A new framework on climate-induced food-security risk for small-scale fishing communities in Tanzania.

Food insecurity is a pressing issue facing our world, particularly affecting coastal communities who rely on marine resources. The problem is further compounded by the rapidly changing climate, a deteriorating environment and growing human populations. It is essential to evaluate this issue accurately to reduce risk and improve the situation of coastal communities, especially in countries with less socioeconomic development. To this end, we develop a food security social-ecological risk assessment framework for developing communities in coastal areas of the Western Indian Ocean facing a changing environment. The framework integrates local ecological knowledge, expert scientific opinion, survey data, and satellite sea surface temperature (SST) and chlorophyll-a observation. We conducted a local-scale case study in four regions in Tanzania; Mafia, Pemba, Tanga, and Unguja, revealing that they face moderate to high risk levels of food insecurity. The highest risk was observed in the island communities of Pemba and Unguja, while the communities of Mafia and Tanga had the lowest risk due to lower exposure and sensitivity to climate change. Our results show that recognizing the key differences across risk components is crucial in identifying effective intervention strategies for local practitioners. This study highlights the need for detailed assessments to provide accurate information on local-scale food security dynamics, specifically when assessing impacts induced by environmental and climatic changes. Supplementary Information: The online version contains supplementary material available at 10.1007/s12571-024-01472-x.

The effects of resistance training to near volitional failure on motor unit recruitment during neuromuscular fatigue.

Background: It is unclear whether chronically training close to volitional failure influences motor unit recruitment strategies during fatigue. Purpose: We compared resistance training to near volitional failure vs. non-failure on individual motor unit action potential amplitude (MUAP) and surface electromyographic excitation (sEMG) during fatiguing contractions. Methods: Nineteen resistance-trained adults (11 males, 8 females) underwent 5 weeks (3×/week) of either low repetitions-in-reserve (RIR; 0-1 RIR) or high RIR training (4-6 RIR). Before and after the intervention, participants performed isometric contractions of the knee extensors at 30% of maximal peak torque until exhaustion while vastus lateralis sEMG signals were recorded and later decomposed. MUAP and sEMG excitation for the vastus lateralis were quantified at the beginning, middle, and end of the fatigue assessment. Results: Both training groups improved time-to-task failure (mean change = 43.3 s, 24.0%), with no significant differences between low and high RIR training groups (low RIR = 28.7%, high RIR = 19.4%). Our fatigue assessment revealed reduced isometric torque steadiness and increased MUAP amplitude and sEMG excitation during the fatiguing task, but these changes were consistent between groups. Conclusion: Both low and high RIR training improved time-to-task failure, but resulted in comparable motor unit recruitment during fatiguing contractions. Our findings indicate that both low and high RIR training can be used to enhance fatiguability among previously resistance-trained adults.

Quantitative structure permeability relationships for phenolic compounds applied to human epidermal membranes in various solvents.

PURPOSE: This study examined how solvent-skin-solute interactions influenced the human epidermal permeation of three similar-sized phenolic compounds applied in a series of different solvents. METHODS: Human epidermal permeation fluxes and lag times of three phenolic compounds were assessed in Franz cells for a range of solvents varying in molecular size and solubility parameters. In order to develop a mechanistic understanding of the determinants of the permeation findings, the solubility of the compounds in solvents and stratum corneum, the extent of solvent uptake by the stratum corneum and the impact of the solvents on skin hydration and transepidermal water loss were also measured. RESULTS: Maximum epidermal fluxes and lag times varied greatly with the various solvent used. Markedly enhanced epidermal permeability fluxes, prolonged lag times and reduced diffusivities of the compounds were evident for many of the solvents. A solvent induced increase in stratum corneum solubility was associated with the uptake of solvent containing dissolved compound. This uptake was dependent on both the solvent molecular size and the solubility of the compounds in the solvents. The imbibed solvent acted as a reservoir in the skin, facilitating uptake and an increased thermodynamic activity that enhanced flux but, at the same time, inhibiting diffusion and prolonging lag time. CONCLUSION: The solubility, permeation and lag times of compounds in the stratum corneum can be modulated by solvent uptake. Whilst a solvent -induced stratum corneum reservoir effect for a compound may prolong its lag time for a compound before steady state permeation is reached, it does not affect its overall steady state transport defined by diffusion of its free form.

