Single cell tracing of Pomc neurons reveals recruitment of 'Ghost' subtypes with atypical identity in a mouse model of obesity.

The hypothalamus contains a remarkable diversity of neurons that orchestrate behavioural and metabolic outputs in a highly plastic manner. Neuronal diversity is key to enabling hypothalamic functions and, according to the neuroscience dogma, it is predetermined during embryonic life. Here, by combining lineage tracing of hypothalamic pro-opiomelanocortin (Pomc) neurons with single-cell profiling approaches in adult male mice, we uncovered subpopulations of 'Ghost' neurons endowed with atypical molecular and functional identity. Compared to 'classical' Pomc neurons, Ghost neurons exhibit negligible Pomc expression and are 'invisible' to available neuroanatomical approaches and promoter-based reporter mice for studying Pomc biology. Ghost neuron numbers augment in diet-induced obese mice, independent of neurogenesis or cell death, but weight loss can reverse this shift. Our work challenges the notion of fixed, developmentally programmed neuronal identities in the mature hypothalamus and highlight the ability of specialised neurons to reversibly adapt their functional identity to adult-onset obesogenic stimuli.

Pseudomonas aeruginosa transcriptome analysis of metal restriction in ex vivo cystic fibrosis sputum.

Chronic Pseudomonas aeruginosa lung infections are a feature of cystic fibrosis (CF) that many patients experience even with the advent of highly effective modulator therapies. Identifying factors that impact P. aeruginosa in the CF lung could yield novel strategies to eradicate infection or otherwise improve outcomes. To complement published P. aeruginosa studies using laboratory models or RNA isolated from sputum, we analyzed transcripts of strain PAO1 after incubation in sputum from different CF donors prior to RNA extraction. We compared PAO1 gene expression in this "spike-in" sputum model to that for P. aeruginosa grown in synthetic cystic fibrosis sputum medium to determine key genes, which are among the most differentially expressed or most highly expressed. Using the key genes, gene sets with correlated expression were determined using the gene expression analysis tool eADAGE. Gene sets were used to analyze the activity of specific pathways in P. aeruginosa grown in sputum from different individuals. Gene sets that we found to be more active in sputum showed similar activation in published data that included P. aeruginosa RNA isolated from sputum relative to corresponding in vitro reference cultures. In the ex vivo samples, P. aeruginosa had increased levels of genes related to zinc and iron acquisition which were suppressed by metal amendment of sputum. We also found a significant correlation between expression of the H1-type VI secretion system and CFTR corrector use by the sputum donor. An ex vivo sputum model or synthetic sputum medium formulation that imposes metal restriction may enhance future CF-related studies.IMPORTANCEIdentifying the gene expression programs used by Pseudomonas aeruginosa to colonize the lungs of people with cystic fibrosis (CF) will illuminate new therapeutic strategies. To capture these transcriptional programs, we cultured the common P. aeruginosa laboratory strain PAO1 in expectorated sputum from CF patient donors. Through bioinformatic analysis, we defined sets of genes that are more transcriptionally active in real CF sputum compared to a synthetic cystic fibrosis sputum medium. Many of the most differentially active gene sets contained genes related to metal acquisition, suggesting that these gene sets play an active role in scavenging for metals in the CF lung environment which may be inadequately represented in some models. Future studies of P. aeruginosa transcript abundance in CF may benefit from the use of an expectorated sputum model or media supplemented with factors that induce metal restriction.

Mitigating Infection Risk in Upper Airway Stimulation.

OBJECTIVE: This study aims to define the incidence of infection with upper airway stimulation (UAS) devices requiring explantation in a single academic center and identify factors that may influence the risk of infection. METHODS: A database of patients who underwent UAS at a single tertiary referral academic center from 2017 to 2021 was retrospectively reviewed to identify patients who developed surgical site infections, with and without subsequent explantation. Additional data for cases complicated by infection was extracted from the electronic medical record (EMR) and included: demographic information, medical history, complications and management, and overall outcomes. In March 2021, 2 modifications to infection control protocols were implemented: double skin preparation with Betadine and chlorhexidine, and MRSA decolonization. Statistical analysis was performed to compare infectious risk before and after these protocol changes. RESULTS: In the study period, 215 patients underwent UAS in the specified time period and 3 cases (1.4%) of postoperative infections were identified, all of which required explantation. The infection rate did not significantly change after modifications to the surgical prep protocol (P = .52). CONCLUSIONS: While no significant difference in infection risk was noted after modifying infection control protocols, additional longer-term study is warranted to elucidate effective infection reduction strategies.

Differential Expression of Circadian Clock Genes in the Bovine Neuroendocrine Adrenal System.

