Preclinical and clinical efficacy of kappa opioid receptor antagonists for depression: A systematic review.

BACKGROUND: Approximately 30 % of persons with Major Depressive Disorder (MDD) inadequately respond to conventional antidepressants. Kappa opioid receptor (KOR) antagonists, aticaprant and navacaprant, are in development as treatments for MDD. Herein, we aim to comprehensively evaluate the safety, efficacy and pharmacology of aticaprant and navacaprant for MDD. METHODS: We performed a systematic review of primary research investigating aticaprant and navacaprant on PubMed, OVID, and Scopus databases from inception to April 2024. Studies that reported on the pharmacological profile and/or safety and efficacy of aticaprant and navacaprant were included. RESULTS: Navacaprant monotherapy and aticaprant adjunctive therapy are in development for MDD. Navacaprant exhibits 300-fold selectivity for the KOR compared to the mu-opioid receptor, while aticaprant exhibits 30-fold selectivity. At clinically-relevant doses, navacaprant and aticaprant occupy 87-95 % and 73-94 % of KORs, respectively. Clinical trials of the foregoing agents (navacaprant as monotherapy and actiprant as adjunctive therapy) reported significant improvement in depressive symptoms and may clinically benefit measures of anhedonia. Both agents appear well-tolerated, with most adverse events mild and no known safety concerns. LIMITATIONS: Aticaprant and navacaprant treatment for MDD are in early stages of clinical trials and results from Phase 3 pivotal trials are not yet available. CONCLUSIONS: Kappa opioid receptor antagonists may serve as mechanistically-novel treatments for MDD and persons who inadequately respond to index conventional antidepressants. Anhedonia is debilitating and insufficiently treated with conventional antidepressants. Future research vistas should establish the efficacy and safety of KORAs in phase 3 studies in both acute and maintenance paradigms.

An evaluation of the outcomes associated with peritoneal catheter use in neonates undergoing cardiac surgery: A multicenter study.

Objective: The study objective was to determine if intraoperative peritoneal catheter placement is associated with improved outcomes in neonates undergoing high-risk cardiac surgery with cardiopulmonary bypass. Methods: This propensity score-matched retrospective study used data from 22 academic pediatric cardiac intensive care units. Consecutive neonates undergoing Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery category 3 to 5 cardiac surgery with cardiopulmonary bypass at centers participating in the NEonatal and Pediatric Heart Renal Outcomes Network collaborative were studied to determine the association of the use of an intraoperative placed peritoneal catheter for dialysis or passive drainage with clinical outcomes, including the duration of mechanical ventilation. Results: Among 1490 eligible neonates in the NEonatal and Pediatric Heart Renal Outcomes Network dataset, a propensity-matched analysis was used to compare 395 patients with peritoneal catheter placement with 628 patients without peritoneal catheter placement. Time to extubation and most clinical outcomes were similar. Postoperative length of stay was 5 days longer in the peritoneal catheter placement cohort (17 vs 22 days, P = .001). There was a 50% higher incidence of moderate to severe acute kidney injury in the no-peritoneal catheter cohort (12% vs 18%, P = .02). Subgroup analyses between specific treatments and in highest risk patients yielded similar associations. Conclusions: This study does not demonstrate improved outcomes among neonates with placement of a peritoneal catheter during cardiac surgery. Outcomes were similar apart from longer hospital stay in the peritoneal catheter cohort. The no-peritoneal catheter cohort had a 50% higher incidence of moderate to severe acute kidney injury (12% vs 18%). This analysis does not support indiscriminate peritoneal catheter use, although it may support the utility for postoperative fluid removal among neonates at risk for acute kidney injury. A multicenter controlled trial may better elucidate peritoneal catheter effects.

Impact of vortioxetine on depressive symptoms moderated by symptoms of anxiety in persons with post-COVID-19 condition: A secondary analysis.

