-1 envelope trimers produce bNAbs with unusually long third heavy complementarity-determining regions (CDRH3s). Alongside neutralization, Fc-mediated effector functions, including antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADP), may be critical for in vivo bNAb antiviral activity. Here, we aimed to augment the Fc-dependent effector functions of a chimeric human-bovine bNAb, NC-Cow1, which binds the CD4 binding site (CD4bs) and exhibits broader and more potent neutralization than most human CD4bs bNAbs by using an exceptionally long 60-amino acid (aa) CDRH3. The bovine variable region of NC-Cow1 was paired with a human IgG1 Fc region mutated to create the following three variants: G236R/L328R (GRLR) that abrogates Fc-gamma receptor (FcγR) binding, and two variants that enhance binding, namely, G236A/S239D/I332E (GASDIE) and G236A/S239D/A330L/I332E (GASDALIE). Both GASDIE and GASDALIE improved binding to human FcγRIIA and FcγRIIIA, enhanced human natural killer (NK) cell activation, and mediated higher levels of ADCC and ADP activity than the wild-type human IgG1 Fc. GASDALIE mediated higher phagocytic activity than GASDIE. As expected, GRLR eliminated binding to FcγRs and did not mediate ADCC or ADP. We demonstrated that mutations in the human Fc region of bovine chimeric antibodies with ultralong CDRH3s could enhance antibody effector functions while maintaining envelope binding and neutralization. This study will have significant implications in the development of multifunctional anti-HIV antibodies, which may be important to prevent HIV-1 transmission in an antibody-based topical microbicide. IMPORTANCE Despite successful antiviral chemotherapy, human immunodeficiency virus (HIV) is still a lifelong persistent virus, and no vaccine yet prevents HIV transmission. Topical microbicides offer an important alternative method to prevent sexual transmission of HIV-1. With the production of highly potent anti-HIV-1 broadly neutralizing antibodies (bNAbs) and multifunctional antibodies, monoclonal antibodies are now important prophylactic agents. Recently discovered anti-HIV-1 bovine bNAbs (with higher potency and breadth than most human bNAbs) could be novel candidates as potent topical microbicides. Our study is significant as it demonstrates the compatibility of combining bovine-derived neutralization with human-derived antibody-effector functions. This study is a new approach to antibody engineering that strengthens the feasibility of using high-potency bovine variable region bNAbs with augmented Fc function and promotes them as a strong candidate for antibody-mediated therapies.

Phenotypic and functional characteristics of highly differentiated CD57+NKG2C+ NK cells in HIV-1-infected individuals.

Natural killer (NK) cells are important anti-viral effector cells. The function and phenotype of the NK cells that constitute an individual's NK cell repertoire can be influenced by ongoing or previous viral infections. Indeed, infection with human cytomegalovirus (HCMV) drives the expansion of a highly differentiated NK cell population characterized by expression of CD57 and the activating NKG2C receptor. This NK cell population has also been noted to occur in HIV-1-infected individuals. We evaluated the NK cells of HIV-1-infected and HIV-1-uninfected individuals to determine the relative frequency of highly differentiated CD57+NKG2C+ NK cells and characterize these cells for their receptor expression and responsiveness to diverse stimuli. Highly differentiated CD57+NKG2C+ NK cells occurred at higher frequencies in HCMV-infected donors relative to HCMV-uninfected donors and were dramatically expanded in HIV-1/HCMV co-infected donors. The expanded CD57+NKG2C+ NK cell population in HIV-1-infected donors remained stable following antiretroviral therapy. CD57+NKG2C+ NK cells derived from HIV-1-infected individuals were robustly activated by antibody-dependent stimuli that contained anti-HIV-1 antibodies or therapeutic anti-CD20 antibody, and these NK cells mediated cytolysis through NKG2C. Lastly, CD57+NKG2C+ NK cells from HIV-1-infected donors were characterized by reduced expression of the inhibitory NKG2A receptor. The abundance of highly functional CD57+NKG2C+ NK cells in HIV-1-infected individuals raises the possibility that these NK cells could play a role in HIV-1 pathogenesis or serve as effector cells for therapeutic/cure strategies.

Soil disturbance and invasion magnify CO2 effects on grassland productivity, reducing diversity.

