Differential Evaluation of Straight and Gay Men for Nonverbal Effeminate Behavior.

The purpose of this study was to determine how violation of gender-based expectancies might influence straight men's attitudes toward men who differ by sexual orientation (i.e., straight or gay). This study was specifically designed to avoid methodological issues that may have been present in similar research. Hypotheses were informed by Expectancy-Violation Theory (EVT) and the Black Sheep Effect (BSE), which together suggest that an effeminate straight man should be evaluated by other straight men more negatively than an effeminate gay man because the former target negatively violated expectations. Additionally, EVT suggests that a masculine gay man should be evaluated more positively than a masculine straight man because the former positively violates expectations, while the BSE instead suggests the latter should be evaluated more positively than the former due to ingroup bias. Self-identified straight men evaluated a male target whose sexual orientation and gender conformity were manipulated through a photo and vignette. A moderated mediation analysis was performed to determine if perceived expectancy violation mediated the relationship between sexual orientation and evaluations for both effeminate and masculine men. Straight effeminate targets were evaluated more negatively than gay effeminate targets; however, straight masculine targets were evaluated more favorably than gay masculine targets, a finding more consistent with the BSE. In addition, perceived expectancy violation did not mediate the relationship between sexual orientation and evaluations regardless of gender expression. More research should be conducted to identify the mechanisms through which evaluations of straight and gay targets differ based on gender expression.

Association of the Revised Trauma Score with Mortality and Prehospital LSI Among Trauma and Non-Trauma Patients.

OBJECTIVES: The combination of broad conditional applicability and ease of data collection make some general risk scores an attractive tool for clinical decision making under acute care conditions. To date, general risk scores have demonstrated moderate levels of accuracy for key outcomes, but there are no definitive general scores integrated universally into prehospital care. The objective of our study was to demonstrate a relationship between the revised trauma score (RTS) and prehospital lifesaving interventions (LSI) and downstream hospital mortality among a large, diverse, multi-year cohort of critical care transport patients. We hypothesized that the RTS is associated with mortality and prehospital LSI generally across all conditions, including non-trauma. METHODS: We conducted a retrospective observational study using a pre-established cohort of sequentially enrolled patients from a regional air medical service between the years 2012 and 2021. Pediatric patients, non-transports, and those transported to hospitals outside the regional health system were excluded from the study. Both trauma and non-trauma patients were included in this study. We performed logistic regressions to evaluate the association between RTS and the outcomes of LSI and hospital mortality, while controlling for age, sex, and medical category. Graphs were constructed to plot RTS against prehospital LSI and survival percentage. RESULTS: Our final patient cohort was 62,424 patients. 58.4% of all patients required a prehospital LSI. Non-trauma cases made up 69.7% of the patient population. The Revised Trauma Score was inversely proportional with both prehospital LSI and mortality. The logistic regression model yielded an odds ratio (OR) of 0.55 (95% CI 0.54 - 0.56) for the association between RTS and death. Additionally, when the components of RTS were associated with mortality, they each showed a statistically significant OR. The Revised Trauma Score was also associated with prehospital LSI (OR 0.10; 95% CI 0.03 - 0.33). CONCLUSIONS: In a large helicopter EMS cohort of both trauma and non-trauma patients, the RTS was inversely associated with prehospital LSI and hospital mortality. The generalized utility of RTS demonstrated in our study warrants further investigation of this measure as a broader triage tool.

Severity-Driven Trends in Mortality in a Large Regionalized Critical Care Transport Service.

OBJECTIVE: The epidemiology accompanying helicopter emergency medical services (HEMS) transport has evolved as agencies have matured and become integrated into regionalized health systems, as evidenced primarily by nationwide systems in Europe. System-level congruence between Europe and the United States, where HEMS is geographically fragmentary, is unclear. In this study, we provide a temporal, epidemiologic characterization of the largest standardized private, nonprofit HEMS system in the United States, STAT MedEvac. METHODS: We obtained comprehensive timing, procedure, and vital signs data from STAT MedEvac prehospital electronic patient care records for all adult patients transported to UPMC Health System hospitals in the period of January 2012 through October 2021. We linked these data with hospital electronic health records available through June 2018 to establish length of stay and vital status at discharge. RESULTS: We studied 90,960 transports and matched 62.8% (n = 57,128) to the electronic health record. The average patient age was 58.6 years ( 19 years), and most were male (57.9%). The majority of cases were interfacility transports (77.6%), and the most common general medical category was nontrauma (72.7%). Sixty-one percent of all patients received a prehospital intervention. Overall, hospital mortality was 15%, and the average hospital length of stay (LOS) was 8.8 days ( 10.0 days). Observed trends over time included increases in nontrauma transports, level of severity, and in-hospital mortality. In multivariable models, case severity and medical category correlated with the outcomes of mortality and LOS. CONCLUSION: In the largest standardized nonprofit HEMS system in the United States, patient mortality and hospital LOS increased over time, whereas the proportion of trauma patients and scene runs decreased.