OBJECTIVE: Recovery from a COVID-19 infection can lead to post-COVID-19 condition (PCC), which causes a multitude of debilitating symptoms that negatively affect an individual's health-related quality of life, including depressive and anxiety symptoms. We aim to examine the mediatory effects of anxiety on depressive symptoms in persons with PCC receiving vortioxetine. METHODS: We performed a post-hoc analysis of a randomized, double-blinded, placebo-controlled clinical trial investigating vortioxetine treatment on cognitive functioning in persons with PCC. Anxiety and depressive symptoms were measured by the 7-Item Generalized Anxiety Disorder (GAD-7) Scale and the 16-Item Quick Inventory of Depressive Symptomatology (QIDS-SR-16), respectively. RESULTS: Based on data of 147 participants, GAD-7 scores were significantly positively associated with QIDS-SR-16 scores (ß=0.038, 95 % CI [0.029,0.047], p < 0.001). After adjusting for covariates, a significant group (χ2=176.786, p < 0.001), time (χ2=8.914, p = 0.003), and treatment x time x GAD-7 score interaction (χ2=236.483, p < 0.001) effect was observed. Vortioxetine-treated participants had a significant difference in overall change in depressive symptoms (mean difference=-3.15, SEM=0.642, 95 % CI [-4.40,-1.89], p < 0.001). CONCLUSION: Anxiety symptoms were significantly associated with depressive symptoms in persons with PCC. Antidepressant efficacy on ameliorating depressive symptoms is dependent on improving anxiety symptoms, underscoring significant implications in improving treatment efficacy and patient quality of life.

Effect of gamification with a support partner to increase physical activity in older adults at risk for Alzheimer's disease: The STEP 4Life randomized clinical trial.

INTRODUCTION: Physical activity is associated with reduced risk of cognitive and functional decline but scalable, sustainable interventions for populations at risk for Alzheimer's disease (AD) and AD and related dementias (ADRD) are lacking. METHODS: A 12-week randomized-controlled trial was conducted with a 3-week follow-up using a national AD prevention registry (GeneMatch). The control group (n = 50) set step goals and received daily feedback. The intervention group (n = 44) also received a behaviorally designed game based on achieving step goals and reinforced by a support partner. RESULTS: Intervention participants (94 participants, mean age 70, 78% female) had greater change in mean daily step count than control of 1699 steps/day (95% confidence interval [CI], 1149-2249), P < 0.0001, which was sustained in the follow-up period at 1219 steps/day (95% CI, 455-1983), P = 0.0018. Carriers of the apolipoprotein E ε4 gene (high risk) did not perform differently than non-carriers; however, high self-reported risk perception was associated with higher activity. DISCUSSION: A gamified intervention was effective in promoting and sustaining higher physical activity in older adults at genetic risk for AD/ADRD. HIGHLIGHTS: A simple game played with a support partner increased walking in older adults at risk for Alzheimer's disease (AD). The game also increased minutes of moderate-to-vigorous physical activity per day. Perception of lifelong AD risk was associated with increased activity but genetic risk (apolipoprotein E ε4+) was not. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05069155.

Gestational exposure to organochlorine compounds and metals and infant birth weight: effect modification by maternal hardships.

BACKGROUND: Gestational exposure to toxic environmental chemicals and maternal social hardships are individually associated with impaired fetal growth, but it is unclear whether the effects of environmental chemical exposure on infant birth weight are modified by maternal hardships. METHODS: We used data from the Maternal-Infant Research on Environmental Chemicals (MIREC) Study, a pan-Canadian cohort of 1982 pregnant females enrolled between 2008 and 2011. We quantified eleven environmental chemical concentrations from two chemical classes - six organochlorine compounds (OCs) and five metals - that were detected in ≥ 70% of blood samples collected during the first trimester. We examined fetal growth using birth weight adjusted for gestational age and assessed nine maternal hardships by questionnaire. Each maternal hardship variable was dichotomized to indicate whether the females experienced the hardship. In our analysis, we used elastic net to select the environmental chemicals, maternal hardships, and 2-way interactions between maternal hardships and environmental chemicals that were most predictive of birth weight. Next, we obtained effect estimates using multiple linear regression, and plotted the relationships by hardship status for visual interpretation. RESULTS: Elastic net selected trans-nonachlor, lead, low educational status, racially minoritized background, and low supplemental folic acid intake. All were inversely associated with birth weight. Elastic net also selected interaction terms. Among those with increasing environmental chemical exposures and reported hardships, we observed stronger negative associations and a few positive associations. For example, every two-fold increase in lead concentrations was more strongly associated with reduced infant birth weight among participants with low educational status (ß = -100 g (g); 95% confidence interval (CI): -215, 16), than those with higher educational status (ß = -34 g; 95% CI: -63, -3). In contrast, every two-fold increase in mercury concentrations was associated with slightly higher birth weight among participants with low educational status (ß = 23 g; 95% CI: -25, 71) compared to those with higher educational status (ß = -9 g; 95% CI: -24, 6). CONCLUSIONS: Our findings suggest that maternal hardships can modify the associations of gestational exposure to some OCs and metals with infant birth weight.

