Semaglutide in Patients with Obesity-Related Heart Failure and Type 2 Diabetes.

BACKGROUND: Obesity and type 2 diabetes are prevalent in patients with heart failure with preserved ejection fraction and are characterized by a high symptom burden. No approved therapies specifically target obesity-related heart failure with preserved ejection fraction in persons with type 2 diabetes. METHODS: We randomly assigned patients who had heart failure with preserved ejection fraction, a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or more, and type 2 diabetes to receive once-weekly semaglutide (2.4 mg) or placebo for 52 weeks. The primary end points were the change from baseline in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS; scores range from 0 to 100, with higher scores indicating fewer symptoms and physical limitations) and the change in body weight. Confirmatory secondary end points included the change in 6-minute walk distance; a hierarchical composite end point that included death, heart failure events, and differences in the change in the KCCQ-CSS and 6-minute walk distance; and the change in the C-reactive protein (CRP) level. RESULTS: A total of 616 participants underwent randomization. The mean change in the KCCQ-CSS was 13.7 points with semaglutide and 6.4 points with placebo (estimated difference, 7.3 points; 95% confidence interval [CI], 4.1 to 10.4; P<0.001), and the mean percentage change in body weight was -9.8% with semaglutide and -3.4% with placebo (estimated difference, -6.4 percentage points; 95% CI, -7.6 to -5.2; P<0.001). The results for the confirmatory secondary end points favored semaglutide over placebo (estimated between-group difference in change in 6-minute walk distance, 14.3 m [95% CI, 3.7 to 24.9; P = 0.008]; win ratio for hierarchical composite end point, 1.58 [95% CI, 1.29 to 1.94; P<0.001]; and estimated treatment ratio for change in CRP level, 0.67 [95% CI, 0.55 to 0.80; P<0.001]). Serious adverse events were reported in 55 participants (17.7%) in the semaglutide group and 88 (28.8%) in the placebo group. CONCLUSIONS: Among patients with obesity-related heart failure with preserved ejection fraction and type 2 diabetes, semaglutide led to larger reductions in heart failure-related symptoms and physical limitations and greater weight loss than placebo at 1 year. (Funded by Novo Nordisk; STEP-HFpEF DM ClinicalTrials.gov number, NCT04916470.).

The orbitofrontal cortex maps future navigational goals.

Accurate navigation to a desired goal requires consecutive estimates of spatial relationships between the current position and future destination throughout the journey. Although neurons in the hippocampal formation can represent the position of an animal as well as its nearby trajectories1-7, their role in determining the destination of the animal has been questioned8,9. It is, thus, unclear whether the brain can possess a precise estimate of target location during active environmental exploration. Here we describe neurons in the rat orbitofrontal cortex (OFC) that form spatial representations persistently pointing to the subsequent goal destination of an animal throughout navigation. This destination coding emerges before the onset of navigation, without direct sensory access to a distal goal, and even predicts the incorrect destination of an animal at the beginning of an error trial. Goal representations in the OFC are maintained by destination-specific neural ensemble dynamics, and their brief perturbation at the onset of a journey led to a navigational error. These findings suggest that the OFC is part of the internal goal map of the brain, enabling animals to navigate precisely to a chosen destination that is beyond the range of sensory perception.

Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity.

BACKGROUND: Heart failure with preserved ejection fraction is increasing in prevalence and is associated with a high symptom burden and functional impairment, especially in persons with obesity. No therapies have been approved to target obesity-related heart failure with preserved ejection fraction. METHODS: We randomly assigned 529 patients who had heart failure with preserved ejection fraction and a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or higher to receive once-weekly semaglutide (2.4 mg) or placebo for 52 weeks. The dual primary end points were the change from baseline in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS; scores range from 0 to 100, with higher scores indicating fewer symptoms and physical limitations) and the change in body weight. Confirmatory secondary end points included the change in the 6-minute walk distance; a hierarchical composite end point that included death, heart failure events, and differences in the change in the KCCQ-CSS and 6-minute walk distance; and the change in the C-reactive protein (CRP) level. RESULTS: The mean change in the KCCQ-CSS was 16.6 points with semaglutide and 8.7 points with placebo (estimated difference, 7.8 points; 95% confidence interval [CI], 4.8 to 10.9; P<0.001), and the mean percentage change in body weight was -13.3% with semaglutide and -2.6% with placebo (estimated difference, -10.7 percentage points; 95% CI, -11.9 to -9.4; P<0.001). The mean change in the 6-minute walk distance was 21.5 m with semaglutide and 1.2 m with placebo (estimated difference, 20.3 m; 95% CI, 8.6 to 32.1; P<0.001). In the analysis of the hierarchical composite end point, semaglutide produced more wins than placebo (win ratio, 1.72; 95% CI, 1.37 to 2.15; P<0.001). The mean percentage change in the CRP level was -43.5% with semaglutide and -7.3% with placebo (estimated treatment ratio, 0.61; 95% CI, 0.51 to 0.72; P<0.001). Serious adverse events were reported in 35 participants (13.3%) in the semaglutide group and 71 (26.7%) in the placebo group. CONCLUSIONS: In patients with heart failure with preserved ejection fraction and obesity, treatment with semaglutide (2.4 mg) led to larger reductions in symptoms and physical limitations, greater improvements in exercise function, and greater weight loss than placebo. (Funded by Novo Nordisk; STEP-HFpEF ClinicalTrials.gov number, NCT04788511.).