Climate change, disturbance, and plant invasion threaten grassland ecosystems, but their combined and interactive effects are poorly understood. Here, we examine how the combination of disturbance and plant invasion influences the sensitivity of mixed-grass prairie to elevated carbon dioxide (eCO2 ) and warming. We established subplots of intact prairie and disturbed/invaded prairie within a free-air CO2 enrichment (to 600 ppmv) by infrared warming (+1.5°C day, 3°C night) experiment and followed plant and soil responses for 5 years. Elevated CO2 initially led to moderate increases in biomass and plant diversity in both intact and disturbed/invaded prairie, but these effects shifted due to strong eCO2 responses of the invasive forb Centaurea diffusa. In the final 3 years, biomass responses to eCO2 in disturbed/invaded prairie were 10 times as large as those in intact prairie (+186% vs. +18%), resulting in reduced rather than increased plant diversity (-17% vs. +10%). At the same time, warming interacted with disturbance/invasion and year, reducing the rate of topsoil carbon recovery following disturbance. The strength of these interactions demonstrates the need to incorporate disturbance into predictions of climate change effects. In contrast to expectations from studies in intact ecosystems, eCO2 may threaten plant diversity in ecosystems subject to soil disturbance and invasion.

Vaginal cuff brachytherapy for endometrial cancer: a review of major clinical trials with a focus on fractionation.

The use of vaginal cuff brachytherapy in the adjuvant management of endometrial cancer has increased over time. Recommendations from the American Brachytherapy Society, American Society of Radiation Oncology, and European Society for Medical Oncology help to guide the application of vaginal cuff brachytherapy. However, wide variation in practice remains regarding treatment techniques. This article reviews the use of vaginal cuff brachytherapy in the post-operative management of endometrial cancer. It covers risk stratification, treatment rationale, outcomes, and treatment planning recommendations with a specific focus on dose-fractionation regimens. The authors performed a thorough literature review of articles pertinent to the goals of this review. Also presented are early results of the Short Course Adjuvant Vaginal Cuff Brachytherapy in Early Endometrial Cancer Compared with Standard of Care (SAVE) trial of a two-fraction vaginal cuff brachytherapy regimen.Adjuvant vaginal cuff brachytherapy for early-stage endometrial cancer results in excellent disease control with minimal toxicity. The PORTEC-2 trial showed that vaginal cuff brachytherapy is non-inferior to external beam radiation for vaginal recurrence in patients at high-intermediate risk. Vaginal cuff brachytherapy may also be used as a boost following external beam radiation in combination with chemotherapy for high-risk histologies. Numerous techniques can be used for vaginal cuff brachytherapy, including various medical devices, dose-fractionation schedules, and treatment planning approaches. The early control results of the SAVE trial are promising and we are hopeful that this trial establishes two fraction regimens as a viable option for vaginal cuff brachytherapy.

Evaluation of 2D FLAIR hyperintensity of the optic nerve and optic nerve head and visual parameters in idiopathic intracranial hypertension.

BACKGROUND AND PURPOSE: T2/FLAIR hyperintensity of the optic nerve/optic nerve head has been described as a sensitive finding in idiopathic intracranial hypertension using post-contrast 3D-T2/FLAIR imaging. The purpose of this study is to assess whether hyperintensity on non-enhanced 2D-T2/FLAIR imaging occurs more likely in diseased patients than controls and to evaluate the relationship between FLAIR signal and visual parameters MATERIALS AND METHODS: A retrospective case-control study was performed of patients with idiopathic intracranial hypertension and controls who underwent orbital MRI. Three neuroradiologists reviewed the FLAIR images, subjectively evaluating for hyperintense signal within the optic nerves/optic nerve heads using a 5-point Likert Scale. Quantitative assessment of optic nerve signal using regions of interests was performed. Clinical parameters were extracted. The diagnostic performance was evaluated, and Spearman correlation calculated to assess the relationship between FLAIR signal and visual outcomes. RESULTS: The sensitivity of abnormal FLAIR signal within the optic nerves and optic nerve heads in patients with idiopathic intracranial hypertension ranged from 25-54% and 4-29%, respectively, with specificities ranging from 67-92% and 83-100%. Quantitative assessment revealed a significant difference in CNR between cases and controls in the left posterior optic nerve (p=.002). A positive linear relationship existed between abnormal optic nerve head signal and papilledema grade (OD: p=.02, OS: p=.008) but not with other visual parameters. CONCLUSION: T2/FLAIR hyperintensity in the optic nerve/optic nerve head may support the diagnosis of idiopathic intracranial hypertension but its absence should not dissuade it. If present, abnormal signal in the optic nerve head correlates with papilledema.