Clinical Outcomes of Arteriovenous Fistula Treatment Using the Penumbra SMART COIL System: A Subgroup Analysis from the Multicenter SMART Registry.

BACKGROUND: Endovascular embolization procedures are typically the primary treatment modality for arteriovenous fistula (AVF). The objective of this subset analysis was to evaluate the prospective long-term clinical outcomes of AVF patients treated with the SMART COIL System. METHODS: Patients who had arteriovenous fistulas (AVF) and underwent endovascular coiling using the Penumbra SMART COIL system were part of a subset analysis within the SMART registry. The SMART registry is a post-market registry that is prospective, multicenter, and single-arm in design. After the treatment, these patients were monitored for a period of 12 ± 6 months. RESULTS: A total of 41 patients were included. No patients (0/41) had a procedural device-related serious adverse event (SAE). Re-access involving a guidewire due to catheter kickout was unnecessary for 85.4% (35/41) of the patients. Complete occlusion after the procedure was achieved in 87.8% (36/41) of patients. The periprocedural SAE rate was 2.4% (1/41), and no periprocedural deaths occurred (0/41). During the follow-up period, there were instances of re-treatment in 3.4% (1/29) of patients. At one year, the lesion occlusion was better or stable in 93.3% (28/30) of patients. The rate of serious adverse events (SAE) from 24 hours to 1 year (±6 months) following the procedure was 26.8% (11/41). The one-year all-cause mortality rate stood at 2.4% (1/ 41), and at the one-year follow-up, 90.9% (20/22) of patients had a modified Rankin Scale score within the range of 0 to 2. CONCLUSION: The coiling procedure for arteriovenous fistulas using the SMART COIL System proved to be safe and effective at the one-year follow-up.

Impact of Bariatric Surgery on Asthma Severity and Medication Use.

INTRODUCTION: Bariatric surgery improves many obesity-related comorbidities, yet the literature remains inconclusive on the impact of bariatric surgery on asthma. Our primary objective was to identify the long-term impact of bariatric surgery on asthma severity and medication use. METHODS: A retrospective review was completed of all patients with a diagnosis of asthma who underwent bariatric surgery over 10 years at a single institution. Primary outcomes were the number of asthma medications prescribed at five time points (preoperative, postoperative < 18 months, 19-36 months, 37-60 months, 60 + months) after bariatric surgery. Secondary outcomes were spirometry results and BMI. RESULTS: There were 260 patients with 84.6% female predominance. There were 168 sleeve gastrectomy patients and 92 Roux-en-Y gastric bypass patients. Mean age was 47.6 ± 10.7 years, mean BMI was 46.0 ± 6.8 kg/m2, and 54.2% were previous tobacco users. The total number of patients on two or more asthma medications decreased from 46% preoperatively to 41% at 18 months, to 36% at 36 months, and to 32% at 60 months after surgery. The total number of patients free from asthma medication increased from 25% preoperatively to 33% at 60 months postoperatively. Asthma medication use decreased in both surgery groups, and neither operation demonstrated superiority. No significant improvement nor differences were found between groups at any time point regarding FEV1/FVC ratio spirometry measures. CONCLUSION: Bariatric surgery reduces the use of medications taken for management of asthma. The amount of asthma medication usage decreases with time and is sustained at 60 months after bariatric surgery.

A Case-based Guide for World Health Organization (WHO) Grade 2 Meningioma Radiosurgery and Radiation Therapy from The Radiosurgery Society.