Effects of Semaglutide on Symptoms, Function, and Quality of Life in Patients With Heart Failure With Preserved Ejection Fraction and Obesity: A Prespecified Analysis of the STEP-HFpEF Trial.

BACKGROUND: Patients with heart failure (HF) with preserved ejection fraction (HFpEF) and obesity experience a high burden of symptoms and functional impairment, and a poor quality of life. In the STEP-HFpEF trial (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity), once-weekly semaglutide 2.4 mg improved symptoms, physical limitations, and exercise function, and reduced inflammation and body weight. This prespecified analysis investigated the effects of semaglutide on the primary and confirmatory secondary end points across the range of the Kansas City Cardiomyopathy Questionnaire (KCCQ) scores at baseline and on all key summary and individual KCCQ domains. METHODS: STEP-HFpEF randomly assigned 529 participants with symptomatic HF, an ejection fraction of ≥45%, and a body mass index of ≥30 kg/m2 to once-weekly semaglutide 2.4 mg or placebo for 52 weeks. Dual primary end points change in KCCQ-Clinical Summary Score (CSS) and body weight. Confirmatory secondary end points included change in 6-minute walk distance, a hierarchical composite end point (death, HF events, and change in KCCQ-CSS and 6-minute walk distance) and change in C-reactive protein. Patients were stratified by KCCQ-CSS tertiles at baseline. Semaglutide effects on the primary, confirmatory secondary, and select exploratory end points (N-terminal pro-brain natriuretic peptide) were examined across these subgroups. Semaglutide effects on additional KCCQ domains (Total Symptom Score [including symptom burden and frequency], Physical Limitations Score, Social Limitations Score, Quality of Life Score, and Overall Summary Score) were also evaluated. RESULTS: Baseline median KCCQ-CSS across tertiles was 37, 59, and 77 points, respectively. Semaglutide consistently improved primary end points across KCCQ tertiles 1 to 3 (estimated treatment differences [95% CI]: for KCCQ-CSS, 10.7 [5.4 to 16.1], 8.1 [2.7 to 13.4], and 4.6 [-0.6 to 9.9] points; for body weight, -11 [-13.2 to -8.8], -9.4 [-11.5 to -7.2], and -11.8 [-14.0 to -9.6], respectively; Pinteraction=0.28 and 0.29, respectively); the same was observed for confirmatory secondary and exploratory end points (Pinteraction>0.1 for all). Semaglutide-treated patients experienced improvements in all key KCCQ domains (estimated treatment differences, 6.7-9.6 points across domains; P≤0.001 for all). Greater proportion of semaglutide-treated versus placebo-treated patients experienced at least 5-, 10-, 15-, and 20-point improvements in all KCCQ domains (odds ratios, 1.6-2.9 across domains; P<0.05 for all). CONCLUSIONS: In patients with HFpEF and obesity, semaglutide produced large improvements in HF-related symptoms, physical limitations, exercise function, inflammation, body weight, and N-terminal pro-brain natriuretic peptide, regardless of baseline health status. The benefits of semaglutide extended to all key KCCQ domains. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04788511.

Semaglutide versus placebo in people with obesity-related heart failure with preserved ejection fraction: a pooled analysis of the STEP-HFpEF and STEP-HFpEF DM randomised trials.

