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The authors identify two genetic markers defining non-overlapping populations of principal cells in the amygdala that respond to stimuli of opposite valence. These two populations of cells contribute to behavioral responses to aversive or rewarding experiences, are distributed along antero-posterior gradients that run in opposite directions, and synaptically suppress each other. The basolateral amygdala (BLA) is a site of convergence of negative and positive stimuli and is critical for emotional behaviors and associations. However, the neural substrate for negative and positive behaviors and relationship between negative and positive representations in the basolateral amygdala are unknown. Here we identify two genetically distinct, spatially segregated populations of excitatory neurons in the mouse BLA that participate in valence-specific behaviors and are connected through mutual inhibition. These results identify a genetically defined neural circuit for the antagonistic control of emotional behaviors and memories.

Unicellular organisms have the prevalent challenge to survive under oxidative stress of reactive oxygen species (ROS) such as hydrogen peroxide (H2O2). ROS are present as by-products of photosynthesis and aerobic respiration. These reactive species are even employed by multicellular organisms as potent weapons against microbes. Although bacterial defences against lethal and sub-lethal oxidative stress have been studied in model bacteria, the role of fluctuating H2O2 concentrations remains unexplored. It is known that sub-lethal exposure of Escherichia coli to H2O2 results in enhanced survival upon subsequent exposure. Here we investigate the priming response to H2O2 at physiological concentrations. The basis and the duration of the response (memory) were also determined by time-lapse quantitative proteomics. We found that a low level of H2O2 induced several scavenging enzymes showing a long half-life, subsequently protecting cells from future exposure. We then asked if the phenotypic resistance against H2O2 alters the evolution of resistance against oxygen stress. Experimental evolution of H2O2 resistance revealed faster evolution and higher levels of resistance in primed cells. Several mutations were found to be associated with resistance in evolved populations affecting different loci but, counterintuitively, none of them was directly associated with scavenging systems. Our results have important implications for host colonisation and infections where microbes often encounter reactive oxygen species in gradients.

Tirzepatide is a once-weekly GIP/GLP-1 receptor agonist. In this phase 3, randomized, open-label trial, insulin-naive adults (≥18 years of age) with type 2 diabetes (T2D) uncontrolled on metformin (with or without a sulphonylurea) were randomized 1:1:1:1 to weekly tirzepatide 5 mg, 10 mg or 15 mg or daily insulin glargine at 66 hospitals in China, South Korea, Australia and India. The primary endpoint was non-inferiority of mean change in hemoglobin A1c (HbA1c) from baseline to week 40 after treatment with 10 mg and 15 mg of tirzepatide. Key secondary endpoints included non-inferiority and superiority of all tirzepatide doses in HbA1c reduction, proportions of patients achieving HbA1c < 7.0% and weight loss at week 40. A total of 917 patients (763 (83.2%) in China) were randomized to tirzepatide 5 mg ( n  = 230), 10 mg ( n  = 228) or 15 mg ( n  = 229) or insulin glargine ( n  = 230). All doses of tirzepatide were non-inferior and superior to insulin glargine for least squares mean (s.e.) reduction in HbA1c from baseline to week 40: tirzepatide 5 mg, 10 mg and 15 mg, −2.24% (0.07), −2.44% (0.07) and −2.49% (0.07), respectively, and insulin glargine, −0.95% (0.07), with a treatment difference ranging from −1.29% to −1.54% (all P  < 0.001). Proportions of patients achieving HbA1c < 7.0% at week 40 were greater in tirzepatide 5-mg (75.4%), 10-mg (86.0%) and 15-mg (84.4%) groups compared to insulin glargine (23.7%) (all P  < 0.001). All tirzepatide doses led to superior body weight reduction at week 40: tirzepatide 5 mg, 10 mg and 15 mg, −5.0 kg (−6.5%), −7.0 kg (−9.3%) and −7.2 kg (−9.4%), respectively, compared to insulin glargine, 1.5 kg (+2.1%) (all P  < 0.001). The most common adverse events with tirzepatide were mild to moderate decreased appetite, diarrhea and nausea. No severe hypoglycemia was reported. Tirzepatide demonstrated superior reductions in HbA1c versus insulin glargine in an Asia-Pacific, predominately Chinese, population with T2D and was generally well tolerated. ClinicalTrials.gov registration: NCT04093752 . Findings from the SURPASS-AP-Combo trial demonstrate that addition of tirzepatide is non-inferior and superior to insulin glargine for glycemic outcomes at 40 weeks when used as second-line or third-line therapy in an Asia-Pacific (predominantly Chinese) population with type 2 diabetes.