PURPOSE: Meningiomas represent the most common primary tumor of the central nervous system. Current treatment options include surgical resection with or without adjuvant radiation therapy (RT), definitive RT, and observation. However, the radiation dose, fractionation, and margins used to treat patients with WHO grade 2 meningiomas, which account for approximately 20% of all meningiomas, are not clearly defined, and deciding on the optimal treatment modality can be challenging owing to the lack of randomized data. METHODS AND MATERIALS: In this manuscript, 3 cases of patients with WHO grade 2 meningiomas are presented with descriptions of treatment options after gross total resection, subtotal resection, and previous irradiation. Treatment recommendations were compiled from 9 central nervous system radiation oncology and neurosurgery experts from The Radiosurgery Society, and the consensus of treatment recommendations is reported. RESULTS: Both conventional and stereotactic RT are treatment options for WHO grade 2 meningiomas. The majority of prospective data in the setting of WHO grade 2 meningiomas involve larger margins. Stereotactic radiosurgery/hypofractionated stereotactic RT are less appropriate in this setting. Conventionally fractionated RT to at least 59.4 Gy is considered standard of care with utilization of preoperative and postoperative imaging to evaluate the extent of disease and possible osseous involvement. After careful discussion, stereotactic radiosurgery/hypofractionated stereotactic RT may play a role for the subset of patients who are unable to tolerate the standard lengthy conventionally fractionated treatment course, for those with prior RT, or for small residual tumors. However, more studies are needed to determine the optimal approach. CONCLUSIONS: This case-based evaluation of the current literature seeks to provide examples for the management of grade 2 meningiomas and give examples of both conventional and stereotactic RT.

Establishing a Collaborative Orthoplastic Approach for the Management of Primary Musculoskeletal Neoplasms: An 8-year Case Series.

Orthoplastic surgery is a multidisciplinary approach that is well-studied for extremity trauma, but not for musculoskeletal oncologic reconstruction. Here, the authors describe the application of a collaborative orthoplastic approach for the management of primary musculoskeletal neoplasms and evaluate its impact. The collaboration protocol, implemented in July 2019, comprises specific checkpoints of interdisciplinary co-management, which span the pre-, intra-, and postoperative treatment period. This involves direct communication between attending surgeons and their respective clinical teams. Patients who underwent resection of a primary musculoskeletal neoplasm between March 2014 and April 2022 were retrospectively categorized into conventional or collaboration groups. Of the 136 total patients, there were 63.2% (n = 86) conventional and 36.8% (n = 50) collaboration; 31.6% (n = 43) had reconstruction and 68.4% (n = 93) did not. Compared with the conventional group, the collaboration group had significantly higher rates of diabetes (18% versus 7%, P = 0.048) and radiation treatment (68% versus 43%, P = 0.005). The collaboration group was significantly more likely to have plastic surgery involvement in their care than the conventional group (38% versus 14%, P = 0.001), and to undergo reconstruction (42% versus 26%, P = 0.047). The groups showed no difference in rates of hematoma, seroma, delayed healing, infection, 30- or 90-day reoperation, or partial or complete flap/graft failure. The collaborative approach described here is feasible and associated with increased plastic surgery involvement and reconstructive surgery. Complications were equivalent despite evidence suggesting increased case complexity in the collaboration group. These early results are promising and could inspire wider adoption of structured orthoplastic protocols for care of these patients.

Effects of volume-matched once-weekly and thrice-weekly high-intensity interval training (HIIT) on body adiposity in adults with central obesity: Study protocol for a randomized controlled trial.