The Relationship Between Glutamate Dynamics and Activity-Dependent Synaptic Plasticity.

The spatiotemporal dynamics of excitatory neurotransmission must be tightly regulated to achieve efficient synaptic communication. By limiting spillover, glutamate transporters are believed to prevent excessive activation of extrasynaptically located receptors that can impair synaptic plasticity. While glutamate transporter expression is reduced in numerous neurodegenerative diseases, the contributions of transporter dysfunction to disease pathophysiology remain ambiguous as the fundamental relationship between glutamate dynamics and plasticity, and the mechanisms linking these two phenomena, remain poorly understood. Here, we combined electrophysiology and real-time high-speed imaging of extracellular glutamate transients during LTP induction and characterized the sensitivity of the relationship between glutamate dynamics during theta burst stimulation (TBS) and the resulting magnitude of LTP consolidation, both in control conditions and following selective and nonselective glutamate transporter blockade. Glutamate clearance times were negatively correlated with LTP magnitude following nonselective glutamate transporter inhibition but not following selective blockade of a majority of GLT-1, the brain's most abundant glutamate transporter. Although glutamate transporter inhibition reduced the postsynaptic population response to TBS, calcium responses to TBS were greatly exaggerated. The source of excess calcium was dependent on NMDARs, L-type VGCCs, GluA2-lacking AMPARs, and internal calcium stores. Surprisingly, inhibition of L-type VGCCs, but not GluA2-lacking AMPARs or ryanodine receptors, was required to restore robust LTP. In all, these data provide a detailed understanding of the relationship between glutamate dynamics and plasticity and uncover important mechanisms by which poor glutamate uptake can negatively impact LTP consolidation.SIGNIFICANCE STATEMENT Specific patterns of neural activity can promote long-term changes in the strength of synaptic connections through a phenomenon known as synaptic plasticity. Synaptic plasticity is well accepted to represent the cellular mechanisms underlying learning and memory, and many forms of plasticity are initiated by the excitatory neurotransmitter glutamate. While essential for rapid cellular communication in the brain, excessive levels of extracellular glutamate can negatively impact brain function. In this study, we demonstrate that pharmacological manipulations that increase the availability of extracellular glutamate during neural activity can have profoundly negative consequences on synaptic plasticity. We identify mechanisms through which excess glutamate can negatively influence synaptic plasticity, and we discuss the relevance of these findings to neurodegenerative diseases and in the aging brain.

Super-resolution imaging reveals extrastriatal synaptic dysfunction in presymptomatic Huntington disease mice.

Synaptic structure and function are compromised prior to cell death and symptom onset in a variety of neurodegenerative diseases. In Huntington disease (HD), a CAG repeat expansion in the gene encoding the huntingtin protein results in a presymptomatic stage that typically spans multiple decades and is followed by striking degeneration of striatal tissue and the progression of debilitating motor symptoms. Many lines of evidence demonstrate that the HD presymptomatic window is associated with injurious effects to striatal synapses, many of which appear to be prerequisites to subsequent cell death. While the striatum is the most vulnerable region in the HD brain, it is widely recognized that HD is a brain-wide disease, affecting numerous extrastriatal regions that contribute to debilitating non-motor symptoms including cognitive dysfunction. Currently, we have a poor understanding of the synaptic integrity, or lack thereof, in extrastriatal regions in the presymptomatic HD brain. If early therapeutic intervention seeks to maintain healthy synaptic function, it is important to understand early HD-associated synaptopathy at a brain-wide, rather than striatal-exclusive, level. Here, we focused on the hippocampus as this structure is generally thought to be affected only in manifest HD despite the subtle cognitive deficits known to emerge in prodromal HD. We used super-resolution microscopy and multi-electrode array electrophysiology as sensitive measures of excitatory synapse structure and function, respectively, in the hippocampus of presymptomatic heterozygous HD mice (Q175FDN model). We found clear evidence for enhanced AMPA receptor subunit clustering and hyperexcitability well before the onset of a detectable HD-like behavioral phenotype. In addition, activity-dependent re-organization of synaptic protein nanostructure, and functional measures of synaptic plasticity were impaired in presymptomatic HD mice. These data demonstrate that synaptic abnormalities in the presymptomatic HD brain are not exclusive to the striatum, and highlight the need to better understand the region-dependent complexities of early synaptopathy in the HD brain.