Knowledge of circadian rhythm clock gene expression outside the suprachiasmatic nucleus is increasing. The purpose of this study was to determine whether expression of circadian clock genes differed within or among the bovine stress axis tissues (e.g., amygdala, hypothalamus, pituitary, adrenal cortex, and adrenal medulla). Tissues were obtained at an abattoir from eight mature nonpregnant Brahman cows that had been maintained in the same pasture and nutritional conditions. Sample tissues were stored in RNase-free sterile cryovials at -80 °C until the total RNA was extracted, quantified, assessed, and sequenced (NovaSeq 6000 system; paired-end 150 bp cycles). The trimmed reads were then mapped to a Bos taurus (B. taurus) reference genome (Umd3.1). Further analysis used the edgeR package. Raw gene count tables were read into RStudio, and low-expression genes were filtered out using the criteria of three minimum reads per gene in at least five samples. Normalization factors were then calculated using the trimmed mean of M values method to produce normalized gene counts within each sample tissue. The normalized gene counts important for a circadian rhythm were analyzed within and between each tissue of the stress axis using the GLM and CORR procedures of the Statistical Analysis System (SAS). The relative expression profiles of circadian clock genes differed (p < 0.01) within each tissue, with neuronal PAS domain protein 2 (NPAS2) having greater expression in the amygdala (p < 0.01) and period circadian regulator (PER1) having greater expression in all other tissues (p < 0.01). The expression among tissues also differed (p < 0.01) for individual circadian clock genes, with circadian locomotor output cycles protein kaput (CLOCK) expression being greater within the adrenal tissues and nuclear receptor subfamily 1 group D member 1 (NR1D1) expression being greater within the other tissues (p < 0.01). Overall, the results indicate that within each tissue, the various circadian clock genes were differentially expressed, in addition to being differentially expressed among the stress tissues of mature Brahman cows. Future use of these findings may assist in improving livestock husbandry and welfare by understanding interactions of the environment, stress responsiveness, and peripheral circadian rhythms.

Impact of mindfulness training and yoga on injury and pain-related impairment: a group randomized trial in basic combat training.

Introduction: Service members are at risk for pain-related difficulties in functioning and physical injury. Previous studies suggest that mindfulness training (MT) and yoga may prevent these outcomes. The present study was designed to determine the impact of MT and yoga on the health, pain, and injury of Army trainees completing 10 weeks of basic combat training (BCT). Methods: Platoons (≈40 trainees per platoon) were randomized to MT and yoga or training-as-usual in October to December 2020 at a large installation in the US. Self-reported outcomes were health, pain level, and pain impact on training, sleep, mood, and stress. Objective outcomes were injury-related medical encounters and number of diagnoses. The trial was registered at ClinicalTrials. Gov (NCT05550610). Results: Intervention trainees reported significantly better health (OR = 1.05, 95% CI [1.00, 1.10]) and less impact of pain on training (OR = 0.81, 95% CI [0.74, 0.90]), sleep (OR = 0.88, 95% CI [0.81, 0.95]), mood (OR = 0.86, 95% CI [0.78, 0.96]), and stress (OR = 0.88, 95% CI [0.79, 0.98]). There was no significant difference in injury-related medical encounters (AOR = 0.70, 95% CI [0.48, 1.03]), but intervention trainees had fewer diagnoses (OR = 0.67, 95% CI [0.47, 0.95]) and were 30% less likely to have a first medical encounter at any time during BCT. This difference emerged 3 weeks into BCT. Discussion: A combined MT and yoga intervention resulted in better trainee health. The US Army and other organizations requiring resilience under extreme stress should consider implementing MT and yoga to offset risks to employee health.

Effects of dietary supplementation of peanut skins (Arachis hypogaea) on performance, digestibility, and rumen fermentation of cattle: a meta-analysis.

This study aimed to estimate the magnitude of the effects of dietary inclusion of peanut skins (PS) byproduct (Arachis hypogea L.) on intake, total-tract digestibility, and rumen fermentation of cattle via meta-analysis. Data were collected following the PRISMA methodology. Nine manuscripts and a graduate thesis met the inclusion criteria from 1983 to 2010. The effect size was estimated by calculating the weighted raw mean differences (RMD) between PS vs. control diets. The RMD was compared with a robust variance estimation method followed by a meta-regression and a dose-response analysis fitting the diet characteristics like crude protein content (CP), NDF content, ether extract content (EE), tannin content, and PS level in diet (0 to 40%) as covariates. Dietary PS decreased (P < 0.01) total-tract CP digestibility (52.0 vs. 64.3%), final body weight (371.5 vs. 397.9 kg), and average daily gain (1.14 vs. 1.44 kg/day) among treatment comparisons. Likewise, PS decreased total VFA (92.6 vs. 107.6 mmol/L) and NH3-N (8.22 vs. 12.1 mg/dL), but no effects were observed on rumen pH (6.47 vs. 6.14) and VFA molar proportions. Despite the between-cluster variance, dietary PS increased the ether extract digestibility (77.5 vs. 70.2%) among treatment comparisons. The subset and dose-response analysis revealed that PS should not exceed 8% (DM basis) in the diet to prevent negative effects on CP digestibility and animal performance. In conclusion, the results of this meta-analysis do not support the dietary inclusion of PS in cattle diets beyond 8%.