Glucose-Induced Activation of mTORC1 is Associated with Hexokinase2 Binding to Sestrins in HEK293T Cells.

BACKGROUND: Sestrins (SESN1-3) act as proximal sensors in leucine-induced activation of the protein kinase mechanistic target of rapamycin (mTOR) in complex 1 (mTORC1), a key regulator of cell growth and metabolism. OBJECTIVE: In the present study, the hypothesis that SESNs also mediate glucose-induced activation of mTORC1 was tested. METHODS: Rats underwent overnight fasting, and in the morning, either saline or a glucose solution (4 g⋅kg-1 BW/10 mL⋅kg-1) was administered by oral gavage; mTORC1 activation in the tibialis anterior muscle was assessed. To further assess the mechanism through which glucose promotes mTORC1 activation, wild-type (WT) HEK293T and HEK293T cells lacking either all 3 SESNs (SESNTKO) or hexokinase 2 (HK2KO) were deprived of glucose, followed by glucose addback, and mTORC1 activation was assessed. In addition, glucose-induced changes in the association of the SESNs with components of the GAP activity toward the Rags (GATOR2) complex and with hexokinase 2 (HK2) were assessed by co-immunoprecipitation. One- and two-way ANOVA with Tukey post hoc comparisons were used. RESULTS: Glucose administration to fasted rats promoted mTORC1 activation. Similarly, glucose readdition (GluAB) to the medium of glucose-deprived WT cells also promoted mTORC1 activation. By contrast, SESNTKO cells demonstrated attenuated mTORC1 activation following GluAB compared with WT cells. Interestingly, HK2 associated with all 3 SESNs in a glucose-dependent manner, i.e., HK2 abundance in SESN immunoprecipitates was high in cells deprived of glucose and decreased in response to GluAB. Moreover, similar to SESNTKO cells, the sensitivity of mTORC1 to GluAB was attenuated in HK2KO cells compared with WT cells. CONCLUSIONS: The results of this study demonstrate that the SESNs and HK2 play important roles in glucose-induced mTORC1 activation in HEK293T cells. However, unlike leucine-induced mTORC1 activation, the effect was independent of the changes in SESN-GATOR2 interaction, and instead, it was associated with alterations in the association of SESNs with HK2.

Evaluation and management of pericarditis in rheumatic diseases.

ABSTRACT: This review summarizes the evaluation for underlying rheumatic conditions in patients presenting with acute pericarditis, treatment considerations for specific rheumatic conditions, and the role of imaging in diagnosis and monitoring. Pericarditis may be one of the initial presentations of a rheumatic disease or identified in a patient with known rheumatic disease. There is also growing evidence for using anti-inflammatory and immunosuppressive agents for treating recurrent pericarditis, which can overlap with the treatment of rheumatic diseases.

Weight-bearing Guidelines for Common Geriatric Upper and Lower Extremity Fractures.

PURPOSE OF REVIEW: The purpose of this review paper is to summarize current weight-bearing guidelines for common geriatric fractures, around weight-bearing joints, of the upper and lower extremities. RECENT FINDINGS: There is an increasing amount of literature investigating the safety and efficacy of early weight-bearing in geriatric fractures, particularly of the lower extremity. Many recent studies, although limited, suggest that early weight-bearing may be safe for geriatric distal femur and ankle fractures. Given the limited data pertaining to early weight-bearing in geriatric fractures, it is difficult to establish concrete weight-bearing guidelines in this population. However, in the literature available, early weight-bearing appears to be safe and effective across most injuries. The degree and time to weight-bearing vary significantly based on fracture type and treatment method. Future studies investigating postoperative weight-bearing protocols should focus on the growing geriatric population and identify methods to address specific barriers to early weight-bearing in these patients such as cognitive impairment, dependence on caregivers, and variations in post-acute disposition.