BACKGROUND: In the STEP-HFpEF (NCT04788511) and STEP-HFpEF DM (NCT04916470) trials, the GLP-1 receptor agonist semaglutide improved symptoms, physical limitations, bodyweight, and exercise function in people with obesity-related heart failure with preserved ejection fraction. In this prespecified pooled analysis of the STEP-HFpEF and STEP-HFpEF DM trials, we aimed to provide a more definitive assessment of the effects of semaglutide across a range of outcomes and to test whether these effects were consistent across key patient subgroups. METHODS: We conducted a prespecified pooled analysis of individual patient data from STEP-HFpEF and STEP-HFpEF DM, randomised, double-blind, placebo-controlled trials at 129 clinical research sites in 18 countries. In both trials, eligible participants were aged 18 years or older, had heart failure with a left ventricular ejection fraction of at least 45%, a BMI of at least 30 kg/m2, New York Heart Association class II-IV symptoms, and a Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS; a measure of heart failure-related symptoms and physical limitations) of less than 90 points. In STEP-HFpEF, people with diabetes or glycated haemoglobin A1c concentrations of at least 6·5% were excluded, whereas for inclusion in STEP-HFpEF DM participants had to have been diagnosed with type 2 diabetes at least 90 days before screening and to have an HbA1c of 10% or lower. In both trials, participants were randomly assigned to either 2·4 mg semaglutide once weekly or matched placebo for 52 weeks. The dual primary endpoints were change from baseline to week 52 in KCCQ-CSS and bodyweight in all randomly assigned participants. Confirmatory secondary endpoints included change from baseline to week 52 in 6-min walk distance, a hierarchical composite endpoint (all-cause death, heart failure events, and differences in changes in KCCQ-CSS and 6-min walk distance); and C-reactive protein (CRP) concentrations. Heterogeneity in treatment effects was assessed across subgroups of interest. We assessed safety in all participants who received at least one dose of study drug. FINDINGS: Between March 19, 2021 and March 9, 2022, 529 people were randomly assigned in STEP-HFpEF, and between June 27, 2021 and Sept 2, 2022, 616 were randomly assigned in STEP-HFpEF DM. Overall, 1145 were included in our pooled analysis, 573 in the semaglutide group and 572 in the placebo group. Improvements in KCCQ-CSS and reductions in bodyweight between baseline and week 52 were significantly greater in the semaglutide group than in the placebo group (mean between-group difference for the change from baseline to week 52 in KCCQ-CSS 7·5 points [95% CI 5·3 to 9·8]; p<0·0001; mean between-group difference in bodyweight at week 52 -8·4% [-9·2 to -7·5]; p<0·0001). For the confirmatory secondary endpoints, 6-min walk distance (mean between-group difference at week 52 17·1 metres [9·2 to 25·0]) and the hierarchical composite endpoint (win ratio 1·65 [1·42 to 1·91]) were significantly improved, and CRP concentrations (treatment ratio 0·64 [0·56 to 0·72]) were significantly reduced, in the semaglutide group compared with the placebo group (p<0·0001 for all comparisons). For the dual primary endpoints, the efficacy of semaglutide was largely consistent across multiple subgroups, including those defined by age, race, sex, BMI, systolic blood pressure, baseline CRP, and left ventricular ejection fraction. 161 serious adverse events were reported in the semaglutide group compared with 301 in the placebo group. INTERPRETATION: In this prespecified pooled analysis of the STEP-HFpEF and STEP-HFpEF DM trials, semaglutide was superior to placebo in improving heart failure-related symptoms and physical limitations, and reducing bodyweight in participants with obesity-related heart failure with preserved ejection fraction. These effects were largely consistent across patient demographic and clinical characteristics. Semaglutide was well tolerated. FUNDING: Novo Nordisk.

Hypothalamic Supramammillary Control of Cognition and Motivation.

The supramammillary nucleus (SuM) is a small region in the ventromedial posterior hypothalamus. The SuM has been relatively understudied with much of the prior focus being on its connection with septo-hippocampal circuitry. Thus, most studies conducted until the 21st century examined its role in hippocampal processes, such as theta rhythm and learning/memory. In recent years, the SuM has been "rediscovered" as a crucial hub for several behavioral and cognitive processes, including reward-seeking, exploration, and social memory. Additionally, it has been shown to play significant roles in hippocampal plasticity and adult neurogenesis. This review highlights findings from recent studies using cutting-edge systems neuroscience tools that have shed light on these fascinating roles for the SuM.

The arousal level of consciousness required for working memory performance: An anaesthesia study.

Regarding the stage of arousal level required for working memory to function properly, limited studies have been conducted on changes in working memory performance when the arousal level of consciousness decreases. This study aimed to experimentally clarify the stages of consciousness necessary for optimal working memory function. In this experiment, the sedation levels were changed step-by-step using anaesthesia, and the performance accuracy during the execution of working memory was assessed using a dual-task paradigm. Participants were required to categorize and remember words in a specific target category. Categorization performance was measured across four different sedative phases: before anaesthesia (baseline), and deep, moderate and light stages of sedation. Short-delay recognition tasks were performed under these four sedative stages, followed by long-delay recognition tasks after participants recovered from sedation. The results of the short-delay recognition task showed that the performance was lowest at the deep stage. The performance of the moderate stage was lower than the baseline. In the long-delay recognition task, the performance under moderate sedation was lower than that under baseline and light sedation. In addition, the performance under light sedation was lower than that under baseline. These results suggest that task performance becomes difficult under half sedation and that transferring information to long-term memory is difficult even under one-quarter sedation.