Entering a new era of quantifying glutamate clearance in health and disease.

Glutamate transporter proteins, expressed on both neurons and glia, serve as the main gatekeepers that dictate the spatial and temporal actions of extracellular glutamate. Glutamate is essential to the function of the healthy brain yet paradoxically contributes to the toxicity associated with many neurodegenerative diseases. Rapid transporter-mediated glutamate uptake, primarily occurring at astrocytic processes, tightens the efficiency of excitatory network activity and prevents toxic glutamate build-up in the extracellular space. Glutamate transporter dysfunction is thought to underlie myriad central nervous system (CNS) diseases including Alzheimer and Huntington disease. Over the past few decades, techniques such as biochemical uptake assays and electrophysiological recordings of transporter currents from individual astrocytes have revealed the remarkable ability of the CNS to efficiently clear extracellular glutamate. In more recent years, the rapidly evolving glutamate-sensing "sniffers" now allow researchers to visualize real-time glutamate transients on a millisecond time scale with single synapse spatial resolution in defined cell populations. As we transition to an increased reliance on optical-based methods of glutamate visualization and quantification, it is of utmost importance to understand not only the advantages that glutamate biosensors bring to the table but also the associated caveats and their implications for data interpretation. In this review, we summarize the strengths and limitations of the commonly used methods to quantify glutamate uptake. We then discuss what these techniques, when viewed as a complementary whole, have told us about the brain's ability to regulate glutamate levels, in both health and in the context of neurodegenerative disease.

Refusal of Local Therapy in Esophageal Cancer and Impact on Overall Survival.

OBJECTIVE: The aim of this study was to understand factors associated with refusal of local therapy in esophageal cancer and compare the overall survival (OS) of patients who refuse therapies with those who undergo recommended treatment. METHODS: National Cancer Database data for patients with non-metastatic esophageal cancer from 2006 to 2013 were pooled. T1N0M0 tumors were excluded. Pearson's Chi-square test and multivariate logistic regression analyses were used to assess demographic, clinical, and treatment factors. After propensity-score matching with inverse probability of treatment weighting, OS was compared between patients who refused therapies and those who underwent recommended therapy, using Kaplan-Meier analyses and doubly robust estimation with multivariate Cox proportional hazards modeling. RESULTS: In total, 37,618 patients were recommended radiation therapy (RT) and/or esophagectomy; we found 1403 (3.7%) refused local therapies. Specifically, 890 of 18,942 (4.6%) patients refused surgery and 667 of 31,937 (2.1%) refused RT. Older patients, females, those with unknown lymphovascular space invasion, and those uninsured or on Medicare were more likely to refuse. Those with squamous cell carcinoma, N1 disease, higher incomes, living farther from care, and those who received chemotherapy were less likely to refuse. Five-year OS was decreased in patients who refused (18.1% vs. 27.6%). The survival decrement was present in adenocarcinoma but not squamous cell carcinoma. In patients who received surgery or ≥ 50.4 Gy RT, there was no OS decrement to refusing the other therapy. CONCLUSIONS: We identified characteristics that correlate with refusal of local therapy. Refusal of therapy was associated with decreased OS. Patients who received either surgery or ≥ 50.4 Gy RT had no survival decrement from refusing the opposite modality.

HIV Reactivation after Partial Protection by Neutralizing Antibodies.