Objective: This study aims to examine the comparative effects of 75 min of volume-matched once-weekly and thrice-weekly high-intensity interval training (HIIT) on body adiposity in adults with central obesity. Methods: This assessor-blinded, three-arm, randomized controlled trial will recruit 315 physically inactive adults with central obesity (aged ≥18 years, body mass index ≥23, waist circumference ≥90 cm for men and ≥80 cm for women). Participants will be randomly allocated to the once-weekly HIIT, thrice-weekly HIIT or usual care control group. Participants in the HIIT groups will receive weekly exercise training sessions for 16 weeks, prescribed either once or three times weekly. Each HIIT session will consist of a supervised program of four 4-min high-intensity intervals at 85%-95% peak heart rate (HRpeak) interspersed with 3-min active recovery intervals at 50%-70% HRpeak. Participants in the once-weekly HIIT group will perform the 25-min HIIT bout three times with a break between each 25-min HIIT bout. The usual care control group will receive bi-weekly health education classes. The outcome assessments will be conducted at baseline, 16 weeks (post-intervention) and 32 weeks (follow-up). The primary outcome will be total body adiposity assessed by dual-energy X-ray absorptiometry (DXA). The secondary outcome measures will include markers of cardiovascular and metabolic health (body composition, cardiorespiratory fitness, blood pressure, and blood lipids), mental health, cognitive performance, health-related quality of life, sleep quality, habitual physical activity, diet, medication, adverse events and adherence to the intervention. Impact of the project: The findings from this study are expected to consolidate the therapeutic efficacy of HIIT for the management of central obesity and inform the comparative compliance, feasibility and suitability of once-weekly and thrice-weekly HIIT as exercise strategies to manage obesity. In particular, the present study is expected to provide a novel perspective on the utility of low-frequency HIIT (i.e., once-weekly) as an effective and sustainable exercise strategy to tackle the obesity pandemic. The anticipated findings will hold substantial translational value by informing public health policies and enhancing exercise compliance in the physically inactive obese population. Trial registration: ClinicalTrials.gov (NCT04887454).

Centers for Medicare and Medicaid Services Coverage of Amyloid PET.

This Viewpoint discusses the ambiguity of amyloid positron emission tomography coverage in the era of anti-amyloid therapeutics and the considerations and consequences of narrow coverage.

HIV-1 Vpr combats the PU.1-driven antiviral response in primary human macrophages.

HIV-1 Vpr promotes efficient spread of HIV-1 from macrophages to T cells by transcriptionally downmodulating restriction factors that target HIV-1 Envelope protein (Env). Here we find that Vpr induces broad transcriptomic changes by targeting PU.1, a transcription factor necessary for expression of host innate immune response genes, including those that target Env. Consistent with this, we find silencing PU.1 in infected macrophages lacking Vpr rescues Env. Vpr downmodulates PU.1 through a proteasomal degradation pathway that depends on physical interactions with PU.1 and DCAF1, a component of the Cul4A E3 ubiquitin ligase. The capacity for Vpr to target PU.1 is highly conserved across primate lentiviruses. In addition to impacting infected cells, we find that Vpr suppresses expression of innate immune response genes in uninfected bystander cells, and that virion-associated Vpr can degrade PU.1. Together, we demonstrate Vpr counteracts PU.1 in macrophages to blunt antiviral immune responses and promote viral spread.

Assessing CT-based Volumetric Analysis via Transfer Learning with MRI and Manual Labels for Idiopathic Normal Pressure Hydrocephalus.

Background: Brain computed tomography (CT) is an accessible and commonly utilized technique for assessing brain structure. In cases of idiopathic normal pressure hydrocephalus (iNPH), the presence of ventriculomegaly is often neuroradiologically evaluated by visual rating and manually measuring each image. Previously, we have developed and tested a deep-learning-model that utilizes transfer learning from magnetic resonance imaging (MRI) for CT-based intracranial tissue segmentation. Accordingly, herein we aimed to enhance the segmentation of ventricular cerebrospinal fluid (VCSF) in brain CT scans and assess the performance of automated brain CT volumetrics in iNPH patient diagnostics. Methods: The development of the model used a two-stage approach. Initially, a 2D U-Net model was trained to predict VCSF segmentations from CT scans, using paired MR-VCSF labels from healthy controls. This model was subsequently refined by incorporating manually segmented lateral CT-VCSF labels from iNPH patients, building on the features learned from the initial U-Net model. The training dataset included 734 CT datasets from healthy controls paired with T1-weighted MRI scans from the Gothenburg H70 Birth Cohort Studies and 62 CT scans from iNPH patients at Uppsala University Hospital. To validate the model's performance across diverse patient populations, external clinical images including scans of 11 iNPH patients from the Universitatsmedizin Rostock, Germany, and 30 iNPH patients from the University of Alabama at Birmingham, United States were used. Further, we obtained three CT-based volumetric measures (CTVMs) related to iNPH. Results: Our analyses demonstrated strong volumetric correlations (ϱ=0.91, p<0.001) between automatically and manually derived CT-VCSF measurements in iNPH patients. The CTVMs exhibited high accuracy in differentiating iNPH patients from controls in external clinical datasets with an AUC of 0.97 and in the Uppsala University Hospital datasets with an AUC of 0.99. Discussion: CTVMs derived through deep learning, show potential for assessing and quantifying morphological features in hydrocephalus. Critically, these measures performed comparably to gold-standard neuroradiology assessments in distinguishing iNPH from healthy controls, even in the presence of intraventricular shunt catheters. Accordingly, such an approach may serve to improve the radiological evaluation of iNPH diagnosis/monitoring (i.e., treatment responses). Since CT is much more widely available than MRI, our results have considerable clinical impact.

