Review of the role of the endogenous opioid and melanocortin systems in the restless legs syndrome.

Restless legs syndrome (RLS) is responsive to opioid, dopaminergic and iron-based treatments. Receptor blocker studies in RLS patients suggest that the therapeutic efficacy of opioids is specific to the opioid receptor and mediated indirectly through the dopaminergic system. An RLS autopsy study reveals decreases in endogenous opioids, ß-endorphin and perhaps Met-enkephalin in the thalamus of RLS patients. A total opioid receptor knock-out (mu, delta and kappa) and a mu-opioid receptor knock-out mouse model of RLS show circadian motor changes akin to RLS and, although both models show sensory changes, the mu-opioid receptor knock mouse shows circadian sensory changes closest to those seen in idiopathic RLS. Both models show changes in striatal dopamine, anaemia and low serum iron. However, only in the total receptor knock-out mouse do we see the decreases in serum ferritin that are normally found in RLS. There are also decreases in serum iron when wild-type mice are administered a mu-opioid receptor blocker. In addition, the mu-opioid receptor knock-out mouse also shows increases in striatal zinc paralleling similar changes in RLS. Adrenocorticotropic hormone and α-melanocyte stimulating hormone are derived from pro-opiomelanocortin as is ß-endorphin. However, they cause RLS-like symptoms and periodic limb movements when injected intraventricularly into rats. These results collectively suggest that an endogenous opioid deficiency is pathogenetic to RLS and that an altered melanocortin system may be causal to RLS as well.

Pregnancy experiences of transgender and gender-expansive individuals: A systematic scoping review from a critical midwifery perspective.

BACKGROUND: Evidence suggests that transgender and gender-expansive people are more likely to have suboptimal pregnancy outcomes compared with cisgender people. The aim of this study was to gain a deeper understanding of the role of midwifery in these inequities by analyzing the pregnancy experiences of transgender and gender-expansive people from a critical midwifery perspective. METHODS: We conducted a systematic scoping review. We included 15 papers published since 2010 that reported on pregnancy experiences of people who had experienced gestational pregnancy at least once, and were transgender, nonbinary, or had other gender-expansive identities. RESULTS: Three themes emerged from our analysis: "Navigating identity during pregnancy," "Experiences with mental health and wellbeing," and "Encounters in the maternal and newborn care system." Although across studies respondents reported positive experiences, both within healthcare and social settings, access to gender-affirmative (midwifery) care and daily social realities were often shaped by trans-negativity and transphobia. DISCUSSION: To improve care outcomes of transgender and gender-expansive people, it is necessary to counter anti-trans ideologies by "fixing the knowledge" of midwifery curricula. This requires challenging dominant cultural norms and images around pregnancy, reconsidering the way in which the relationship among "sex," "gender," and "pregnancy" is understood and given meaning to in midwifery, and applying an intersectional lens to investigate the relationship between gender inequality and reproductive inequity of people with multiple, intersecting marginalized identities who may experience the accumulated impacts of racism, ageism, and classism. Future research should identify pedagogical frameworks that are suitable for guiding implementation efforts.

Impact of Biannual Mass Azithromycin Treatment on Enteropathogen Carriage in Children <5 Years Old in Niger.

We analyzed samples obtained at baseline and 24 months in a mass azithromycin administration trial in Niger using quantitative polymerase chain reaction. In villages randomized to azithromycin, Shigella was the only pathogen reduced at 24 months (prevalence ratio, 0.36 [95% confidence interval: .17-.79]; difference in log quantity, -.42 [-.75 to -.10]).

Evaluation of Adult Neurology Residency Program Websites.