It is widely thought that generating broadly neutralizing anti-HIV antibodies (BnAbs) will protect humans against HIV, given promising data from in vitro experiments and in vivo macaque studies. The primary action of BnAbs is preventing cell-free virus from entering cells. Recent in vitro and macaque data suggest that BnAbs are less potent against cell-associated virus exposure. We speculate that BnAb-based suppression of HIV transmission, particularly if mediated by cell-cell transmission, may result in some exposed subjects carrying a form of latent (or 'occult') HIV infection. Such largely hidden HIV infections may subsequently reactivate when BnAb levels decline. This concept has implications for the achievement of long-term sterilizing immunity to HIV.

Risk of secondary malignancies in ovarian cancer survivors: 52,680 patients analyzed with over 40 years of follow-up.

OBJECTIVE: Survivors of ovarian cancer are at risk of developing a secondary malignancy (SM). We sought to evaluate the risk of developing SM, stratified by treatment modality. METHODS: Standardized incidence ratios (SIR, observed-to-expected [O/E] ratio) were assessed in 52,680 patients diagnosed with ovarian cancer between 1975 and 2016 in the National Cancer Institute's Surveillance, Epidemiology, and End Results Program. RESULTS: Of the 52,680 patients, 3366 patients (6.4%) developed SM, which was more than the endemic rate (O/E 1.13; p < .05). Patients who received any radiation (RT) had an increased risk of overall SM compared to those who didn't (O/E 1.42 vs 1.11; p < .05), and specifically, in the bladder (O/E 2.81). Patients who received any chemotherapy (CT) had an increased risk of leukemia (O/E 3.06), and a similar risk of overall SM compared to those not treated with CT (O/E 1.11 vs 1.14; p < .05). The excess risk of developing a solid tumor SM was greatest at latencies of 10-20 years. Patients younger than 50 had the highest risk of developing SM. Non-White patients had a higher risk of SM compared to White patients. CONCLUSIONS: This is the largest study to examine the risk of SM in patients with ovarian cancer and has the longest follow-up. Risk of SM was increased after ovarian cancer and varied with treatment modality, race, latency, and age. These results may help inform SM screening protocols for women diagnosed with ovarian cancer.

The use and efficacy of chemotherapy and radiotherapy in children and adults with pilocytic astrocytoma.

PURPOSE: The aim of this study was to understand the use of chemotherapy (CMT) and radiotherapy (RT) in pilocytic astrocytoma (PA) and their impact on overall survival (OS). METHODS: Data from the National Cancer Database (NCDB) for patients with non-metastatic WHO grade I PA from 2004 to 2014 were analyzed. Pearson's chi-squared test and multivariate logistic regression analyses were performed to assess the distribution of demographic, clinical, and treatment factors. Inverse probability of treatment weighting (IPTW) was used to account for differences in baseline characteristics. Kaplan-Meier analyses and doubly-robust estimation with multivariate Cox proportional hazards modeling were used to analyze OS. RESULTS: Of 3865 patients analyzed, 294 received CMT (7.6%), 233 received RT (6.0%), and 42 (1.1%) received both. On multivariate analyses, decreasing extent of surgical resection was associated with receipt of both CMT and RT. Brainstem tumors were associated with RT, optic nerve tumors were associated with CMT. Cerebellar tumors were inversely associated with both CMT and RT. Younger age was associated with receipt of CMT; conversely, older age was associated with receipt of RT. After IPTW, receipt of CMT and/or RT were associated with an OS decrement compared with matched patients treated with surgery alone or observation (HR 3.29, p < 0.01). CONCLUSIONS: This is the largest study to date to examine patterns of care and resultant OS outcomes in PA. We identified patient characteristics associated with receipt of CMT and RT. After propensity score matching, receipt of CMT and/or RT was associated with decreased OS.

Defining nocturnal polyuria in women.

AIMS: Nocturnal polyuria (NP) is defined by the International Continence Society (ICS) as "excessive production of urine during the main sleep period" and is one of the main causes of nocturia. The ICS recognized that "excessive" is not clearly defined and that this needs to be highlighted in both clinical and research settings. The aim of this study was to identify different definitions of NP and apply them to a population of women attending the Urogynaecology clinic. METHODS: This was a retrospective study of complete bladder diaries collected from women attending a tertiary Urogynaecology Unit. Six different definitions were identified and were divided into "absolute," "relative," and "functional definitions." Prevalence data were calculated and values generated for sensitivity, specificity, positive and negative predictive values when related to women voiding ≥ 2 times per night. RESULTS: Complete bladder diaries were obtained from 1398 women, over 6 years, with a mean age of 57 years. Prevalence varied across the definitions from 21.5% (absolute definition) to 77% (relative definition). Sensitivity ranged from 43% (absolute) to 87% (relative). The definitions that showed the highest combined sensitivity and specificity were the functional definitions. CONCLUSION: From this study it is clear that more work needs to be done to arrive at a consensus for defining NP to enable accurate diagnosis and development of treatment pathways. We propose that a relative definition may provide a more clinically relevant method of defining NP.