Standardized Radiomics Analysis of Clinical Myocardial Perfusion Stress SPECT Images to Identify Coronary Artery Calcification.

PURPOSE: Myocardial perfusion (MP) stress single-photon emission computed tomography (SPECT) is an established diagnostic test for patients suspected of coronary artery disease (CAD). Meanwhile, coronary artery calcification (CAC) scoring obtained from diagnostic CT is a highly sensitive test, offering incremental diagnostic information in identifying patients with significant CAD yet normal MP stress SPECT (MPSS) scans. However, after decades of wide utilization of MPSS, CAC is not commonly reimbursed (e.g. by the CMS), nor widely deployed in community settings. We studied the potential of complementary information deduced from the radiomics analysis of normal MPSS scans in predicting the CAC score. METHODS: We collected data from 428 patients with normal (non-ischemic) MPSS (99mTc-sestamibi; consensus reading). A nuclear medicine physician verified iteratively reconstructed images (attenuation-corrected) to be free from fixed perfusion defects and artifactual attenuation. Three-dimensional images were automatically segmented into four regions of interest (ROIs), including myocardium and three vascular segments (left anterior descending [LAD]-left circumference [LCX]-right coronary artery [RCA]). We used our software package, standardized environment for radiomics analysis (SERA), to extract 487 radiomic features in compliance with the image biomarker standardization initiative (IBSI). Isotropic cubic voxels were discretized using fixed bin-number discretization (eight schemes). We first performed blind-to-outcome feature selection focusing on a priori usefulness, dynamic range, and redundancy of features. Subsequently, we performed univariate and multivariate machine learning analyses to predict CAC scores from i) selected radiomic features, ii) 10 clinical features, and iii) combined radiomics + clinical features. Univariate analysis invoked Spearman correlation with Benjamini-Hotchberg false-discovery correction. The multivariate analysis incorporated stepwise linear regression, where we randomly selected a 15% test set and divided the other 85% of data into 70% training and 30% validation sets. Training started from a constant (intercept) model, iteratively adding/removing features (stepwise regression), invoking the Akaike information criterion (AIC) to discourage overfitting. Validation was run similarly, except that the training output model was used as the initial model. We randomized training/validation sets 20 times, selecting the best model using log-likelihood for evaluation in the test set. Assessment in the test set was performed thoroughly by running the entire operation 50 times, subsequently employing Fisher's method to verify the significance of independent tests. RESULTS: Unsupervised feature selection significantly reduced 8×487 features to 56. In univariate analysis, no feature survived the false-discovery rate (FDR) to directly correlate with CAC scores. Applying Fisher's method to the multivariate regression results demonstrated combining radiomics with the clinical features to enhance the significance of the prediction model across all cardiac segments.  Conclusions: Our standardized and statistically robust multivariate analysis demonstrated significant prediction of the CAC score for all cardiac segments when combining MPSS radiomic features with clinical features, suggesting radiomics analysis can add diagnostic or prognostic value to standard MPSS for wide clinical usage.

A Randomized Trial of Intravenous Iron Supplementation and Exercise on Exercise Capacity in Iron-Deficient Nonanemic Patients With CKD.