Association Between Aortic Valve Calcification and Severity of Concomitant Aortic Regurgitation in Patients With Severe Aortic Stenosis.

BACKGROUND: Patients with severe aortic stenosis (AS) frequently have concomitant aortic regurgitation (AR), but the association between aortic valvular calcification (AVC) and the severity of AR remains unclear.Methods and Results: We retrospectively reviewed patients with severe AS who underwent transthoracic echocardiography and multidetector computed tomography (MDCT) within 1 month. The patients were divided into 3 groups according to the degree of concomitant AR. The association between AVC and the severity of concomitant AR was assessed in patients with severe AS. The study population consisted of 95 patients: 43 men and 52 women with a mean age of 82±7 years. Of the 95 patients with severe AS, 27 had no or trivial AR, 53 had mild AR, and 15 had moderate AR. The AVC score (AVCS) and AVC volume (AVCV) significantly increased as the severity of concomitant AR increased (P=0.014 for both), and similar findings were obtained for the AVCS and AVCV indexes (P=0.004 for both). CONCLUSIONS: The severity of AR correlated with AVCS and AVCV measured by MDCT in patients with severe AS. AVC may cause concomitant AR, leading to worsening of disease condition.

Incidence of Bowel Wall Swelling Induced by Iodine-Contrast Media and Its Association With Gastrointestinal Manifestation.

PURPOSE: The aim of this study was to investigate the incidence of bowel wall swelling after iodine-contrast media injection and its relationship with gastrointestinal symptoms. METHODS: The incidence of bowel wall swelling was examined in 75 patients who showed adverse reactions to iodine-contrast media (AR[+] group) and 75 controls without adverse reactions (AR[-] group). Bowel wall swelling was identified if there was increased wall thickness on postcontrast computed tomography when compared with precontrast computed tomography. Swelling less than 2-fold of the original wall thickness was defined as grade 1 bowel angioedema, and swelling more than 2-fold was defined as grade 2. RESULTS: The incidence of bowel wall swelling was significantly higher in the AR(+) group (26.6%) than in the AR(-) group (10.6%) ( P = 0.01). Grade 1 bowel wall swelling was observed in 12.0% and 10.7% of AR(+) and AR(-) groups, respectively, whereas grade 2 was observed in 14.7% and 0%, respectively. Bowel wall swelling was observed in the duodenum and jejunum but not in the stomach, ileum, or colon in any patient in either group. In the AR(+) group, nausea and/or vomiting was observed in 15 patients, among whom bowel wall swelling was observed in 9 patients (60%). The frequency of nausea and/or vomiting was significantly higher in the patients with bowel wall swelling (45.0%, 9/20) compared with those without (10.9%, 6/55). CONCLUSION: Bowel wall swelling was more frequent and severe in patients with adverse reactions to iodine-contrast media than those without and was associated with nausea and/or vomiting.

The Relationship Between Conventionally Obtained Serum-Based Liver Function Indices and Intravoxel Incoherent Motion Diffusion-Weighted Imaging and Magnetic Resonance Elastography in Patients With Hepatocellular Carcinoma.

OBJECTIVES: To investigate the relationship between conventionally obtained serum-based biochemical indices and intravoxel incoherent motion imaging (IVIM) parameters compared with magnetic resonance elastography (MRE). METHODS: Patients with hepatocellular carcinoma who underwent ≥2 liver magnetic resonance imaging (MRI) scan, including IVIM and MRE, between 2017 and 2020 and biochemical testing within 1 week before or after MRI were included in this study. Biochemical tests were performed to determine the albumin-bilirubin (ALBI) score and modified ALBI (mALBI) grade, aspartate aminotransferase to platelet ratio index (APRI), and fibrosis-4 index (FIB-4). The diffusion coefficient ( D ), pseudo-diffusion coefficient ( D *), fractional volume occupied by flowing spins ( f ), and apparent diffusion coefficient were calculated for IVIM. The correlations between (1) the imaging parameters and biochemical indices and (2) the changes in mALBI grades and imaging parameters were evaluated. RESULTS: This study included 98 scans of 40 patients (31 men; mean age, 67.7 years). The correlation analysis between the biochemical and IVIM parameters showed that ALBI score and D* had the best correlation ( r = -0.3731, P < 0.001), and the correlation was higher than that with MRE ( r = 0.3289, P < 0.001). However, among FIB-4, APRI, and MRI parameters, MRE outperformed IVIM parameters (MRE and FIB-4, r = 0.3775, P < 0.001; MRE and APRI, r = 0.4687, P < 0.001). There were significant differences in the changes in MRE among the 3 groups (improved, deteriorated, and unchanged mALBI groups) in the analysis of covariance ( P = 0.0434). There were no significant changes in IVIM. CONCLUSIONS: Intravoxel incoherent motion imaging has the potential to develop into a more readily obtainable method of liver function assessment.