Effect of Short versus Long Duration Naps on Blood Pressure during Simulated Night Shift Work: A Randomized Crossover Trial.

OBJECTIVE: Blunting of the sleep-related dip in blood pressure (BP) has been linked to numerous cardiovascular outcomes including myocardial infarction. Blunting of BP dipping occurs during night shift work and previous research suggest that a 60-min or longer on-shift nap is needed to restore normal/healthy BP dipping. We sought to determine the effect of different durations of napping on BP during and following simulated night shifts. We hypothesized that the greatest benefit in terms of restoration of normal BP dipping during night shift work would be observed during a longer duration nap versus a shorter nap opportunity. METHODS: We used a randomized crossover laboratory-based study design. Participants consented to complete three separate 72-hr conditions that included a 12-hr simulated night shift. Nap conditions included a 30-min and 2-hr nap compared to a no-nap condition. Ambulatory BP monitoring was assessed hourly and every 10-30 mins during in-lab naps. Blunted BP dipping during in-lab naps was the primary outcome. Goal enrollment of 25 (35 with attrition) provided 80% power to detect a mean difference of 5 mmHg in BP between nap conditions. RESULTS: Of the 58 screened, 28 were consented, and 26 completed all three 72-hr conditions. More than half (53.6%) were female. Mean age was 24.4 years (SD7.2). Most (85.7%) were certified as emergency medical technicians or paramedics. The mean percentage dip in systolic BP (SBP) and diastolic BP (DBP) did not differ between the 30-min and 2-hr nap conditions (p > 0.05), yet a greater proportion of participants experienced a 10-20% dip in SBP or DBP during the 2-hr nap versus the 30-min nap (p < 0.05). For every additional minute of total sleep during the 30-min nap, the percentage of SBP dip improved by 0.60%, and the percentage of DBP dip improved by 0.68% (p < 0.05). These improvements approximate to a 6% per minute relative advancement toward normal/healthy BP dipping. CONCLUSIONS: Restoration of a normal/healthy dip in BP is achievable during short and long duration nap opportunities during simulated night shift work. Our findings support the hypothesis that BP dipping is more common during longer 2-hr versus shorter 30-min naps. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04469803. Registered on 9 July 2020.

Are Short Duration Naps Better than Long Duration Naps for Mitigating Sleep Inertia? Brief Report of a Randomized Crossover Trial of Simulated Night Shift Work.

OBJECTIVE: We sought to test the effects of different duration naps on post-nap cognitive performance during simulated night shifts. METHODS: We used a randomized laboratory-based crossover trial design with simulated 12-hr night shifts and each participant completing three conditions of 72 hrs each (Clinicaltrials.gov; registration # NCT04469803). The three conditions tested included no-nap, a 30-min nap opportunity, and a 2-hr nap opportunity. Naps occurred at 02:00 hrs. Cognitive performance was assessed with the Brief 3-min Psychomotor Vigilance Test (PVT-B). Four PVT-B measures include: reaction time (RT in milliseconds (ms)), lapses (RT > 355 ms), false starts (reactions before stimulus or RT <100 ms), and speed (1,000/RT). The PVT-B was performed at the start of the simulated night shift (19:00), end of shift (07:00), pre-nap (02:00), and at 0 mins, 10 mins, 20 mins, and 30 mins following the 30-min and 2-hr nap conditions. Simultaneously, participants reported subjective ratings of fatigue and other constructs. RESULTS: Twenty-eight (15 female), mostly certified emergency medical technicians or paramedics, consented to participate. For all three conditions, looking within condition, PVT-B lapse performance at the end of the 12-hr simulated night shift (at 07:00) was poorer compared to shift start (p < 0.05). Performance on PVT-B speed, RT, and false starts were poorer at shift end than shift start for the no-nap and 30-min nap conditions (p < 0.05), but not for the 2-hr nap condition (p > 0.05). Compared to pre-nap measures, performance on the PVT-B assessed at 0 mins post-nap showed significant performance declines for lapses and speed for both the 30-min and 2-hr nap conditions (p < 0.05), but not at 10, 20, or 30 mins post-nap. After waking from the 2-hr on-shift nap opportunity (at 0 mins), participants rated sleepiness, difficulty with concentration, and alertness poorer than pre-nap (p < 0.05). Participants in the 30-min nap condition rated alertness poorer immediately after the nap (at 0 mins) compared to pre-nap (p < 0.05). CONCLUSIONS: While sleep inertia was detectable immediately following short 30-min and long 2-hr nap opportunities during simulated night shift work, deficits in cognitive performance and subjective ratings quickly dissipated and were not detectable at 10-30 mins post-nap.