OBJECTIVE: Neurology residency program websites often serve as the initial face of a program for prospective residents early in the application process. We evaluated adult neurology residency program websites to determine their comprehensiveness to identify areas for improvement. METHODS: A list of adult neurology residency programs in the United States was compiled using information on the Electronic Residency Application Service (ERAS) and Fellowship and Residency Electronic Interactive Database (FREIDA) websites. A total of 24 website criteria covering educational, recruitment, and compensation content were assessed for comprehensiveness. Programs' website comprehensiveness was compared based on geographic location, program affiliation (community and/or academic), program size, and program/hospital Doximity and U.S. News & World Report rankings. RESULTS: A total of 153 US adult neurology residency program websites were evaluated. Fewer than one-half of program websites were accessible with a direct link from either FREIDA or ERAS. The number of residency program websites reporting each content criterion varied greatly. Mean percentage of overall website comprehensiveness among neurology residency programs was 65.9%. Northeast location, academic affiliation, larger programs, and top-ranked programs on Doximity were associated with greater program website comprehensiveness. INTERPRETATION: There is opportunity for all neurology residency programs to improve their websites to provide prospective applicants with a more informed and comprehensive perspective of programs during the application process. ANN NEUROL 2021;89:637-642.

Long-term survive of Aliarcobacter butzleri in two models symbiotic interaction with Acanthamoeba castellanii.

Aliarcobacter butzleri (formerly known as Arcobacter butzleri) is an emerging food-borne zoonotic pathogen that establishes in vitro endosymbiotic relationships with Acanthamoeba castellanii, a free-living amoeba. Previously, we described that this bacterium acts as an endocytobiont of A. castellanii, surviving for at least 10 days in absence of bacterial replication. Thus, the aim of this study was to evaluate the ability of A. butzleri to survive as a long-term endosymbiont of A. castellanii for 30 days in two models of symbiotic interaction with A. castellanii: (i) endosymbiotic culture followed by gentamicin protection assay and (ii) transwell co-culture assay. The results allow us to conclude that A. butzleri is capable of surviving as an endosymbiont of A. castellanii for at least 30 days, without multiplying, under controlled laboratory conditions. In addition, in the absence of nutrients and as both microorganisms remain in the same culture, separated by semi-permeable membranes, A. castellanii does not promote the survival of A. butzleri, nor does it multiply. Our findings suggest that the greater survival capacity of A. butzleri is associated with their endosymbiont status inside A. castellanii, pointing out the complexity of this type of symbiotic relationship.

Clinically Significant Prostate Cancer Detection After a Negative Prebiopsy MRI Examination: Comparison of Biparametric Versus Multiparametric MRI.

BACKGROUND. The frequency of clinically significant prostate cancer (csPCa) following negative biparametric MRI (bpMRI) and multiparametric MRI (mpMRI) has not been well investigated in direct comparative studies. OBJECTIVE. The purposes of this study were to compare the frequency of csPCa after negative prebiopsy bpMRI and mpMRI and to evaluate factors predictive of csPCa in the two cohorts. METHODS. This retrospective study included 232 men (mean age, 64.5 years) with negative bpMRI from August 2017 to March 2020 and 193 men (mean age, 69.0 years) with negative mpMRI from January 2018 to December 2018. PI-RADS category 1 or 2 was defined as negative. The study institution offered bpMRI as a low-cost self-pay option for patients without insurer coverage of prebiospy mpMRI. Patient characteristics and subsequent biopsy results were recorded. CsPCa was defined as Gleason score of 3 + 4 or greater. Multivariable regression analyses were performed to identify independent predictors of csPCa. The AUC of PSA density (PSAD) for csPCA was computed, and the diagnostic performance of PSAD was assessed at a clinically established threshold of 0.15 ng/mL2. RESULTS. Systematic biopsy was performed after negative bpMRI for 41.4% (96/232) of patients and after negative mpMRI for 30.5% (59/193) (p = .02). Among those undergoing biopsy, csPCa was present in 15.6% (15/96) in the bpMRI cohort versus 13.6% (8/59) in the mpMRI cohort (p = .69). The NPV for csPCa was 84% (81/96) for bpMRI and 86% (51/59) for mpMRI. In multivariable analyses, independent predictors of csPCa included smaller prostate volume (OR, 0.27; p < .001) and greater PSAD (OR, 3.09; p < .001). In multivariable models, bpMRI (compared with mpMRI) was not independently predictive of csPCa (p > .05). PSAD had an AUC for csPCa of 0.71 (95% CI, 0.56-0.87) in the bpMRI cohort versus 0.68 (95% CI, 0.42-0.93) in the mpMRI cohort. For detecting csPCa, a PSAD threshold of 0.15 ng/mL2 had NPV of 90% and PPV of 28%, in the bpMRI cohort versus NPV of 92% and PPV of 44% in the mpMRI cohort. CONCLUSION. The frequencies of csPCa were not significantly different at systematic biopsy performed after negative bpMRI and mpMRI examinations. PSAD had similar diagnostic utility for csPCa in the two cohorts. CLINICAL IMPACT. Either bpMRI or mpMRI, in combination with PSAD measurement, can help avoid negative prostate biopsies.