Introduction: Patients with chronic kidney disease (CKD) are often iron deficient, even when not anemic. This trial evaluated whether iron supplementation enhances exercise capacity of nonanemic patients with CKD who have iron-deficiency. Methods: Prospective, multicenter double-blind randomized controlled trial of nondialysis patients with CKD and iron-deficiency but without anemia (Hemoglobin [Hb] >110 g/l). Patients were assigned 1:1 to intravenous (IV) iron therapy, or placebo. An 8-week exercise program commenced at week 4. The primary outcome was the mean between-group difference in 6-minute walk test (6MWT) at 4 weeks. Secondary outcomes included 6MWT at 12 weeks, transferrin saturation (TSAT), serum ferritin (SF), Hb, renal function, muscle strength, functional capacity, quality of life, and adverse events at baseline, 4 weeks, and at 12 weeks. Mean between-group differences were analyzed using analysis of covariance models. Results: Among 75 randomized patients, mean (SD) age for iron therapy (n = 37) versus placebo (n = 38) was 54 (16) versus 61 (12) years; estimated glomerular filtration rate (eGFR) (34 [12] vs. 35 [11] ml/min per 1.73 m2], TSAT (23 [12] vs. 21 [6])%; SF (57 [64] vs. 62 [33]) µg/l; Hb (122.4 [9.2] vs. 127 [13.2] g/l); 6MWT (384 [95] vs. 469 [142] meters) at baseline, respectively. No significant mean between-group difference was observed in 6MWT distance at 4 weeks. There were significant increases in SF and TSAT at 4 and 12 weeks (P < 0.02), and Hb at 12 weeks (P = 0.009). There were no between-group differences in other secondary outcomes and no adverse events attributable to iron therapy. Conclusion: This trial did not demonstrate beneficial effects of IV iron therapy on exercise capacity at 4 weeks. A larger study is needed to confirm if IV iron is beneficial in nondialysis patients with CKD who are iron-deficient.

Qualitative evaluation of the implementation and future sustainability of an e-referral system for smoking cessation at a US NCI-designated comprehensive cancer center: lessons learned.

BACKGROUND: Promoting smoking cessation is recognized as an essential part of cancer care. Moffitt Cancer Center, supported by the National Cancer Institute Cancer Moonshot Cancer Center Cessation Initiative, developed and implemented an opt-out-based automatic electronic health record (EHR)-mediated referral (e-referral) system for Tobacco Quitline services along with options for local group cessation support and an in-house tobacco treatment specialist. This study evaluated barriers and facilitators for implementation of the e-referral system. METHOD: Steering committee members (N=12) responsible for developing and implementing the new clinical workflow and nurses (N=12) who were expected to use the new e-referral system completed semi-structured interviews. Qualitative thematic content analyses were conducted. RESULTS: Interviewees perceived the e-referral system as an effective strategy for identifying and referring smokers to cessation services. However, barriers were noted including competing demands and perceptions that smoking cessation was a low priority and that some patients were likely to have low motivation to quit smoking. Suggestions to improve future implementation and sustainability included providing regular trainings and e-referral outcome reports and increasing the visibility of the e-referral system within the EHR. CONCLUSION: Initial implementation of the e-referral system was perceived as successful; however, additional implementation strategies are needed to ensure sustainability at both the clinician and system levels. Recommendations for future modifications include providing regular clinician trainings and developing a fully closed-loop system. Implications for cancer survivors Initial implementation of an e-referral system for smoking cessation for cancer patients revealed opportunities to improve the smoking cessation referral process at cancer centers.

Aquatic phosphorus behaviour within a UK Ramsar wetland: Impacts of seasonality and hydrology on algal growth and implications for management.

Fundamental to all life, phosphorus is an essential nutrient and, contrastingly, a significant threat to surface water biodiversity globally as one of the most common causes of eutrophication in surface waters worldwide. Freshwater wetland ditches affected by these conditions undergo a conversion from primarily submerged aquatic vegetation to algae or duckweed dominance, leading to anoxic conditions. However, macrophyte biomass harvesting in eutrophic water systems is a promising means of remediation and nutrient recycling. This study seasonally assesses spatial distribution and chemical fractionation of surface water phosphorus, as well as surface biomass abundance and total phosphorus content in the ditch systems at West Sedgemoor (Somerset, UK), a designated site of special scientific interest. Elevated phosphorus concentrations in the surface water were observed across the site, with all sites exceeding e hi the Common Standards Monitoring environmental quality standard value of 0.1 mg L-1 during summer and autumn Sites lacking hydrological flow connectivity with contaminated freshwater inputs, typically had lower surface water phosphorus concentrations than the rest of the moor, with localised hotspots associated with likely cattle related agricultural activity. Summer and autumn were determined as the dominant duckweed growth seasons, in which an estimated 39 kg of phosphorus could be removed via duckweed biomass harvesting, per harvest period.

Pilot randomized controlled trial of mindfulness-based relapse prevention vs cognitive behavioral therapy for smoking and alcohol use.