Convergence of signaling pathways in mediating actions of leucine and IGF-1 on mTORC1 in L6 myoblasts.

Leucine and insulin-like growth factor-1 (IGF-1) are important regulators of protein synthesis in skeletal muscle. The mechanistic target of rapamycin complex 1 (mTORC1) is of particular importance in their mechanism of action. In the present study, pathways through which leucine and IGF-1 converge to mediate activation of mTORC1 were examined in L6 myoblasts that were deprived of leucine and serum followed by readdition of either leucine or IGF-1. Compared with leucine- and serum-deprived myoblasts, IGF-1, but not leucine, promoted phosphorylation of protein kinase B (AKT), tuberous sclerosis complex 2 (TSC2), and the autophosphorylation site on mTOR (S2481) and also stimulated mTOR kinase activity in mTOR immunoprecipitated samples. Both leucine and IGF-1 promoted phosphorylation of mTOR on S2448. The association of mTOR with the regulatory-associated protein of mTOR (Raptor) was altered by IGF-1 treatment and trended (P = 0.065) to be altered by leucine treatment. Alterations in the association of mTOR with Raptor were proportional to changes in phosphorylation of the mTOR substrates, eIF4E-binding protein 1 (4E-BP1), and ribosomal protein S6 Kinase-ß1 (p70S6K1). Surprisingly, leucine, but not IGF-1, stimulated protein synthesis suggesting a unique role for nutrients in regulating protein synthesis. Overall, the results are consistent with a model whereby IGF-1 stimulates phosphorylation of 4E-BP1 and p70S6K1 in L6 myoblasts through an AKT-TSC2-mTORC1 signaling pathway that also involves changes in the interaction between mTOR and Raptor. In contrast, leucine signaling to mTOR results in alterations in certain mTOR phosphorylation sites and the interaction between mTOR and Raptor and stimulates protein synthesis.

Imaging Prostate Cancer: Clinical Utility of Prostate-Specific Membrane Antigen.

PURPOSE: Our goal was to review the pathway and pertinent materials leading to approval of prostate-specific membrane antigen (PSMA) scanning by the U.S. Food and Drug Administration (FDA). MATERIALS AND METHODS: Beginning with the pivotal trials and working backward, we summarize the evolution of PSMA scanning, beginning with the discovery of the molecule, the mechanism of action to identify prostate cancer, the route to the present-day test and some of the major publications leading to each step of the sequence. From the thousands of PSMA articles listed on PubMed®, the present review is focused on the 4 large U.S. trials incorporating university studies of the gallium-68 compound and commercial studies of the fluorine-18 compound. The review further focuses on the role of PSMA scanning for both initial staging of prostate cancer and diagnosis of recurrent prostate cancer. RESULTS: PSMA is a transmembrane-bound glycoprotein which is overexpressed by 100-1,000-fold in prostate cancer cells. Preclinical PSMA studies at Cornell and Johns Hopkins in the 1990s were followed by early human studies in Germany in the early 2010s, then pivotal clinical trials at University of California, Los Angeles and University of California, San Francisco, leading to the first FDA approval in December 2020 (68Ga-PSMA-11). In January 2021, a commercially available product (18F-DCFPyL) was approved on the basis of multisite registration trials (CONDOR and OSPREY). Sensitivity and specificity of PSMA scanning exceeds that of any other imaging method currently available for initial staging of prostate cancer and diagnosis of recurrent disease. The accuracy of PSMA scanning is attributed to the great image contrast (high signal-to-noise ratio), a property deriving from the high PSMA tracer uptake by prostate cancer cells. That property can be estimated quantitatively by a metric, the standardized uptake value. A follow-on PSMA compound, the theranostic lutetium-177, is currently pending FDA approval for treatment of metastases. CONCLUSIONS: PSMA scanning is a disruptive technology that promises to transform the way prostate cancer is initially staged, recurrence is diagnosed and some advanced cases are treated.