Respiratory Displacement of the Right Adrenal Vein: Comparison of Inspiratory and Expiratory Computed Tomography With Catheter Venography.

OBJECTIVE: The aim of the study is to reveal the respiratory displacement of the right adrenal vein (RAV) to predict the exact location of the RAV during adrenal venous sampling (AVS). METHODS: Computed tomography (CT) scans obtained 45 seconds (breath-hold at inhalation) and 70 seconds (breath-hold at exhalation) after contrast material injection were compared to venograms of the RAV of patients with primary aldosteronism who underwent AVS between January 2016 and December 2020. The craniocaudal distance between the center of the Th11/12 disc and the RAV orifice was measured; the craniocaudal location of the RAV orifice was also specified relative to vertebral bodies and intervertebral discs on inspiratory phase CT (In-CT), expiratory phase CT (Ex-CT), and catheter venography. The transverse and vertical angles of the RAV and the position of the RAV orifice on the inferior vena cava (IVC) circumference were measured on In-CT and Ex-CT. RESULTS: In total, 51 patients (30 males, 21 females; mean age, 54.9 ± 11.1 years) were included. Craniocaudal distances between the center of the Th11/12 disc and RAV orifice were significantly different among the following 3 acquisitions: catheter venography versus In-CT (15.2 ± 8.4 mm); venography versus Ex-CT (5.6 ± 4.1 mm); and In-CT versus Ex-CT (19.6 ± 8.0 mm) (all, P < 0.001). The craniocaudal location of the RAV orifice on venography was significantly closer to that on Ex-CT than on In-CT (P < 0.001); measurements using venograms compared with In-CT and Ex-CT scans were within 1 level difference in 18 (35.3%) and 47 (92.2%) patients, respectively (P < 0.001). The vertical angle of the RAV was significantly more likely to be smaller on In-CT than on Ex-CT (P < 0.001). CONCLUSIONS: RAV locations and angles change with respiratory motion. It is crucial to consider the respiratory phase of CT because it can enable a more accurate prediction of the location of the RAV during AVS.

Prognostic significance of left atrial strain combined with left ventricular strain using cardiac magnetic resonance feature tracking in patients with heart failure with preserved ejection fraction.

We aimed to evaluate the prognostic value of left ventricular global longitudinal strain (LVGLS) and left atrial strain (LAS) obtained from magnetic resonance imaging (MRI) feature tracking in patients with heart failure with preserved ejection fraction (HFpEF). We retrospectively enrolled consecutive patients with HFpEF admitted to our hospital who underwent cardiac MRI. LVGLS and LAS were obtained from cine MRI by feature tracking. The end point was defined as a composite of all-cause death, myocardial infarction, and hospitalization due to decompensated HF. One-hundred patients with HFpEF were enrolled. Mean LVGLS and LAS were - 13.7 ± 3.7% and 22.5 ± 11.6%, respectively. During follow-up of 4.4 ± 1.9 years, 24 events occurred. Multivariate Cox proportional hazards model analysis demonstrated LAS was independently associated with adverse cardiac events. Kaplan-Meier curve analysis revealed that the patients with both LVGLS and LAS worse than the median (LVGLS ≥ - 12.2% and LAS ≤ 13.8%) had a significantly lower event-free rate compared to those with preserved strain (Log-rank P < 0.001). Simultaneous assessment of LVGLS and LAS using MRI was useful for risk stratification in the patients with HFpEF.

Does a Commercially Available Augmented Reality-based Portable Hip Navigation System Improve Cup Positioning During THA Compared With the Conventional Technique? A Randomized Controlled Study.