BACKGROUND: The combined use of cigarettes and alcohol is associated with a synergistic increase in the risk of morbidity and mortality. Continued alcohol use during a smoking quit attempt is a considerable risk factor for smoking relapse. As such, there is a need for interventions that address both behaviors concurrently. Mindfulness-based interventions hold much promise for simultaneously addressing tobacco and alcohol use. METHOD: This pilot study evaluated the feasibility and acceptability of a mindfulness-based intervention using a two-arm randomized controlled trial of Mindfulness-Based Relapse Prevention for Smoking and Alcohol (MBRP-SA) vs Cognitive Behavioral Therapy (CBT). Interventions were delivered via telehealth in a group setting; all participants received a 6-week supply of the nicotine patch. Participants (N = 69) were adults who smoked cigarettes who reported binge drinking and were motivated to both quit smoking and change their alcohol use. Primary outcomes were feasibility and acceptability of MBRP-SA compared to CBT. Changes in tobacco and alcohol use are also presented. RESULTS: Participants in MBRP-SA and CBT indicated that the treatments were highly acceptable, meeting a priori benchmarks. Feasibility was mixed with some outcomes meeting benchmarks (e.g., recruitment) and others falling below (e.g., retention). Participants in both conditions demonstrated significant reductions in tobacco and alcohol use at the end of treatment. CONCLUSIONS: In sum, MBRP-SA had comparable outcomes to CBT on all metrics measured. Future research should evaluate the efficacy of MBRP-SA on smoking abstinence and drinking reductions in a large-scale, fully powered trial. This study was registered on clinicaltrials.gov (NCT03734666).

Optimizing Performance and Mental Skills With Mindfulness-Based Attention Training: Two Field Studies With Operational Units.

INTRODUCTION: Mental skills such as focusing attention and managing emotions are essential for optimal performance in high-stress occupations. Studies with military samples have demonstrated that mindfulness training (MT) led to improved computer-based cognitive performance. MATERIALS AND METHODS: To examine the impact of MT on operational performance, mental skills, and psychological health, a short-form program, Mindfulness-Based Attention Training (MBAT), was delivered to active duty soldiers as part of two randomized trials. Participants in study 1 (n = 121) and study 2 (n = 77) were randomized to one of three conditions: MT with proctored practice, MT with unproctored practice, or a waitlist control. Weekly 2-hour MBAT sessions were offered to participants in both MT conditions for 4 weeks. Beyond these sessions, participants also engaged in mindfulness practice that was proctored (within the occupational context) or unproctored (left up to the individual) for four subsequent weeks. RESULTS: Overall, the frequency of mindfulness practice was generally associated with better performance and improvements in mental skills. In study 1, those who practiced 3 or more days per week performed better on marksmanship under physical stress and reported fewer attentional lapses, less emotion regulation difficulties, greater mental toughness, and higher self-reported mindfulness compared to those who did not practice. In study 2, the frequency of mindfulness practice was associated with fewer attentional lapses and emotion regulation difficulties. CONCLUSIONS: Consistent with prior findings, results suggest that regular engagement in MT practice may help to optimize operational performance and improve mental skills in military cohorts.

Exploring the acute cardiovascular effects of Floatation-REST.

The central nervous system (CNS) exerts a strong regulatory influence over the cardiovascular system in response to environmental demands. Floatation-REST (Reduced Environmental Stimulation Therapy) is an intervention that minimizes stimulation from the environment, yet little is known about the autonomic consequences of reducing external sensory input to the CNS. We recently found that Floatation-REST induces a strong anxiolytic effect in anxious patients while paradoxically enhancing their interoceptive awareness for cardiorespiratory sensations. To further investigate the physiologic nature of this anxiolytic effect, the present study measured acute cardiovascular changes during Floatation-REST using wireless and waterproof equipment that allowed for concurrent measurement of heart rate, heart rate variability (HRV), breathing rate, and blood pressure. Using a within-subjects crossover design, 37 clinically anxious participants with high levels of anxiety sensitivity and 20 non-anxious comparison participants were randomly assigned to undergo a 90-min session of either Floatation-REST or an exteroceptive comparison condition that entailed watching a relaxing nature film. Measures of state anxiety and serenity were collected before and after each session, while indices of autonomic activity were measured throughout each session. HRV was calculated using both time-series and frequency domain analyses. Linear mixed-effects modeling revealed a significant main effect of condition such that relative to the film condition, Floatation-REST elicited significant decreases (p < 0.001) in diastolic blood pressure, systolic blood pressure, breathing rate, and certain metrics of HRV including the standard deviation of the interbeat interval (SDNN), low-frequency HRV, and very low-frequency HRV. Heart rate showed a non-significant trend (p = 0.073) toward being lower in the float condition, especially toward the beginning of the session. The only metric that showed a significant increase during Floatation-REST was normalized high-frequency HRV (p < 0.001). The observed physiological changes were consistent across both anxious and non-anxious participants, and there were no significant group by condition interactions. Blood pressure was the only cardiac metric significantly associated with float-related reductions in state anxiety and increases in serenity. These findings suggest that Floatation-REST lowers sympathetic arousal and alters the balance of the autonomic nervous system toward a more parasympathetic state. Clinical trial registration: [https://clinicaltrials.gov/show/NCT03051074], identifier [NCT03051074].