Magnetic Resonance Imaging-Guided Biopsy in Active Surveillance of Prostate Cancer.

PURPOSE: The underlying premise of prostate cancer active surveillance (AS) is that cancers likely to metastasize will be recognized and eliminated before cancer-related disease can ensue. Our study was designed to determine the prostate cancer upgrading rate when biopsy guided by magnetic resonance imaging (MRGBx) is used before entry and during AS. MATERIALS AND METHODS: The cohort included 519 men with low- or intermediate-risk prostate cancer who enrolled in prospective studies (NCT00949819 and NCT00102544) between February 2008 and February 2020. Subjects were preliminarily diagnosed with Gleason Grade Group (GG) 1 cancer; AS began when subsequent MRGBx confirmed GG1 or GG2. Participants underwent confirmatory MRGBx (targeted and systematic) followed by surveillance MRGBx approximately every 12 to 24 months. The primary outcome was tumor upgrading to ≥GG3. RESULTS: Upgrading to ≥GG3 was found in 92 men after a median followup of 4.8 years (IQR 3.1-6.5) after confirmatory MRGBx. Upgrade-free probability after 5 years was 0.85 (95% CI 0.81-0.88). Cancer detected in a magnetic resonance imaging lesion at confirmatory MRGBx increased risk of subsequent upgrading during AS (HR 2.8; 95% CI 1.3-6.0), as did presence of GG2 (HR 2.9; 95% CI 1.1-8.2) In men who upgraded ≥GG3 during AS, upgrading was detected by targeted cores only in 27%, systematic cores only in 25% and both in 47%. In 63 men undergoing prostatectomy, upgrading from MRGBx was found in only 5 (8%). CONCLUSIONS: When AS begins and follows with MRGBx (targeted and systematic), upgrading rate (≥GG3) is greater when tumor is initially present within a magnetic resonance imaging lesion or when pathology is GG2 than when these features are absent.

Expectant management for men with early stage prostate cancer.

Since the dissemination of prostate-specific antigen screening, most men with prostate cancer are now diagnosed with localized, low-risk prostate cancer that is unlikely to be lethal. Nevertheless, nearly all of these men undergo primary treatment with surgery or radiation, placing them at risk for longstanding side effects, including erectile dysfunction and impaired urinary function. Active surveillance and other observational strategies (ie, expectant management) have produced excellent long-term disease-specific survival and minimal morbidity for men with prostate cancer. Despite this, expectant management remains underused for men with localized prostate cancer. In this review, various approaches to the expectant management of men with prostate cancer are summarized, including watchful waiting and active surveillance strategies. Contemporary cancer-specific and health care quality-of-life outcomes are described for each of these approaches. Finally, contemporary patterns of use, potential disparities in care, and ongoing research and controversies surrounding expectant management of men with localized prostate cancer are discussed.

Chemical weathering as a mechanism for the climatic control of bedrock river incision.

Feedbacks between climate, erosion and tectonics influence the rates of chemical weathering reactions, which can consume atmospheric CO2 and modulate global climate. However, quantitative predictions for the coupling of these feedbacks are limited because the specific mechanisms by which climate controls erosion are poorly understood. Here we show that climate-dependent chemical weathering controls the erodibility of bedrock-floored rivers across a rainfall gradient on the Big Island of Hawai'i. Field data demonstrate that the physical strength of bedrock in streambeds varies with the degree of chemical weathering, which increases systematically with local rainfall rate. We find that incorporating the quantified relationships between local rainfall and erodibility into a commonly used river incision model is necessary to predict the rates and patterns of downcutting of these rivers. In contrast to using only precipitation-dependent river discharge to explain the climatic control of bedrock river incision, the mechanism of chemical weathering can explain strong coupling between local climate and river incision.

Optimizing Spatial Biopsy Sampling for the Detection of Prostate Cancer.