Management of Proximal Hamstring Injuries: Non-operative and Operative Treatment.

PURPOSE OF REVIEW: To evaluate the current evidence and literature on treatment options for proximal hamstring injuries. RECENT FINDINGS: Patients with 3-tendon complete tears with greater than 2 cm of retraction have worse outcomes and higher complication rates compared to those with less severe injuries. Endoscopic and open proximal hamstring repair both have favorable patient reported outcomes at 5-year follow up. Proximal hamstring repair in patients who are male, with isolated semimembranosus injury, and have proximal hamstring free tendon rupture are more likely to have earlier return to sports. The Parisian Hamstring Avulsion Score (PHAS) is a validated patient-reported outcome measure to predict return to sports. Proximal hamstring injuries may occur in both elite and recreational athletes and may present with varying degrees of chronicity and severity. Injuries occur most commonly during forceful eccentric contraction of the hamstrings and often present with ischial tuberosity tenderness, ecchymosis, and hamstring weakness. Treatment decision-making is dictated by the tendons involved and chronicity. Many proximal hamstring injuries can be successfully treated with non-surgical measures. However, operative treatment of appropriately indicated proximal hamstring tendon injuries can result in significantly better functional outcomes and faster and more reliable return to sports compared to nonoperative treatment. Both endoscopic and open surgical repair techniques show high satisfaction levels and excellent patient-reported outcomes at short- and mid-term follow-up. Postoperative rehabilitation protocols vary across the literature and ongoing study is needed to clarify the optimal program, though emphasis on eccentric hamstring strengthening may be beneficial.

Chronic hyperglycemia aggravates lung function in a Scnn1b-Tg murine model.

Cystic fibrosis-related diabetes (CFRD), the most common comorbidity in cystic fibrosis (CF), leads to increased mortality by accelerating the decline in lung function. Scnn1b-Tg transgenic mice overexpressing the epithelial sodium channel ß subunit exhibit spontaneous CF-like lung disease, including airway mucus obstruction and chronic inflammation. Here, we established a chronic CFRD-like model utilizing Scnn1b-Tg mice made diabetic by injection of streptozotocin. In Ussing chamber recordings of trachea, Scnn1b-Tg mice exhibited larger amiloride-sensitive currents and forskolin-activated currents, without a difference in ATP-activated currents compared to wildtype (WT) littermates. Both diabetic WT (WT-D) and diabetic Scnn1b-Tg (Scnn1b-Tg-D) mice on the same genetic background exhibited substantially elevated blood glucose at 8 weeks; glucose levels also were elevated in bronchoalveolar lavage fluid (BALF) Bulk lung RNA-seq data showed significant differences between WT-D and Scnn1b-Tg-D mice. Neutrophil counts in BALF were substantially increased in Scnn1b-Tg-D lungs compared to controls (Scnn1b-Tg-con) and compared to WT-D lungs. Lung histology data showed enhanced parenchymal destruction, alveolar wall thickening, and neutrophilic infiltration in Scnn1b-Tg-D mice compared to WT-D mice, consistent with development of a spontaneous lung infection. We intranasally administered Pseudomonas aeruginosa to induce lung infection in these mice for 24 hours, which led to severe lung leukocytic infiltration and an increase in pro-inflammatory cytokine levels in the BALF. In summary, we established a chronic CFRD-like lung mouse model using the Scnn1b-Tg mice. The model can be utilized for future studies toward understanding the mechanisms underlying the lung pathophysiology associated with CFRD and developing novel therapeutics.