A Decade of Success in Melanoma Immunotherapy and Targeted Therapy: What Every Radiologist Should Know.

ABSTRACT: Treatment strategies for malignant melanoma have rapidly evolved over the past decade. Because of its propensity to develop advanced stage and metastatic disease, melanoma has contributed to the majority of mortalities among patients with skin cancer. The development of novel therapeutics such as immunotherapy and targeted molecular therapies has revolutionized the treatment of patients with advanced stage and metastatic malignant melanoma. Immune checkpoint inhibitors, BRAF/MEK inhibitors, and other revolutionary therapies have demonstrated remarkable success in the treatment of this common malignancy. Along with these advancements in systemic therapies, imaging has continued to play a critical role in the diagnosis and follow-up of patients with malignant melanoma. As the use of these novel therapies continues to expand, knowledge of the evolving therapeutic landscape of melanoma is becoming critical for radiologists. In this review, we provide a primer for radiologists outlining the evolution of immunotherapy and targeted therapy in the treatment of melanoma. We discuss the critical role of imaging in evaluation of treatment response, including a summary of current imaging response guidelines. Last, we summarize the essential role of imaging in the evaluation of potential adverse events seen in patients with malignant melanoma undergoing treatment with immune checkpoint inhibitors.

Seed management using NGS technology to rapidly eliminate a deleterious allele from rice breeder seeds.

Spontaneous mutations are stochastic phenomena that occur in every population. However, deleterious mutated allele present in seeds distributed to farmers must be detected and removed. Here, we eliminated undesirable mutations from the parent population in one generation through a strategy based on next-generation sequencing (NGS). This study dealt with a spontaneous albino mutant in the 'Hinohikari' rice variety grown at the Miyazaki Comprehensive Agricultural Experiment Station, Japan. The incidence of albinism in the population was 1.36%. NGS analysis revealed the genomic basis for differences between green and albino phenotypes. Every albino plant had a C insertion in the Snow-White Leaf1 (SWL1) gene on chromosome 4 causing a frameshift mutation. Selfing plants heterozygous for the mutant allele, swl1-R332P, resulted in a 3:1 green/albino ratio, confirming that a single recessive gene controls albinism. Ultrastructural leaf features in the swl1-R332P mutants displayed deformed chlorophyll-associated organelles in albino plants that were similar to those of previously described swl1 mutants. Detection of the causative gene and its confirmation using heterozygous progenies were completed within a year. The NGS technique outlined here facilitates rapid identification of spontaneous mutations that can occur in breeder seeds.

Role of Key Guidelines in an Era of Precision Oncology: A Primer for the Radiologist.

OBJECTIVE. The purpose of this article is to familiarize radiologists with the evidence-based imaging guidelines of major oncologic societies and organizations and to discuss approaches to effective implementation of the most recent guidelines in daily radiology practice. CONCLUSION. In an era of precision oncology, radiologists in practice and radiologists in training are key stakeholders in multidisciplinary care, and their awareness and understanding of society guidelines is critically important.

Past, Present, and Future of Serum Tumor Markers in Management of Ovarian Cancer: A Guide for the Radiologist.