PURPOSE: The appropriate number of systematic biopsy cores to retrieve during magnetic resonance imaging (MRI)-targeted prostate biopsy is not well defined. We aimed to demonstrate a biopsy sampling approach that reduces required core count while maintaining diagnostic performance. MATERIALS AND METHODS: We collected data from a cohort of 971 men who underwent MRI-ultrasound fusion targeted biopsy for suspected prostate cancer. A regional targeted biopsy (RTB) was evaluated retrospectively; only cores within 2 cm of the margin of a radiologist-defined region of interest were considered part of the RTB. We compared detection rates for clinically significant prostate cancer (csPCa) and cancer upgrading rate on final whole mount pathology after prostatectomy between RTB, combined, MRI-targeted, and systematic biopsy. RESULTS: A total of 16,459 total cores from 971 men were included in the study data sets, of which 1,535 (9%) contained csPCa. The csPCa detection rates for systematic, MRI-targeted, combined, and RTB were 27.0% (262/971), 38.3% (372/971), 44.8% (435/971), and 44.0% (427/971), respectively. Combined biopsy detected significantly more csPCa than systematic and MRI-targeted biopsy (p <0.001 and p=0.004, respectively) but was similar to RTB (p=0.71), which used on average 3.8 (22%) fewer cores per patient. In 102 patients who underwent prostatectomy, there was no significant difference in upgrading rates between RTB and combined biopsy (p=0.84). CONCLUSIONS: A RTB approach can maintain state-of-the-art detection rates while requiring fewer retrieved cores. This result informs decision making about biopsy site selection and total retrieved core count.

Factors Associated with Time to Conversion from Active Surveillance to Treatment for Prostate Cancer in a Multi-Institutional Cohort.

PURPOSE: We examined the demographic and clinicopathological parameters associated with the time to convert from active surveillance to treatment among men with prostate cancer. MATERIALS AND METHODS: A multi-institutional cohort of 7,279 patients managed with active surveillance had data and biospecimens collected for germline genetic analyses. RESULTS: Of 6,775 men included in the analysis, 2,260 (33.4%) converted to treatment at a median followup of 6.7 years. Earlier conversion was associated with higher Gleason grade groups (GG2 vs GG1 adjusted hazard ratio [aHR] 1.57, 95% CI 1.36-1.82; ≥GG3 vs GG1 aHR 1.77, 95% CI 1.29-2.43), serum prostate specific antigen concentrations (aHR per 5 ng/ml increment 1.18, 95% CI 1.11-1.25), tumor stages (cT2 vs cT1 aHR 1.58, 95% CI 1.41-1.77; ≥cT3 vs cT1 aHR 4.36, 95% CI 3.19-5.96) and number of cancerous biopsy cores (3 vs 1-2 cores aHR 1.59, 95% CI 1.37-1.84; ≥4 vs 1-2 cores aHR 3.29, 95% CI 2.94-3.69), and younger age (age continuous per 5-year increase aHR 0.96, 95% CI 0.93-0.99). Patients with high-volume GG1 tumors had a shorter interval to conversion than those with low-volume GG1 tumors and behaved like the higher-risk patients. We found no significant association between the time to conversion and self-reported race or genetic ancestry. CONCLUSIONS: A shorter time to conversion from active surveillance to treatment was associated with higher-risk clinicopathological tumor features. Furthermore, patients with high-volume GG1 tumors behaved similarly to those with intermediate and high-risk tumors. An exploratory analysis of self-reported race and genetic ancestry revealed no association with the time to conversion.

O-GlcNAcylation alters the selection of mRNAs for translation and promotes 4E-BP1-dependent mitochondrial dysfunction in the retina.

Diabetes promotes the posttranslational modification of proteins by O-linked addition of GlcNAc (O-GlcNAcylation) to Ser/Thr residues of proteins and thereby contributes to diabetic complications. In the retina of diabetic mice, the repressor of mRNA translation, eIF4E-binding protein 1 (4E-BP1), is O-GlcNAcylated, and sequestration of the cap-binding protein eukaryotic translation initiation factor (eIF4E) is enhanced. O-GlcNAcylation has also been detected on several eukaryotic translation initiation factors and ribosomal proteins. However, the functional consequence of this modification is unknown. Here, using ribosome profiling, we evaluated the effect of enhanced O-GlcNAcylation on retinal gene expression. Mice receiving thiamet G (TMG), an inhibitor of the O-GlcNAc hydrolase O-GlcNAcase, exhibited enhanced retinal protein O-GlcNAcylation. The principal effect of TMG on retinal gene expression was observed in ribosome-associated mRNAs (i.e. mRNAs undergoing translation), as less than 1% of mRNAs exhibited changes in abundance. Remarkably, ∼19% of the transcriptome exhibited TMG-induced changes in ribosome occupancy, with 1912 mRNAs having reduced and 1683 mRNAs having increased translational rates. In the retina, the effect of O-GlcNAcase inhibition on translation of specific mitochondrial proteins, including superoxide dismutase 2 (SOD2), depended on 4E-BP1/2. O-GlcNAcylation enhanced cellular respiration and promoted mitochondrial superoxide levels in WT cells, and 4E-BP1/2 deletion prevented O-GlcNAcylation-induced mitochondrial superoxide in cells in culture and in the retina. The retina of diabetic WT mice exhibited increased reactive oxygen species levels, an effect not observed in diabetic 4E-BP1/2-deficient mice. These findings provide evidence for a mechanism whereby diabetes-induced O-GlcNAcylation promotes oxidative stress in the retina by altering the selection of mRNAs for translation.