Refusal of surgery and survival outcomes in endometrial cancer.

OBJECTIVES: The goal of this study was to determine the impact refusal of surgery has on overall survival in patients with endometrial cancer. METHODS: From January 2004 to December 2015, the National Cancer Database was queried for patients with pathologically proven endometrial cancer who were recommended surgery and refused. Inverse probability of treatment weighting was used to account for differences in baseline characteristics between patients who underwent surgery and those who refused. Kaplan-Meier analyses and doubly robust estimation with multivariate Cox proportional hazards modeling were used to analyze overall survival. RESULTS: Of the 300 675 patients identified, 534 patients (0.2%) were recommended surgical treatment but refused: 18% (95/534) were age ≤40 years. The 5-year overall survival for all patients who refused surgery was significantly decreased compared with patients who underwent surgery (29.2% vs 71.9%, P<0.01). This was demonstrated at ages 41-64 years (65.5% vs 91.0%, P<0.01) and ≥65 years (23.4% vs 75.3%, P<0.01). The 5-year overall survival did not meet statistical significance at age ≤40 years (90.1% vs 87.8% P<0.19). However, there were few patients in this cohort. On multivariate analysis, factors associated with refusal of surgery included: Medicaid insurance, Black race, Hispanic Race, Charlson Comorbidity Index scores of 2 or greater, stage II or III, and if patient received external beam radiation therapy alone. Factors associated with undergoing surgery included: age greater than 41, stage IB, and if the patient received brachytherapy. CONCLUSIONS: Refusal of surgery for endometrial cancer is uncommon and leads to decreased overall survival.

Evaluating the effect of a post-processing algorithm in detection of annular fissure on MR imaging.

BACKGROUND AND PURPOSE: Visualization of annular fissures on MRI is becoming increasingly important but remains challenging. Our purpose was to test whether an image processing algorithm could improve detection of annular fissures. MATERIALS AND METHODS: In this retrospective study, two neuroradiologists identified 56 IVDs with annular fissures and 97 IVDs with normal annulus fibrosus in lumbar spine MRIs of 101 patients (58 M, 43 F; age ± SD 15.1 ± 3.0 years). Signal intensities of diseased and normal annulus fibrosus, and contrast-to-noise ratio between them on sagittal T2-weighted images were calculated before and after processing with a proprietary software. Effect of processing on detection of annular fissures by two masked neuroradiologists was also studied for IVDs with Pfirrmann grades of ≤ 2 and > 2. RESULTS: Mean (SD) signal baseline intensities of diseased and normal annulus fibrosus were 57.6 (23.3) and 24.4 (7.8), respectively (p < 0.001). Processing increased (p < 0.001) the mean (SD) intensity of diseased annulus to 110.6 (47.9), without affecting the signal intensity of normal annulus (p = 0.14). Mean (SD) CNR between the diseased and normal annulus increased (p < 0.001) from 11.8 (14.1) to 29.6 (29.1). Both masked readers detected more annular fissures after processing in IVDs with Pfirrmann grade of ≤ 2 and > 2, with an apparent increased sensitivity and decreased specificity using predefined image-based human categorization as a reference standard. CONCLUSIONS: Image processing improved CNR of annular fissures and detection rate of annular fissures. However, further studies with a more stringent reference standard are needed to assess its effect on sensitivity and specificity.

The Effect of Measured Radiotherapy Dose on Intrathecal Drug Delivery System Function.