BACKGROUND: Portable hip navigation systems have been developed to combine the accuracy of cup positioning by large console navigation systems with the ease of use and convenience of conventional surgical techniques. Although a novel augmented reality-based portable hip navigation system using a smartphone (AR navigation) has become available recently, no studies, to our knowledge, have compared commercially available AR navigation with the conventional technique. Additionally, no studies, except for those from designer-surgeon series, have demonstrated the results of AR navigation. QUESTIONS/PURPOSES: (1) Does intraoperative use of commercially available AR navigation improve cup positioning compared with the conventional technique? (2) Are operative factors, clinical scores, and postoperative course different between the two groups? METHODS: In this randomized trial, 72 patients undergoing THA were randomly assigned to undergo either commercially available AR navigation or a conventional technique for cup placement. All patients received the same cementless acetabular cups through a posterior approach in the lateral decubitus position. The primary outcome of the present study was cup positioning, including the absolute differences between the intended target and angle achieved, as well as the number of cups inside the Lewinnek safe zone. Our target cup position was 40° abduction and 20° anteversion. Secondary outcomes were operative factors, between-group difference in improvement in the Hip Disability and Osteoarthritis Outcome Score (HOOS), and the postoperative course, including the operative time (between the start of the surgical approach and skin closure), procedure time (between the first incision and skin closure, including the time to insert pins, registration, and transfer and redrape patients in the navigation group), time taken to insert pins and complete registration in the navigation group, intraoperative and postoperative complications, and reoperations. The minimum follow-up period was 6 months, because data regarding the primary outcome-cup positioning-were collected within 1 week after surgery. The between-group difference in improvement in HOOS, which was the secondary outcome, was much lower than the minimum clinically important difference for the HOOS. No patients in either group were lost to follow-up, and there was no crossover (the randomized treatment was performed in all patients, so there was no difference between an intention-to-treat and a per-protocol analysis). RESULTS: The use of the commercially available AR navigation slightly improved cup positioning compared with the conventional technique in terms of the absolute difference between the desired and achieved amounts of cup abduction and anteversion (which we defined as "absolute differences"; median 1° [IQR 0° to 4.0°] versus median 5° [IQR 3.0° to 7.5°], difference of medians 4°; p < 0.001 and median 2° [IQR 1.9° to 3.7°] versus median 5° [IQR 3.2° to 9.7°], difference of medians 2°; p = 0.001). A higher proportion of cups were placed inside the Lewinnek safe zone in the navigation group than in the control group (94% [34 of 36] compared with 64% [23 of 36]; p < 0.001). Median operative times were not different between the two groups (58 minutes [IQR 49 to 72 minutes] versus 57 minutes [IQR 49 to 69 minutes], difference of medians 1 minute; p = 0.99). The median procedure time was longer in the navigation group (95 minutes [IQR 84 to 109 minutes] versus 57 minutes [IQR 49 to 69 minutes], difference of medians 38 minutes; p < 0.001). There were no differences between the two groups in improvement in HOOS (27 ± 17 versus 28 ± 19, mean difference -1 [95% CI -9.5 to 7.4]; p = 0.81). In the navigation group, no complications occurred in the pin sites; however, one anterior dislocation occurred. In the conventional group, one hip underwent reoperation because of a deep infection. CONCLUSION: Although the use of commercially available AR navigation improved cup positioning in THA, the improvement in clinical scores and postoperative complication rates were not different between the two groups, and the overall magnitude of the difference in accuracy was small. Future studies will need to determine whether the improvement in the percentage of hips inside the Lewinnek safe zone results in differences in late dislocation or polyethylene wear, and whether such benefits-if any-justify the added costs and surgical time. Until or unless more compelling evidence in favor of the new system emerges, we recommend against widespread use of the system in clinical practice. LEVEL OF EVIDENCE: Level Ⅱ, therapeutic study.

Temporal dynamics of gait function in acute cervical spinal cord injury.

BACKGROUND: Following spinal cord injury (SCI), gait function reaches a post-recovery plateau that depends on the paralysis severity. However, the plateau dynamics during the recovery period are not known. This study aimed to examine the gait function temporal dynamics after traumatic cervical SCI (CSCI) based on paralysis severity. METHODS: This retrospective cohort study included 122 patients with traumatic CSCI admitted to a single specialized facility within 2 weeks after injury. The Walking Index for Spinal Cord Injury II (WISCI II) was estimated at 2 weeks and 2, 4, 6, and 8 months postinjury for each American Spinal Injury Association Impairment Scale (AIS) grade, as determined 2 weeks postinjury. Statistical analysis was performed at 2 weeks to 2 months, 2-4 months, 4-6 months, and 6-8 months, and the time at which no significant difference was observed was considered the time at which the gait function reached a plateau. RESULTS: In the AIS grade A and B groups, no significant differences were observed at any time point, while in the AIS grade C group, the mean WISCI II values continued to significantly increase up to 6 months. In the AIS grade D group, the improvement in gait function was significant during the entire observation period. CONCLUSIONS: The plateau in gait function recovery was reached at 2 weeks postinjury in the AIS grade A and B groups and at 6 months in the AIS grade C group.

Three types of university students with subthreshold depression characterized by distinctive cognitive behavioral skills.