Glucagon-Dependent Suppression of mTORC1 is Associated with Upregulation of Hepatic FGF21 mRNA Translation.

Fibroblast growth factor 21 (FGF21) is a peptide hormone that acts to enhance insulin sensitivity and reverse many of the metabolic defects associated with consumption of a high-fat diet. Recent studies show that the liver is the primary source of FGF21 in the blood, and that hepatic FGF21 expression is upregulated by glucagon. Interestingly, glucagon acts to upregulate FGF21 production by primary cultures of rat hepatocytes and H4IIE and HepG2 hepatocarcinoma cells independent of changes in FGF21 mRNA abundance, suggesting that FGF21 protein expression is regulated post-transcriptionally. Based on these observations, the goal of the present study was to assess whether or not FGF21 mRNA is translationally regulated. The results show that FGF21 mRNA translation and secretion of the hormone are significantly upregulated in H4IIE cells exposed to 25 nM glucagon, independent of changes in FGF21 mRNA abundance. Furthermore, the glucagon-induced upregulation of FGF21 mRNA translation is associated with suppressed activity of the mechanistic target of rapamycin in complex 1 (mTORC1). Similarly, the results show that rapamycin-induced suppression of mTORC1 leads to upregulation of FGF21 mRNA translation with no change in FGF21 mRNA abundance. In contrast, activation of mTORC1 by refreshing the culture medium leads to downregulation of FGF21 mRNA translation. Notably, re-feeding fasted rats also leads to downregulation of FGF21 mRNA translation concomitantly with activation of mTORC1 in the liver. Overall, the findings support a model in which glucagon acts to upregulate FGF21 production by hepatocytes through suppression of mTORC1 and subsequent upregulation of FGF21 mRNA translation.

Prostate Cancer Detection Rate of Freehand versus 3-Dimensional Template Mapping Biopsy Using a Magnetic Resonance Imaging-Ultrasound Fusion Device in Biopsy Naïve Men.

PURPOSE: Targeted prostate biopsy devices include a 3-dimensional digital template grid to guide systematic biopsy locations. Following a template could better ensure uniform and well distributed sampling of the prostate compared to the traditional freehand biopsy approach, possibly decreasing the chance of false-negative biopsy. Thus, we determined cancer detection rates obtained by conventional freehand systematic sampling vs template mapping sampling using a magnetic resonance imaging-ultrasound fusion device. MATERIALS AND METHODS: Men who underwent first line conventional or image guided prostate biopsy were identified retrospectively in an institutional review board approved protocol. Excluded from study were men with prior biopsy or treatment or fewer than 10 cores taken. Targeted cores obtained by image guided biopsy were censored from analysis to simulate systematic template biopsy. The resulting cancer detection rate was compared to that of conventional biopsy. RESULTS: We identified 1,582 patients between 2006 and 2014 who met the criteria for analysis, including 1,052 who underwent conventional biopsy and 530 who underwent template biopsy with a magnetic resonance imaging-ultrasound fusion device. Patient age, prostate specific antigen and the number of systematic cores were the same in the 2 groups. Template biopsy detected any prostate cancer in 257 of 530 men (48.5%) and clinically significant cancer in 196 (37.0%) while conventional biopsy detected any cancer in 432 of 1,052 (41.0%) (p=0.005) and clinically significant cancer in 308 (29.2%) (p=0.002). CONCLUSIONS: Template mapping systematic biopsy detected more prostate cancer than conventional sampling in biopsy naïve men. It is a promising cost-effective alternative to magnetic resonance imaging-ultrasound fusion biopsy as an upfront screening tool.