The ability to accurately detect early ovarian cancer and subsequently monitor treatment response is essential to improving survival for patients with ovarian malignancies. Several serum tumor markers (STMs)-including cancer antigen 125 (CA-125), human epididymis protein 4 (HE4), cancer antigen 19-9 (CA 19-9), and carcinoembryonic antigen (CEA)-have been used as a noninvasive method of identifying ovarian cancer in conjunction with imaging. Although current guidelines do not recommend use of STMs as screening tools for ovarian cancer, these markers have clinical utility in both diagnosis and surveillance for women with ovarian cancer. CA-125 is the most commonly used STM; its level may be elevated in several types of ovarian cancer, including epithelial cell tumors, carcinosarcoma, teratomas, and secondary ovarian malignancies. An elevated level of CA 19-9 is associated with clear cell tumors, teratomas, and secondary malignancies. CEA is most commonly associated with mucinous ovarian cancers. Finally, HE4 is being increasingly used to identify certain subtypes of epithelial ovarian cancers, particularly serous and endometrioid tumors. Diagnosis of ovarian cancers relies on a combination of CA-125 levels and US findings, which include a large adnexal mass or high-risk features, including septa and increased vascularity. CT is preferred for staging and is used along with PET and STM monitoring for surveillance. Increasingly, MRI is being used to characterize ovarian lesions that are indeterminate at US or CT. The future of STM testing involves development of "liquid biopsies," in which plasma samples are analyzed for evidence of tumors, including circulating tumor DNA or tumor cells and tumor micro-RNA. When combined with traditional imaging techniques, liquid biopsies may lead to earlier diagnosis and improved survival. An invited commentary by Shinagare is available online. ©RSNA, 2021.

RBM5, 6, and 10 differentially regulate NUMB alternative splicing to control cancer cell proliferation.

RBM5, a regulator of alternative splicing of apoptotic genes, and its highly homologous RBM6 and RBM10 are RNA-binding proteins frequently deleted or mutated in lung cancer. We report that RBM5/6 and RBM10 antagonistically regulate the proliferative capacity of cancer cells and display distinct positional effects in alternative splicing regulation. We identify the Notch pathway regulator NUMB as a key target of these factors in the control of cell proliferation. NUMB alternative splicing, which is frequently altered in lung cancer, can regulate colony and xenograft tumor formation, and its modulation recapitulates or antagonizes the effects of RBM5, 6, and 10 in cell colony formation. RBM10 mutations identified in lung cancer cells disrupt NUMB splicing regulation to promote cell growth. Our results reveal a key genetic circuit in the control of cancer cell proliferation.

Considerations in imaging interpretations for colitis in critically ill patients during the COVID-19 era.

OBJECTIVE: The study aims to demonstrate risk factors for colitis in intensive care unit patients with and without coronavirus disease 2019 (COVID-19). METHODS: Retrospective review was performed to identify intensive care unit (ICU) patients with the diagnosis of COVID-19 with computed tomography (CT) between March 20 and December 31, 2020. ICU patients without COVID-19 diagnosis with CT between March 20 and May 10, 2020 were also identified. CT image findings of colitis or terminal ileitis as well as supportive treatment including ventilator, vasopressors, or extracorporeal membrane oxygenation (ECMO) were recorded. Statistical analysis was performed to determine if clinical factors differed in patients with and without positive CT finding. RESULTS: Total 61 ICU patients were selected, including 32 (52%) COVID-19-positive patients and 29 (48%) non-COVID-19 patients. CT findings of colitis or terminal ileitis were identified in 27 patients (44%). Seventy-four percent of the patients with positive CT findings (20/27) received supportive therapies prior to CT, while 56% of the patients without abnormal CT findings (19/34) received supportive therapies. Vasopressor treatment was significantly associated with development of colitis and/or terminal ileitis (p = 0.04) and COVID-19 status was not significantly different between these groups (p = 0.07). CONCLUSIONS: In our study, there was significant correlation between prior vasopressor therapy and imaging findings of colitis or terminal ileitis in ICU patients, independent of COVID-19 status. Our observation raises a possibility that the reported COVID-19-related severe gastrointestinal complications and potential poor outcome could have been confounded by underlying severe critically ill status, and warrants a caution in diagnosis of gastrointestinal complication.

Diagnostic utility of computed tomography in patients presenting to the emergency department with unintended weight loss.