Subthreshold depression impairs young people's quality of life and places them at greater risk of developing major depression. Cognitive behavioral therapy (CBT) is an evidence-based approach for addressing such depressive states. This study identified subtypes of university students with subthreshold depression and revealed discrete profiles of five CBT skills: self-monitoring, cognitive restructuring, behavioral activation, assertive communication, and problem solving. Using data from the Healthy Campus Trial (registration number: UMINCTR-000031307), a hierarchical clustering analysis categorized 1,080 students into three clusters: Reflective Low-skilled, Non-reflective High-skilled, and Non-reflective Low-skilled students. Non-reflective Low-skilled students were significantly more depressed than other students (p < .001). The severity of depression seemed to be related to the combination of self-monitoring skills and other CBT skills. Considering the high prevalence of poor self-monitoring skills in persons with autism, the most severe depression was observed in the significant association between Non-reflective Low-skilled students and autistic traits (p = .008). These findings suggest that subthreshold depression can be categorized into three subtypes based on CBT skill profiles. The assessment of autistic traits is also suggested when we provide CBT interventions for Non-reflective Low-skilled students.

Predictive Value of Aortic Valve Calcium Volume Measured by Computed Tomography for Paravalvular Leakage After Transcatheter Aortic Valve Implantation.

Paravalvular leakage (PVL) is a complication of transcatheter aortic valve implantation (TAVI) for aortic stenosis, leading to an adverse prognosis. We investigated whether aortic valve calcium volume (Ca-Vol) measured by preoperative cardiac computed tomography had a predictive value for PVL after TAVI using a third-generation self-expandable valve.We retrospectively analyzed 59 consecutive patients who underwent TAVI using a third-generation self-expandable valve. We measured Ca-Vol in the aortic valve and each cusp (non-coronary cusp [NCC], right-coronary cusp [RCC], and left-coronary cusp [LCC]). We divided the patients into 2 groups: a PVL group (32.2%) and a non-PVL group (67.8%). Total Ca-Vol was significantly higher in the PVL group than in the non-PVL group (P < 0.001). Ca-Vol in each cusp was also significantly higher in the PVL group ([NCC] P < 0.001, [RCC] P = 0.001, [LCC] P < 0.001). Univariate logistic regression analysis for PVL indicated that the total and per-cusp Ca-Vols were predictors for PVL (total, odds ratio [OR] 4.0, P < 0.001; NCC, OR 12.5, P = 0.002; RCC, OR 16.0, P = 0.008; LCC, OR 44.5, P < 0.001).Receiver operating characteristic curve analysis of Ca-Vol for predicting PVL revealed the optimal cut-off values of Ca-Vol were 2.4 cm3 for the total, 0.74 cm3 for NCC, 0.73 cm3 for RCC, and 0.56 cm3 for LCC (area under the curve, 0.85, 0.79, 0.76, and 0.83, respectively).Preoperative total, NCC, RCC, and LCC calcium volumes were significant predictors for PVL after TAVI using third-generation self-expandable valves.

Root PRR7 Improves the Accuracy of the Shoot Circadian Clock through Nutrient Transport.

The circadian clock allows plants to anticipate and adapt to periodic environmental changes. Organ- and tissue-specific properties of the circadian clock and shoot-to-root circadian signaling have been reported. While this long-distance signaling is thought to coordinate physiological functions across tissues, little is known about the feedback regulation of the root clock on the shoot clock in the hierarchical circadian network. Here, we show that the plant circadian clock conveys circadian information between shoots and roots through sucrose and K+. We also demonstrate that K+ transport from roots suppresses the variance of period length in shoots and then improves the accuracy of the shoot circadian clock. Sucrose measurements and qPCR showed that root sucrose accumulation was regulated by the circadian clock. Furthermore, root circadian clock genes, including PSEUDO-RESPONSE REGULATOR7 (PRR7), were regulated by sucrose, suggesting the involvement of sucrose from the shoot in the regulation of root clock gene expression. Therefore, we performed time-series measurements of xylem sap and micrografting experiments using prr7 mutants and showed that root PRR7 regulates K+ transport and suppresses variance of period length in the shoot. Our modeling analysis supports the idea that root-to-shoot signaling contributes to the precision of the shoot circadian clock. We performed micrografting experiments that illustrated how root PRR7 plays key roles in maintaining the accuracy of shoot circadian rhythms. We thus present a novel directional signaling pathway for circadian information from roots to shoots and propose that plants modulate physiological events in a timely manner through various timekeeping mechanisms.

Comparison of Pharmacokinetics of the GalNAc-Conjugated Antisense Oligonucleotide GSK3389404 in Participants with Chronic Hepatitis B Infection across the Asia-Pacific Region.