Contrast-enhanced Mammography versus Contrast-enhanced Breast MRI: A Systematic Review and Meta-Analysis.

Background Contrast-enhanced mammography (CEM) is a more accessible alternative to contrast-enhanced MRI (CE-MRI) in breast imaging, but a summary comparison of published studies is lacking. Purpose To directly compare the performance of CEM and CE-MRI regarding sensitivity, specificity, and negative predictive value in detecting breast cancer, involving all publicly available studies in the English language. Materials and Methods Two readers extracted characteristics of studies investigating the comparative diagnostic performance of CEM and CE-MRI in detecting breast cancer. Studies published until April 2021 were eligible. Sensitivity, specificity, negative predictive value, and positive and negative likelihood ratios were calculated using bivariate random effects models. A Fagan nomogram was used to identify the maximum pretest probability at which posttest probabilities of a negative CEM or CE-MRI examination were in line with the 2% malignancy rate benchmark for downgrading a Breast Imaging Reporting and Data System (BI-RADS) category 4 to a BI-RADS category 3 result. I 2 statistics, Deeks funnel plot asymmetry test for publication bias, and meta-regression were used. Results Seven studies investigating 1137 lesions (654 malignant, 483 benign) with an average cancer prevalence of 65.3% (range: 47.3%-82.2%) were included. No publication bias was found (P = .57). While the positive likelihood ratio was equal at a value of 3.1 for CE-MRI and 3.6 for CEM, the negative likelihood ratio of CE-MRI (0.04) was lower than that with CEM (0.12). CE-MRI had higher sensitivity for breast cancer than CEM (97% [95% CI: 86, 99] vs 91% [95% CI: 77, 97], respectively; P < .001) but lower specificity (69% [95% CI: 46, 85] vs 74% [95% CI: 52, 89]; P = .09). A Fagan nomogram demonstrated that the maximum pretest probability at which both tests could rule out breast cancer was 33% for CE-MRI and 14% for CEM. Furthermore, iodine concentration was positively associated with CEM sensitivity and negatively associated with its specificity (P = .04 and P < .001, respectively). Conclusion Contrast-enhanced MRI had superior sensitivity and negative likelihood ratios with higher pretest probabilities to rule out malignancy compared with contrast-enhanced mammography. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Mann and Veldhuis in this issue.

Effects of subacute cadmium exposure and subsequent deferiprone treatment on cadmium accumulation and on the homeostasis of essential elements in the mouse brain.

INTRODUCTION: Cadmium (Cd) is а hazardous multi-organ toxin. In this study, we provide the first results about the effect of oral administration of deferiprone (DFP) on Cd accumulation and on the homeostasis of essential elements in the brain of Cd-exposed mice. METHODS: Adult Institute of Cancer Research (ICR) male mice were randomized into four experimental groups: untreated controls - administered distilled water for 28 days; Cd-exposed group - exposed to 18 mg/kg body weight (b.w.) Cd(II) acetate for 14 days followed by the administration of distilled water for two weeks; Cd + DFP (low dose) - Cd-intoxicated mice subsequently treated with 19 mg/kg b.w. DFP for two weeks; and Cd + DFP (high dose) - Cd-exposed mice administered high-dose DFP (135 mg/kg b.w.) for 14 days. Brains were subjected to inductively coupled plasma-mass spectrometry (ICP-MS) and histological analysis. RESULTS: The results revealed that exposure of mice to Cd for 14 days significantly increased Cd concentration and significantly decreased magnesium (Mg), phosphorus (P), and zinc (Zn) contents in the brain compared to untreated controls. This effect was accompanied by necrotic-degenerative changes in both the cerebrum and cerebellum. Oral administration of low-dose DFP to Cd-exposed mice decreased the concentration of the toxic metal in the brain by 16.37% and restored the concentration of the essential elements to normal control values. Histological analysis revealed substantially improved cerebral and cerebellar histoarchitectures. In contrast, oral administration of high-dose DFP increased Cd content and significantly decreased selenium (Se) concentration in the brain. Necrotic neurons and Purkinje cells were still observed in the cerebral and cerebellar cortices. CONCLUSION: The results demonstrated that oral administration of DFP at low doses has a better therapeutic potential for the treatment of Cd-induced brain damage compared to high doses.

Yin-Yang control of energy balance by lipids in the hypothalamus: The endocannabinoids vs bile acids case.