Variation in Magnetic Resonance Imaging-Ultrasound Fusion Targeted Biopsy Outcomes in Asian American Men: A Multicenter Study.

PURPOSE: Asian American men have distinctly different prostate cancer epidemiology than other men. To our knowledge the role of multiparametric magnetic resonance imaging and targeted biopsy for elevated prostate specific antigen in this population has not been assessed. We sought to define imaging and targeted biopsy outcomes in Asian American men compared to other men. MATERIALS AND METHODS: We accrued a multicenter, prospective cohort of men who underwent magnetic resonance imaging targeted and systematic biopsy for elevated prostate specific antigen. The outcome of interest was a diagnosis of clinically significant prostate cancer (Gleason Grade Group 2 or greater) stratified by the PI-RADS™ (Prostate Imaging-Reporting and Data System) score and a history of negative biopsy. Multivariable logistic regression was used to assess the effect of Asian American race on cancer detection. RESULTS: Of the 2,571 men 275 (11%) were Asian American. Clinically significant prostate cancer was detected in 37% of Asian American men compared to 48% of men of other races (p <0.001). Asian American men were also less likely to be diagnosed with Grade Group 1 cancer (12% vs 18%, p=0.007). Additionally, there was significantly lower detection of significant cancer using PI-RADS 3 in Asian American men vs men of other races (12% vs 21%, p=0.032). On adjusted analysis Asian American men were less likely to be diagnosed with significant cancer (OR 0.57, 95% CI 0.42-0.79, p <0.001) and Grade Group 1 cancer (OR 0.57, 95% CI 0.38-0.84, p=0.005) than nonAsian men. CONCLUSIONS: Asian American men are less likely to be diagnosed with clinically significant prostate cancer on targeted biopsy, illustrating the different performance of PI-RADS in this population. Conventional risk assessment tools should be modified when selecting Asian American men for biopsy.

Risk of Prostate Cancer after a Negative Magnetic Resonance Imaging Guided Biopsy.

PURPOSE: Magnetic resonance imaging guided biopsy which reveals no cancer may impart reassurance beyond that offered by ultrasound guided biopsy. However, followup of men after a negative magnetic resonance imaging guided biopsy has been mostly by prostate specific antigen testing and reports of followup tissue confirmation are few. We investigated the incidence of clinically significant prostate cancer in such men who, because of persistent cancer suspicion, subsequently underwent a repeat magnetic resonance imaging guided biopsy. MATERIALS AND METHODS: Subjects were all men with a negative initial magnetic resonance imaging guided biopsy who underwent at least 1 further magnetic resonance imaging guided biopsy due to continued clinical suspicion of clinically significant prostate cancer (September 2009 to July 2019). Biopsies were magnetic resonance imaging-ultrasound fusion with targeted and systematic cores. Regions of interest from initial magnetic resonance imaging and any new regions of interest at followup magnetic resonance imaging guided biopsy were targeted. The primary end point was detection of clinically significant prostate cancer (Gleason Grade Group 2 or greater). RESULTS: Of 2,716 men 733 had a negative initial magnetic resonance imaging guided biopsy. Study subjects were 73/733 who underwent followup magnetic resonance imaging guided biopsy. Median (IQR) age and prostate specific antigen density were 64 years (59-67) and 0.12 ng/ml/cc (0.08-0.17), respectively. Baseline PI-RADS® scores were 3 or greater in 74%. At followup magnetic resonance imaging guided biopsy (median 2.4 years, IQR 1.3-3.6), 17/73 (23%) were diagnosed with clinically significant prostate cancer. When followup magnetic resonance imaging revealed a lesion (PI-RADS 3 or greater), clinically significant prostate cancer was found in 17/53 (32%). When followup magnetic resonance imaging was negative (PI-RADS less than 3), cancer was not found (0/20) (p <0.01). Overall 54% of men with PI-RADS 5 at followup magnetic resonance imaging guided biopsy were found to have clinically significant prostate cancer. CONCLUSIONS: Men with negative magnetic resonance imaging following an initial negative magnetic resonance imaging guided biopsy are unlikely to harbor clinically significant prostate cancer and may avoid repeat biopsy. However, when lesions are seen on followup magnetic resonance imaging, repeat magnetic resonance imaging guided biopsy is warranted.