PURPOSE: Unintended weight loss (UWL) is a common presenting symptom in the emergency department (ED) with several etiologies. Our study looks to evaluate the diagnostic utility of computed tomography (CT) in the evaluation of UWL in the ED. METHODS: We identified all patients who underwent CT of the chest, abdomen, or pelvis in the ED at our institution for the diagnosis of UWL from 2004 to 2020 and retrospectively reviewed their clinical history and imaging. CT findings were organized into 4 types: (1) definite cause for UWL identified, (2) possible findings for UWL, (3) incidental findings unrelated to UWL, and (4) normal scan. Associations between clinical and laboratory findings with positive CT scans were also examined. RESULTS: One hundred seventy-three eligible patients were identified; 40 patients were excluded due to history of malignancy or inadequate follow-up. One hundred thirty-three patients were included in the final cohort. Overall, the most common causes of UWL were non-malignant gastrointestinal (GI) conditions (n = 41, 30%) and cancer (n = 30, 23%). True-positive CT findings were identified in 48.8% of patients (65/133). Elevated white blood cell counts (p = <0.0001) and physical exam abnormalities (p = 0.02) were both significantly associated with CT abnormalities. CONCLUSION: The use of CT scanning in the evaluation of UWL in the ED yielded a diagnosis in approximately half of all cases, indicating good diagnostic value. The most common causes of UWL were non-malignant GI conditions and cancer in this cohort.

Utility of Iodine Density Perfusion Maps From Dual-Energy Spectral Detector CT in Evaluating Cardiothoracic Conditions: A Primer for the Radiologist.

OBJECTIVE. The purpose of this article is to outline the utility of iodine density maps for evaluating cardiothoracic disease and abnormalities. Multiple studies have shown that the variety of images generated from dual-energy spectral detector CT (SDCT) improve identification of cardiothoracic conditions. CONCLUSION. Understanding the technique of SDCT and being familiar with the features of different cardiothoracic conditions on iodine density map images help the radiologist make a better diagnosis.

Multimodality approach to the diagnosis and management of constrictive pericarditis.

Despite advances in cardiovascular imaging, the diagnosis of constrictive pericarditis remains challenging. A multimodality approach to the diagnosis of CP is essential to (a) fully assess the extent of pericardial thickening and calcification, (b) detect the functional and hemodynamic consequences of the constricting pericardium, and (c) implement the optimal management strategy in these often complex cases. This case-based review highlights the role and diagnostic ambiguities of multimodality imaging.

Quantifying the decrease in emergency department imaging utilization during the COVID-19 pandemic at a multicenter healthcare system in Ohio.

PURPOSE: To illustrate the change in emergency department (ED) imaging utilization at a multicenter health system in the state of Ohio during the COVID-19 pandemic. METHODS: A retrospective observational study was conducted assessing ED imaging volumes between March 1, 2020, and May 11, 2020, during the COVID-19 crisis. A rolling 7-day total value was used for volume tracking and comparison. Total imaging utilization in the ED was compared with new COVID-19 cases in our region. Utilization was first categorized by modality and then by plain films and computed tomography (CT) scans grouped by body part. CT imaging of the chest was specifically investigated by assessing both CT chest only exams and CT chest, abdomen, and pelvis (C/A/P) exams. Ultimately, matching pair-wise statistical analysis of exam volumes was performed to assess significance of volume change. RESULTS: Our multicenter health system experienced a 46% drop in imaging utilization (p < 0.0001) during the pandemic. Matching pair-wise analysis showed a statistically significant volume decrease by each modality and body part. The exceptions were non-contrast chest CT, which increased (p = 0.0053), and non-trauma C/A/P CT, which did not show a statistically significant volume change (p = 0.0633). CONCLUSION: ED imaging utilization trends revealed through actual health system data will help inform evidence-based decisions for more accurate volume predictions and therefore institutional preparedness for current and future pandemics.

Altered CD4+ T cell immunity in nurses occupationally exposed to viral pathogens.