Deuterium Metabolic Imaging of Alzheimer Disease at 3-T Magnetic Field Strength: A Pilot Case-Control Study.

Background Impaired glucose metabolism is characteristic of several types of dementia, preceding cognitive symptoms and structural brain changes. Reduced glucose uptake in specific brain regions, detected using fluorine 18 (18F) fluorodeoxyglucose (FDG) PET, is a valuable diagnostic marker in Alzheimer disease (AD). However, the use of 18F-FDG PET in clinical practice may be limited by equipment availability and high cost. Purpose To test the feasibility of using MRI-based deuterium (2H) metabolic imaging (DMI) at a clinical magnetic field strength (3 T) to detect and localize changes in the concentration of glucose and its metabolites in the brains of patients with a clinical diagnosis of AD. Materials and Methods Participants were recruited for this prospective case-control pilot study between March 2021 and February 2023. DMI was performed at 3 T using a custom birdcage head coil following oral administration of deuterium-labeled glucose (0.75 g/kg). Unlocalized whole-brain MR spectroscopy (MRS) and three-dimensional MR spectroscopic imaging (MRSI) (voxel size, 3.2 cm cubic) were performed. Ratios of 2H-glucose, 2H-glutamate and 2H-glutamine (2H-Glx), and 2H-lactate spectroscopic peak signals to 2H-water peak signal were calculated for the whole-brain MR spectra and for individual MRSI voxels. Results A total of 19 participants, including 10 participants with AD (mean age, 68 years ± 5 [SD]; eight males) and nine cognitively healthy control participants (mean age, 70 years ± 6; six males) were evaluated. Whole-brain spectra demonstrated a reduced ratio of 2H-Glx to 2H-glucose peak signals in participants with AD compared with control participants (0.41 ± 0.09 vs 0.58 ± 0.20, respectively; P = .04), suggesting an impairment of oxidative glucose metabolism in AD. However, there was no evidence of localization of these changes to the expected regions of metabolic impairment at MRSI, presumably due to insufficient spatial resolution. Conclusion DMI at 3 T demonstrated impairment of oxidative glucose metabolism in the brains of patients with AD but no evidence of regional signal differences. © RSNA, 2024 Supplemental material is available for this article.

Glucose-6-phosphate dehydrogenase maintains redox homeostasis and biosynthesis in LKB1-deficient KRAS-driven lung cancer.

Cancer cells depend on nicotinamide adenine dinucleotide phosphate (NADPH) to combat oxidative stress and support reductive biosynthesis. One major NADPH production route is the oxidative pentose phosphate pathway (committed step: glucose-6-phosphate dehydrogenase, G6PD). Alternatives exist and can compensate in some tumors. Here, using genetically-engineered lung cancer mouse models, we show that G6PD ablation significantly suppresses KrasG12D/+;Lkb1-/- (KL) but not KrasG12D/+;P53-/- (KP) lung tumorigenesis. In vivo isotope tracing and metabolomics reveal that G6PD ablation significantly impairs NADPH generation, redox balance, and de novo lipogenesis in KL but not KP lung tumors. Mechanistically, in KL tumors, G6PD ablation activates p53, suppressing tumor growth. As tumors progress, G6PD-deficient KL tumors increase an alternative NADPH source from serine-driven one carbon metabolism, rendering associated tumor-derived cell lines sensitive to serine/glycine depletion. Thus, oncogenic driver mutations determine lung cancer dependence on G6PD, whose targeting is a potential therapeutic strategy for tumors harboring KRAS and LKB1 co-mutations.

Provider and administrator attitudes and experiences with implementing telebuprenorphine during the COVID-19 pandemic: a mixed-methods survey.