Obesity is a chronic and debilitating disorder that originates from alterations in energy-sensing brain circuits controlling body weight gain and food intake. The dysregulated syntheses and actions of lipid mediators in the hypothalamus induce weight gain and overfeeding, but the molecular and cellular underpinnings of these alterations remain elusive. In response to changes in the nutritional status, different lipid sensing pathways in the hypothalamus direct body energy needs in a Yin-Yang model. Endocannabinoids orchestrate the crosstalk between hypothalamic circuits and the sympathetic nervous system to promote food intake and energy accumulation during fasting, whereas bile acids act on the same top-down axis to reduce energy intake and possibly storage after the meal. In obesity, the bioavailability and downstream cellular actions of endocannabinoids and bile acids are altered in hypothalamic neurons involved in body weight and metabolic control. Thus, the onset and progression of this disease might result from an imbalance in hypothalamic sensing of multiple lipid signals, which are possibly integrated by common molecular nodes. In this viewpoint, we discuss a possible model that explains how bile acids and endocannabinoids may exert their effects on energy balance regulation via interconnected mechanisms at the level of the hypothalamic neuronal circuits. Therefore, we propose a new conceptual framework for understanding and treating central mechanisms of maladaptive lipid action in obesity.

Towards sustainability: Threat of water quality degradation and eutrophication in Usangu agro-ecosystem Tanzania.

The agrochemicals and nutrient losses from farming areas such as paddy farming significantly dictate quality and eutrophication of the freshwater resource. However, how farming and land use pattern affect water qualities and eutrophication remain poorly understood in most African agro-ecosystems. The present study characterized how paddy farming influences water qualities and eutrophication in 10 irrigation schemes in Usangu agro-ecosystem (UA). About 42 water samples were sampled from intakes, channels, paddy fields, and drainages and analyzed for EC, Cl, P, NH4-N, NO3-N, TN, Zn, Cu, Ca, and Mg. We observed water pH ranging from 4.89 to 6.76, which was generally below the acceptable range (6.5-8.4) for irrigation water. NH4-N concentration was in a range of 10.6-70.0 mg/L, NO3-N (8.4-33.9 mg/L), and TN (19.1-21,104 mg/L). NH4-N increased along sampling transect (sampling points) from intakes (5.7-29.1 mg/L), channels (19-20 mg/L), fields (12.9-35.8 mg/L), and outflow (10.6-70.0 mg/L), the same trend were found for NO3-N and TN. The TP determined in water samples were in the range of 0.01 to 1.65 mg/L; where some sites had P > 0.1 mg/L exceeding the allowable P concentration in freshwater resource, thus indicating P enrichment and eutrophication status. The P concentration was observed to increase from intake through paddy fields to drainages, where high P was determined in drainages (0.02-1.65 mg/L) and fields (0.0-0.54 mg/L) compared to channels (0.01-0.13 mg/L) and intakes (0.01-0.04 mg/L). Furthermore, we determined appreciable amount of potentially toxic elements (PTEs) such as Cu, Pb, Cd and Cr in studied water samples. The high N, P, and PTEs in drainages indicate enrichment from agricultural fields leading to water quality degradation and contaminations (eutrophication). The study demonstrates that water quality in UA is degrading potentially due to paddy rice farming and other associated activities in the landscape. Thus, the current study recommends starting initiatives to monitor irrigation water quality in UA for better crop productivity, and improved quality of drainage re-entering downstream through the introduction of mandatory riparian buffer, revising irrigation practices, to include good agronomic practices (GAP) to ensure water quality and sustainability.

The effect of intravenous iron supplementation on exercise capacity in iron-deficient but not anaemic patients with chronic kidney disease: study design and baseline data for a multicentre prospective double-blind randomised controlled trial.

BACKGROUND: Many people living with chronic kidney disease (CKD) are iron deficient, even though they may not be anaemic. The Iron and Muscle study aims to evaluate whether iron supplementation reduces symptoms of fatigue, improves muscle metabolism, and leads to enhanced exercise capacity and physical function. We report here the trial design and baseline characteristics. METHODS: This is a prospective, double-blind multicentre randomised controlled trial (RCT) including 75 non-dialysis stage 3-4 CKD patients with iron deficiency but without anaemia. Patients were randomly (1:1) assigned to either: i) intravenous iron therapy, or ii) placebo, with concurrent recruitment of eight CKD non-iron deficient participants and six healthy volunteers. The primary outcome of the study is the six-minute walk test (6MWT) distance between baseline and four-weeks. An additional exercise training programme for patients in both groups was initiated and completed between 4 and 12 weeks, to determine the effect of iron repletion compared to placebo treatment in the context of patients undertaking an exercise programme. Additional secondary outcomes include fatigue, physical function, muscle strength, muscle metabolism, quality of life, resting blood pressure, clinical chemistry, safety and harms associated with the iron therapy intervention and the exercise training intervention, and hospitalisations. All outcomes were conducted at baseline, 4, and 12 weeks, with a nested qualitative study, to investigate the experience of living with iron deficiency and intervention acceptability. The cohort have been recruited and baseline assessments undertaken. RESULTS: Seventy-five individuals were recruited. 44% of the randomised cohort were male, the mean (SD) age was 58 (14) years, and 56% were White. Body mass index was 31 (7) kg/m2; serum ferritin was 59 (45) µg/L, transferrin saturation was 22 (10) %, and haemoglobin was 125 (12) g/L at randomisation for the whole group. Estimated glomerular filtration rate was 35 (12) mL/min/1.73 m2 and the baseline 6MWT distance was 429 (174) m. CONCLUSION: The results from this study will address a substantial knowledge gap in the effects of intravenous iron therapy, and offer potential clinical treatment options, to improve exercise capacity, physical function, fatigue, and muscle metabolism, for non-dialysis patients with CKD who are iron-deficient but not anaemic. It will also offer insight into the potential novel effects of an 8-week exercise training programme. TRIAL REGISTRATION: EudraCT: 2018-000,144-25 Registered 28/01/2019.