Pathogen exposure, including but not limited to herpesviruses, moulds the shape of the immune system, both at a basal state and in response to immune challenge. However, little is known about the impact of high exposure to other viruses on baseline immune signatures and how the immune system copes with repetitive exposures to maintain a balanced functionality. Here we investigated baseline immune signatures, including detailed T cell phenotyping, antigen-specific CD4+ and CD8+ T cell responses and cytokine profile in paediatric (PED) nurses, who have high occupational exposure to viral pathogens including varicella zoster virus (VZV) and respiratory viruses, and in neonatal intensive care unit (NICU) nurses, as a control group with infrequent occupational exposure. Our results show a lower CD4+ T cell response to two VZV proteins (IE62 and gE) and to tetanus toxoid (TT) in PED nurses who are cytomegalovirus (CMV)-seronegative, compared to CMV-seronegative NICU nurses, and that the decline might be more pronounced the more sustained the exposure. This decline might be due to an attrition of VZV- and TT-specific T cells as a result of the continuous pressure on the CD4+ T cell compartment. Moreover, our data suggest that the distinct T cell phenotypes known to be associated with CMV-seropositivity might be less prominent in PED nurses compared to NICU nurses, implying a plausible attenuating effect of occupational exposure on CMV-associated immunosenescence. Overall, this pilot study reveals an impact of occupational exposure to viral pathogens on CD4+ T cell immunity and supports further investigation in a larger cohort.

A Randomized Comparative Study Evaluating Various Cough Stress Tests and 24-Hour Pad Test with Urodynamics in the Diagnosis of Stress Urinary Incontinence.

PURPOSE: The cough stress test is a common and accepted tool to evaluate stress urinary incontinence but there is no agreement on how the test should be performed. We assessed the diagnostic ability of different cough stress tests performed when varying patient position and bladder volume using urodynamic stress urinary incontinence as the gold standard. The 24-hour pad test was also evaluated. MATERIALS AND METHODS: We recruited women who presented to specialty outpatient clinics with the complaint of urinary incontinence and who were recommended to undergo urodynamic testing. A total of 140 patients were randomized to 4 cough stress test groups, including group 1-a comfortably full bladder, group 2-an empty bladder, group 3- a bladder infused with 200 cc saline and group 4-a bladder filled to half functional capacity. The sequence of standing and sitting was randomly assigned. The groups were compared by 1-way ANOVA or the generalized Fisher exact test. The κ statistic was used to evaluate agreement between the sitting and standing positions. The 95% CIs of sensitivity and specificity were calculated using the Wilson method. ROC analysis was done to evaluate the performance of the 24-hour pad test. RESULTS: The cough stress test performed with a bladder filled to half functional capacity was the best performing test with 83% sensitivity and 90% specificity. There was no statistically significant evidence that the sensitivity or specificity of 1 cough stress test differed from that of the others. The pad test had no significant predictive ability to diagnose urodynamic stress urinary incontinence (AUC 0.60, p = 0.08). CONCLUSIONS: Cough stress tests were accurate to diagnose urodynamic stress urinary incontinence. The 24-hour pad test was not predictive of urodynamic stress urinary incontinence and not helpful when used in conjunction with the cough stress test.

Method Used for Tumor Bed Closure (Suture vs. Sealant), Ischemia Time and Duration of Surgery are Independent Predictors of Post-Nephron Sparing Surgery Acute Kidney Injury.

INTRODUCTION: The aim of our study was to examine the influence of tumor complexity and operative variables on the degree and rate of post-nephron sparing surgery (NSS) acute kidney injury (AKI). METHODS: We retrospectively reviewed the records of 477 patients who underwent NSS for enhancing renal masses in our institution. AKI was determined using the latest definition by AKIN and RIFLE criteria. Serum creatinine was assessed daily starting from day 1 post-surgery and until discharge (usually on postoperative day 3). Estimated glomerular filtration was determined using the Modification of Diet in Renal Disease equation. RESULTS: Overall, 191 patients (40%) developed postoperative AKI, and most of them (88%) were grade 1. Multivariate analysis revealed that the most significant and independent variables associated with AKI were operation time (p = 0.02), ischemia time (p = 0.02), and the use of tissue adhesive for tumor bed closure (p = 0.02). Other important factors (by univariate analysis) were the need for blood transfusion (p = 0.003) and estimated blood loss (p = 0.007). CONCLUSIONS: Operative time, ischemia, and tumor bed closure method are independent predictors of post-NSS AKI. Efforts should be made to limit prolonged ischemia and to reduce viable parenchymal loss. Further studies concerning the functional impact of AKI in these patients will be required.