OBJECTIVES: Radiation therapy (RT) and intrathecal drug delivery systems (IDDS) are often used concurrently to optimize pain management in patients with cancer. Concern remains among clinicians regarding the potential for IDDS malfunction in the setting of RT. Here we assessed the frequency of IDDS malfunction in a large cohort of patients treated with RT. MATERIALS AND METHODS: Cancer patients with IDDS and subsequent RT at our institution from 2011 to 2019 were eligible for this study. Patients were excluded in the rare event that their IDDS was managed by an outside clinic and follow-up documentation was unavailable. Eighty-eight patients aged 22-88 years old (43% female, 57% male) representing 106 separate courses of RT were retrospectively identified. Patients received varying levels of radiation for treatment of cancer and cumulative dose to the IDDS was calculated. IDDS interrogation was subsequently performed by a pain specialist. Malfunction was recorded as deviation from the expected drug volume and/or device errors reported upon interrogation as defined by the manufacturer. RESULTS: Total measured RT dose to the IDDS ranged from 0 to 18.0 Gy (median = 0.2 Gy) with median dose of 0.04 Gy/fraction (range, 0-3.2 Gy/fraction). Ten pumps received a total dose >2 Gy and three received ≥5 Gy. Eighty-two percentage of patients had follow-up with a pain specialist for IDDS interrogation and all patients underwent follow-up with a healthcare provider following RT. There were zero incidences of IDDS malfunction related to RT. No patient had clinical evidence of radiation related pump malfunction at subsequent encounters. CONCLUSIONS: We found no evidence that RT in patients with IDDS led to device failure or dysfunction. While radiation oncologists and pain specialists should coordinate patient care, it does not appear that RT dose impacts the function of the IDDS to warrant significant clinical concern.

Impact of HIV-1 viremia or sexually transmitted infection on semen-derived anti-HIV-1 antibodies and the immunosuppressive capacity of seminal plasma.

Semen from HIV-1-infected men contains anti-HIV-1 antibodies and immunosuppressive factor(s). We assessed if suppression of viremia with antiretroviral therapy impacted seminal plasma immunosuppressive capacity or the Fc-dependent functions of seminal anti-HIV-1 antibodies. We also tested if active bacterial sexually transmitted infections altered the immunosuppressive capacity of seminal plasma.

CD4- and Time-Dependent Susceptibility of HIV-1-Infected Cells to Antibody-Dependent Cellular Cytotoxicity.

HIV-1-specific antibody-dependent cellular cytotoxicity (ADCC) antibodies within HIV-1-positive (HIV-1+) individuals predominantly target CD4-induced (CD4i) epitopes on HIV-1 envelope glycoprotein (Env). These CD4i epitopes are usually concealed on the surface of infected cells due to CD4 downregulation by the HIV-1 accessory proteins Nef and Vpu. We hypothesized that early-stage infected cells in the process of downregulating CD4 could be more susceptible to ADCC than late-stage infected cells that have fully downregulated CD4. There was significantly higher binding of antibodies within plasma from HIV-1-infected individuals to early-stage infected cells expressing intermediate levels of CD4 (CD4-intermediate cells) than in late-stage infected cells expressing low levels of CD4 (CD4-low cells). However, we noted that HIV-1-uninfected bystander cells and HIV-1-infected cells, at various stages of downregulating CD4, were all susceptible to NK cell-mediated ADCC. Importantly, we observed that the cytolysis of bystander cells and early infected cells in this culture system was driven by sensitization of target cells by inoculum-derived HIV-1 Env or virions. This phenomenon provided Env to target cells prior to de novo Env expression, resulting in artifactual ADCC measurements. Future studies should take into consideration the inherent caveats of in vitro infection systems and develop improved models to address the potential role for ADCC against cells with nascent HIV-1 infection.IMPORTANCE An increasing body of evidence suggests that ADCC contributes to protection against HIV-1 acquisition and slower HIV-1 disease progression. Targeting cells early during the infection cycle would be most effective in limiting virus production and spread. We hypothesized that there could be a time-dependent susceptibility of HIV-1-infected cells to ADCC in regard to CD4 expression. We observed NK cell-mediated ADCC of HIV-1-infected cells at multiple stages of CD4 downregulation. Importantly, ADCC of early infected cells appeared to be driven by a previously unappreciated problem of soluble Env and virions from the viral inoculum sensitizing uninfected cells to ADCC prior to de novo Env expression. These results have implications for studies examining ADCC against cells with nascent HIV-1 infection.