Cardiac arrest is the leading cause of natural death in the United States, and most surviving patients suffer from neurological dysfunction. Although this is recognized as a problem, there have been very few changes to the cardiopulmonary resuscitation (CPR) procedure. Tourniquets have been recognized for their ability to increase truncal blood pressure and have been shown to improve CPR outcomes in animal models. However, the relationship between tourniquet application and blood pressure elevation has not been adequately explored in healthy human adults. The objective of this study is to demonstrate that bilateral, non-invasive, peripheral vascular occlusion in the thighs results in an increased proximal systolic blood pressure ≥ 10 mmHg. This is a single-center, non-blinded clinical trial. Volunteers will be screened for eligibility at least 24 hours before the day of the trial. On the day of the trial, volunteers will undergo an informed consent process. If they choose to participate in the trial after informed consent, their baseline blood pressure will be measured. Volunteers will then have a Combat Application Tourniquet (CAT) applied to each thigh, and the windlasses will be tightened by IRB-approved personnel. Once no pulse can be felt in the lower extremity, blood pressure will be measured in the arm. This will be replicated three times, and the tourniquets will be loosened between trials to allow the volunteers to rest. Any complications that arise during the trial will be handled by the physician that is present. Changes in systolic blood pressure and diastolic blood pressure will be analyzed using a Shapiro-Wilk test. Then, a one-way repeated measures analysis of variance (ANOVA) will be performed with a Holm-Sidak post-hoc test to determine the mean differences. The significance level will be set to 5% for statistical significance. Clinicaltrials.gov, NCT05324306.

Just as the pandemic will change American higher education, the choices we make now will change what college looks like for generations to come.

Background Historically, men have been shamed if they cared seemingly too much about their appearance and especially, if they pursued aesthetic surgery. However, due to the changing landscape of the culture, this stigma has seemed to decrease. Men have diverse and quickly changing interests in particular procedures that have not been readily explored in the currently available reports. To examine this, we analyzed interest in specific plastic surgery procedures in men over the last two decades using the Google Trends tool. Methods The most common cosmetic procedures were chosen from the American Society of Plastic Surgeons website and served as the search terms for the Google Trends tool from 2004 to 2021. All 19 procedures were examined for overall trends and for changes in the last decade through comparing the data in bisected time periods. Results Interest in all plastic surgery procedures in men increased since 2004 except for breast reduction. Most notably, jawline filler, Botox, microneedling, lip filler, chemical peel, CoolSculpting, and butt lift had the largest trend increases. In the last decade, all procedures showed a significant increase in interest. Conclusions While surgical volume data are valuable, our study shows that Google Trends is a beneficial tool to predict quickly changing and specific trends, especially as the patient population of plastic surgery grows with increased diversity and generational changes. Our study shows that there is an increase in male-centered plastic surgery procedures, especially nonsurgical facial procedures. Male interest in plastic surgery will continue to increase with time. Level of Evidence IV This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors   www.springer.com/00266 .

Background Lung transplantation (LT) represents a high-risk procedure for end-stage lung diseases. This study describes the outcomes of patients undergoing LT that require massive transfusions as defined by the universal definition of perioperative bleeding (UDPB). Methods Adult patients who underwent bilateral LT at a single academic center were surveyed retrospectively. Patients were grouped by insignificant, mild, or moderate perioperative bleeding (insignificant-to-moderate bleeders) and severe or massive perioperative bleeding (severe-to-massive bleeders) based on the UDPB classification. Outcomes included 1-year survival and primary graft dysfunction (PGD) of grade 3 at 72 h postoperatively. Multivariable models were adjusted for recipient age, sex, body mass index (BMI), Lung allocation score (LAS), preoperative hemoglobin (Hb), preoperative extracorporeal membrane oxygenation (ECMO) status, transplant number, and donor status. An additional multivariable model was created to find preoperative and intraoperative predictors of severe-to-massive bleeding. A p -value less than 0.05 was selected for significance. Results A total of 528 patients were included, with 357 insignificant-to-moderate bleeders and 171 severe-to-massive bleeders. Postoperatively, severe-to-massive bleeders had higher rates of PGD grade 3 at 72 h, longer hospital stays, higher mortality rates at 30 days and one year, and were less likely to achieve textbook outcomes for LT. They also required postoperative ECMO, reintubation for over 48 h, tracheostomy, reintervention, and dialysis at higher rates. In the multivariate analysis, severe-to-massive bleeding was significantly associated with adverse outcomes after adjusting for recipient and donor factors, with an odds ratio of 7.73 (95% CI: 4.27–14.4, p  < 0.001) for PGD3 at 72 h, 4.30 (95% CI: 2.30–8.12, p  < 0.001) for 1-year mortality, and 1.75 (95% CI: 1.52–2.01, p  < 0.001) for longer hospital stays. Additionally, severe-to-massive bleeders were less likely to achieve textbook outcomes, with an odds ratio of 0.07 (95% CI: 0.02–0.16, p  < 0.001). Preoperative and intraoperative predictors of severe/massive bleeding were identified, with White patients having lower odds compared to Black patients (OR: 041, 95% CI: 0.22–0.80, p  = 0.008). Each 1-unit increase in BMI decreased the odds of bleeding (OR: 0.89, 95% CI: 0.83–0.95, p  < 0.001), while each 1-unit increase in MPAP increased the odds of bleeding (OR: 1.04, 95% CI: 1.02–1.06, p  < 0.001). First-time transplant recipients had lower risk (OR: 0.16, 95% CI: 0.06–0.36, p  < 0.001), whereas those with DCD donors had a higher risk of severe-to-massive bleeding (OR: 3.09, 95% CI: 1.63–5.87, p  = 0.001). Conclusion These results suggest that patients at high risk of massive bleeding require higher utilization of hospital resources. Understanding their outcomes is important, as it may inform future decisions to transplant comparable patients.