Mismatch Negativity in Response to Auditory Deviance and Risk for Future Psychosis in Youth at Clinical High Risk for Psychosis.

Importance: Although clinical criteria for identifying youth at risk for psychosis have been validated, they are not sufficiently accurate for predicting outcomes to inform major treatment decisions. The identification of biomarkers may improve outcome prediction among individuals at clinical high risk for psychosis (CHR-P). Objective: To examine whether mismatch negativity (MMN) event-related potential amplitude, which is deficient in schizophrenia, is reduced in young people with the CHR-P syndrome and associated with outcomes, accounting for effects of antipsychotic medication use. Design, Setting, and Participants: MMN data were collected as part of the multisite case-control North American Prodrome Longitudinal Study (NAPLS-2) from 8 university-based outpatient research programs. Baseline MMN data were collected from June 2009 through April 2013. Clinical outcomes were assessed throughout 24 months. Participants were individuals with the CHR-P syndrome and healthy controls with MMN data. Participants with the CHR-P syndrome who developed psychosis (ie, converters) were compared with those who did not develop psychosis (ie, nonconverters) who were followed up for 24 months. Analysis took place between December 2019 and December 2021. Main Outcomes and Measures: Electroencephalography was recorded during a passive auditory oddball paradigm. MMN elicited by duration-, pitch-, and duration + pitch double-deviant tones was measured. Results: The CHR-P group (n = 580; mean [SD] age, 19.24 [4.39] years) included 247 female individuals (42.6%) and the healthy control group (n = 241; mean age, 20.33 [4.74] years) included 114 female individuals (47.3%). In the CHR-P group, 450 (77.6%) were not taking antipsychotic medication at baseline. Baseline MMN amplitudes, irrespective of deviant type, were deficient in future CHR-P converters to psychosis (n = 77, unmedicated n = 54) compared with nonconverters (n = 238, unmedicated n = 190) in both the full sample (d = 0.27) and the unmedicated subsample (d = 0.33). In the full sample, baseline medication status interacted with group and deviant type indicating that double-deviant MMN, compared with single deviants, was reduced in unmedicated converters compared with nonconverters (d = 0.43). Further, within the unmedicated subsample, deficits in double-deviant MMN were most strongly associated with earlier conversion to psychosis (hazard ratio, 1.40 [95% CI, 1.03-1.90]; P = .03], which persisted over and above positive symptom severity. Conclusions and Relevance: This study found that MMN amplitude deficits were sensitive to future psychosis conversion among individuals at risk of CHR-P, particularly those not taking antipsychotic medication at baseline, although associations were modest. While MMN shows limited promise as a biomarker of psychosis onset on its own, it may contribute novel risk information to multivariate prediction algorithms and serve as a translational neurophysiological target for novel treatment development in a subgroup of at-risk individuals.

Specialized pro-resolving mediators as modulators of immune responses.

Specialized pro-resolving mediators (SPMs) are endogenous small molecules produced mainly from dietary omega-3 polyunsaturated fatty acids by both structural cells and cells of the active and innate immune systems. Specialized pro-resolving mediators have been shown to both limit acute inflammation and promote resolution and return to homeostasis following infection or injury. There is growing evidence that chronic immune disorders are characterized by deficiencies in resolution and SPMs have significant potential as novel therapeutics to prevent and treat chronic inflammation and immune system disorders. This review focuses on important breakthroughs in understanding how SPMs are produced by, and act on, cells of the adaptive immune system, specifically macrophages, B cells and T cells. We also highlight recent evidence demonstrating the potential of SPMs as novel therapeutic agents in topics including immunization, autoimmune disease and transplantation.