GSK3389404, an N-acetyl galactosamine-conjugated antisense oligonucleotide (ASO), was in clinical development for chronic hepatitis B (CHB) treatment. Few studies have examined ASOs in Asian participants. In this analysis, the plasma pharmacokinetics (PK) of GSK3389404 were characterized and compared in patients with CHB across the Asia-Pacific region (N = 64), including mainland China (n = 16), Hong Kong (n = 8), Japan (n = 21), South Korea (n = 12), Singapore (n = 4), and the Philippines (n = 3), from a phase 2a, multicenter, randomized, double-blind, placebo-controlled study (NCT03020745). Hepatitis B(e) antigen-positive and -negative patients (on or not on stable nucleos[t]ide regimens) received single (30 mg or 120 mg) or multiple (30 mg, 60 mg, or 120 mg weekly or 120 mg biweekly) subcutaneous GSK3389404 injections. The plasma concentrations were measured on day 1 in all cohorts as well as on days 29 and 57 in the multiple-dose cohorts. The GSK3389404 plasma PK were similar to those reported in a previous study in non-Asian healthy participants with a median time to peak concentration (tmax) of 1 to 4 h postdose, a mean half-life of 3 to 5 h across cohorts, and no accumulation following repeat dosing. The GSK3389404 plasma tmax and half-life values were dose-independent. The increase in the plasma peak concentration (Cmax) and the area under the concentration versus time curve (AUC) was dose-proportional from 60 to 120 mg and greater than dose-proportional from 30 to 60 or 120 mg. The GSK3389404 plasma concentration versus time profiles, half-life, tmax, Cmax, and AUC values were all comparable across the Asia-Pacific populations. Given the similarity of the PK among ASOs, this analysis suggests that the PK from any Asia-Pacific population may be used to guide ASO dose selection in the Asia-Pacific region.

The Adaptation Front Equation Explains Innovation-Driven Taxonomic Turnovers and Living Fossilization.

AbstractEvolutionary taxonomic turnovers are often associated with innovations beneficial in various ecological niches. Such innovations can repeatedly occur in species occupying optimum niches for a focal species group, resulting in their repeated diversifications and species flows from optimum to suboptimum niches, at the expense of less innovated ones. By combining species packing theory and adaptive dynamics theory, we develop an equation that allows analytical prediction for such innovation-driven species flows over a niche space of arbitrary dimension under a unimodal carrying capacity distribution. The developed equation and simulated evolution show that central niches (with the highest carrying capacities) tend to attain the fastest innovation speeds to become biodiversity sources. Species that diverge from the central niches outcompete the indigenous species in peripheral niches. The outcompeted species become extinct or evolve directionally toward far more peripheral niches. Because of this globally acting process over niches, species occupying the most peripheral niches are the least innovated and have deep divergence times from their closest relatives, and thus they correspond to living fossils. The extension of this analysis for multiple geographic regions shows that living fossils are also expected in geographically peripheral regions for the focal species group.

Temporary balloon occlusion test can overestimate the risk of acute pulmonary edema after transcatheter atrial septal defect closure.

BACKGROUND: Atrial septal defect (ASD) closure can cause acute pulmonary edema. Before transcatheter closure is performed, temporary balloon occlusion test (BOT) is recommended in patients with left ventricular dysfunction to predict the risk of pulmonary edema. However, the accuracy of BOT has not been verified. This study aimed to compare hemodynamic differences between BOT and transcatheter closure. METHODS: A total of 42 patients with a single ASD over age 18 years who underwent BOT before transcatheter ASD closure between October 2010 and May 2020 were analyzed. Pulmonary capillary wedge pressure (PCWP) was measured using a Swan-Ganz catheter placed in the pulmonary artery at baseline, after 10 min of BOT, and after transcatheter closure. Amplatzer septal occluder was used for all transcatheter closures. RESULTS: Mean patient age was 64 ± 18 years (range, 18-78). Mean ASD diameter and pulmonary to systemic flow ratio were 18 ± 5 and 2.8 ± 1.0 mm, respectively. Mean PCWP at baseline, during BOT, and after transcatheter closure was 8.9 ± 2.9, 13.5 ± 4.2, and 9.5 ± 2.6 mmHg, respectively. The difference between BOT and after transcatheter closure values was significant (p < 0.001). During BOT, PCWP increased ≥18 mmHg in 7 patients, whereas after ASD closure, PCWP was <18 mmHg in all 7 and none developed acute pulmonary edema. CONCLUSION: Temporary balloon occlusion of an ASD and transcatheter ASD closure result in different hemodynamic change. BOT overestimates increase of PCWP after transcatheter ASD closure and requires careful interpretation. Well-designed, larger studies in higher-risk patients are warranted to verify the clinical implications of BOT in more detail.