To evaluate the image quality, dosimetric properties, setup reproducibility, and planar cine motion detection of a high‐resolution brain coil and integrated stereotactic brain immobilization system that constitute a new brain treatment package (BTP) on a low‐field magnetic resonance imaging (MRI) linear accelerator (MR‐linac). Image quality of the high‐resolution brain coil was evaluated with the 17 cm diameter spherical phantom and the American College of Radiology (ACR) Large MRI Phantom. Patient imaging studies approved by the institutional review board (IRB) assisted in selecting image acquisition parameters. Radiographic and dosimetric evaluation of the high‐resolution brain coil and the associated immobilization devices was performed using dose calculations and ion chamber measurements. End‐to‐end testing was performed simulating a cranial lesion in a phantom. Inter‐fraction setup variability and motion detection tests were evaluated on four healthy volunteers. Inter‐fraction variability was assessed based on three repeat setups for each volunteer. Motion detection was evaluated using three‐plane (axial, coronal, and sagittal) MR‐cine imaging sessions, where volunteers were asked to perform a set of specific motions. The images were post‐processed and evaluated using an in‐house program. Contrast resolution of the high‐resolution brain coil is superior to the head/neck and torso coils. The BTP receiver coils have an average HU value of 525 HU. The most significant radiation attenuation (3.14%) of the BTP, occurs through the lateral portion of the overlay board where the high‐precision lateral‐profile mask clips attach to the overlay. The greatest inter‐fraction setup variability occurred in the pitch (average 1.08 degree) and translationally in the superior/inferior direction (average 4.88 mm). Three plane cine imaging with the BTP was able to detect large and small motions. Small voluntary motions, sub‐millimeter in magnitude (maximum 0.9 mm), from motion of external limbs were detected. Imaging tests, inter‐fraction setup variability, attenuation, and end‐to‐end measurements were quantified and performed for the BTP. Results demonstrate better contrast resolution and low contrast detectability that allows for better visualization of soft tissue anatomical changes relative to head/neck and torso coil systems.

Background The purpose of this study is to comprehensively evaluate the suitability of Gafchromic EBT3 and EBT-XD film for dosimetric quality assurance in 0.35 T MR-guided radiotherapy. Methods A 0.35 T magnetic field strength was utilized to evaluate magnetic field effects on EBT3 and EBT-XD Gafchromic films by studying the effect of film exposure time within the magnetic field using two timing sequences and film not exposed to MR, the effect of magnetic field exposure on the crystalline structure of the film, and the effect of orientation of the film with respect to the bore within the magnetic field. The orientation of the monomer crystal was qualitatively evaluated using scanning electron microscopy (SEM) compared to unirradiated film. Additionally, dosimetric impact was evaluated through measurements of a series of open field irradiations (0.83 × 0.83-cm 2 to 19.92 × 19.92-cm 2 ) and patient specific quality assurance measurements. Open fields were compared to planned dose and an independent dosimeter. Film dosimetry was applied to twenty conventional and twenty stereotactic body radiotherapy (SBRT) patient specific quality assurance cases. Results No visual changes in crystal orientation were observed in any evaluated SEM images nor were any optical density differences observed between films irradiated inside or outside the magnetic field for both EBT3 and EBT-XD film. At small field sizes, the average difference along dose profiles measured in film compared to the same points measured using an independent dosimeter and to predicted treatment planning system values was 1.23% and 1.56%, respectively. For large field sizes, the average differences were 1.91% and 1.21%, respectively. In open field tests, the average gamma pass rates were 99.8% and 97.2%, for 3%/3 mm and 3%/1 mm, respectively. The median (interquartile range) 3%/3 mm gamma pass rates in conventional QA cases were 98.4% (96.3 to 99.2%), and 3%/1 mm in SBRT QA cases were 95.8% (95.0 to 97.3%). Conclusions MR exposure at 0.35 T had negligible effects on EBT3 and EBT-XD Gafchromic film. Dosimetric film results were comparable to planned dose, ion chamber and diode measurements.