Introduction: This mixed-methods study assessed buprenorphine provider and administrator perceptions and experiences in offering telebuprenorphine during the COVID-19 pandemic. Methods: Semi-structured interviews were conducted between June 2021 and September 2021 among telebuprenorphine providers and administrators (N=16) and assessed for program design and implementation strategies, clinical workflow, patient-level factors influencing program entry and retention, and challenges and solutions to improving clinical care. Results: Clinician (n=15) and administrator (n=1) participants identified changes to clinical workflow, including increased administrative tasks to confirm patient receipt of prescribed medications, completion of referrals to community- or specialty treatment, and locating available pharmacies and laboratory services. Challenges consisted of staff redeployment to COVID-19 related responsibilities, prior authorization requirements for buprenorphine prescriptions, billing structures that under-reimbursed for telephone or video visits, and concerns with changes in government regulations. Strategies to improving telebuprenorphine included offering "hotlines" to facilitate same-day visits, expanding between-visit support, establishing workflows with community pharmacies to ensure seamless dispensing of buprenorphine, co-location of behavioral health providers, and distributing donated mobile phones to patients. Suggested technologies for enhancing care included text messaging (75%) and smartphone applications (56.3%). Conclusions: Findings from this study highlight considerable heterogeneity in the delivery of telebuprenorphine services.

Engaging Mood Brain Circuits with Psilocybin (EMBRACE): a study protocol for a randomized, placebo-controlled and delayed-start, neuroimaging trial in depression.

BACKGROUND: Major depressive disorder (MDD) is a leading cause of disability worldwide across domains of health and cognition, affecting overall quality of life. Approximately one third of individuals with depression do not fully respond to treatments (e.g., conventional antidepressants, psychotherapy) and alternative strategies are needed. Recent early phase trials suggest psilocybin may be a safe and efficacious intervention with rapid-acting antidepressant properties. Psilocybin is thought to exert therapeutic benefits by altering brain network connectivity and inducing neuroplastic changes that endure for weeks post-treatment. Although early clinical results are encouraging, psilocybin's acute neurobiological effects on neuroplasticity have not been fully investigated. We aim to examine for the first time how psilocybin acutely (intraday) and subacutely (weeks) alters functional brain networks implicated in depression. METHODS: Fifty participants diagnosed with MDD or persistent depressive disorder (PDD) will be recruited from a tertiary mood disorders clinic and undergo 1:1 randomization into either an experimental or control arm. Participants will be given either 25 mg psilocybin or 25 mg microcrystalline cellulose (MCC) placebo for the first treatment. Three weeks later, those in the control arm will transition to receiving 25 mg psilocybin. We will investigate whether treatments are associated with changes in arterial spin labelling and blood oxygenation level-dependent contrast neuroimaging assessments at acute and subacute timepoints. Primary outcomes include testing whether psilocybin demonstrates acute changes in (1) cerebral blood flow and (2) functional brain activity in networks associated with mood regulation and depression when compared to placebo, along with changes in MADRS score over time compared to placebo. Secondary outcomes include changes across complementary clinical psychiatric, cognitive, and functional scales from baseline to final follow-up. Serum peripheral neurotrophic and inflammatory biomarkers will be collected at baseline and follow-up to examine relationships with clinical response, and neuroimaging measures. DISCUSSION: This study will investigate the acute and additive subacute neuroplastic effects of psilocybin on brain networks affected by depression using advanced serial neuroimaging methods. Results will improve our understanding of psilocybin's antidepressant mechanisms versus placebo response and whether biological measures of brain function can provide early predictors of treatment response. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT06072898. Registered on 6 October 2023.

Human promoter directionality is determined by transcriptional initiation and the opposing activities of INTS11 and CDK9.

RNA polymerase II (RNAPII) transcription initiates bidirectionally at many human protein-coding genes. Sense transcription usually dominates and leads to messenger RNA production, whereas antisense transcription rapidly terminates. The basis for this directionality is not fully understood. Here, we show that sense transcriptional initiation is more efficient than in the antisense direction, which establishes initial promoter directionality. After transcription begins, the opposing functions of the endonucleolytic subunit of Integrator, INTS11, and cyclin-dependent kinase 9 (CDK9) maintain directionality. Specifically, INTS11 terminates antisense transcription, whereas sense transcription is protected from INTS11-dependent attenuation by CDK9 activity. Strikingly, INTS11 attenuates transcription in both directions upon CDK9 inhibition, and the engineered recruitment of CDK9 desensitises transcription to INTS11. Therefore, the preferential initiation of sense transcription and the opposing activities of CDK9 and INTS11 explain mammalian promoter directionality.