GluN2C/D-containing NMDA receptors enhance temporal summation and increase sound-evoked and spontaneous firing in the inferior colliculus.

Along the ascending auditory pathway, there is a broad shift from temporal coding, which is common in the lower auditory brainstem, to rate coding, which predominates in auditory cortex. This temporal-to-rate transition is particularly prominent in the inferior colliculus (IC), the midbrain hub of the auditory system, but the mechanisms that govern how individual IC neurons integrate information across time remain largely unknown. Here, we report the widespread expression of Glun2c and Glun2d mRNA in IC neurons. GluN2C/D-containing NMDA receptors are relatively insensitive to voltage-dependent Mg2+ blockade, and thus can conduct current at resting membrane potential. Using in situ hybridization and pharmacology, we show that vasoactive intestinal peptide neurons in the IC express GluN2D-containing NMDA receptors that are activatable by commissural inputs from the contralateral IC. In addition, GluN2C/D-containing receptors have much slower kinetics than other NMDA receptors, and we found that GluN2D-containing receptors facilitate temporal summation of synaptic inputs in vasoactive intestinal peptide neurons. In a model neuron, we show that a GluN2C/D-like conductance interacts with the passive membrane properties of the neuron to alter temporal and rate coding of stimulus trains. Consistent with this, we show in vivo that blocking GluN2C/D-containing receptors decreases both the spontaneous firing rate and the overall firing rate elicited by amplitude-modulated sounds in many IC neurons. These results suggest that GluN2C/D-containing NMDA receptors influence rate coding for auditory stimuli in the IC by facilitating the temporal integration of synaptic inputs. KEY POINTS: NMDA receptors are critical components of most glutamatergic circuits in the brain, and the diversity of NMDA receptor subtypes yields receptors with a variety of functions. We found that many neurons in the auditory midbrain express GluN2C and/or GluN2D NMDA receptor subunits, which are less sensitive to Mg2+ blockade than the more commonly expressed GluN2A/B subunits. We show that GluN2C/D-containing receptors conducted current at resting membrane potential and enhanced temporal summation of synaptic inputs. In a model, we show that GluN2C/D-containing receptors provide additive gain for input-output functions driven by trains of synaptic inputs. In line with this, we found that blocking GluN2C/D-containing NMDA receptors in vivo decreased both spontaneous firing rates and firing evoked by amplitude-modulated sounds.

Using machine learning to predict carotid artery symptoms from CT angiography: A radiomics and deep learning approach.

Purpose: To assess radiomics and deep learning (DL) methods in identifying symptomatic Carotid Artery Disease (CAD) from carotid CT angiography (CTA) images. We further compare the performance of these novel methods to the conventional calcium score. Methods: Carotid CT angiography (CTA) images from symptomatic patients (ischaemic stroke/transient ischaemic attack within the last 3 months) and asymptomatic patients were analysed. Carotid arteries were classified into culprit, non-culprit and asymptomatic. The calcium score was assessed using the Agatston method. 93 radiomic features were extracted from regions-of-interest drawn on 14 consecutive CTA slices. For DL, convolutional neural networks (CNNs) with and without transfer learning were trained directly on CTA slices. Predictive performance was assessed over 5-fold cross validated AUC scores. SHAP and GRAD-CAM algorithms were used for explainability. Results: 132 carotid arteries were analysed (41 culprit, 41 non-culprit, and 50 asymptomatic). For asymptomatic vs symptomatic arteries, radiomics attained a mean AUC of 0.96(± 0.02), followed by DL 0.86(± 0.06) and then calcium 0.79(± 0.08). For culprit vs non-culprit arteries, radiomics achieved a mean AUC of 0.75(± 0.09), followed by DL 0.67(± 0.10) and then calcium 0.60(± 0.02). For multi-class classification, the mean AUCs were 0.95(± 0.07), 0.79(± 0.05), and 0.71(± 0.07) for radiomics, DL and calcium, respectively. Explainability revealed consistent patterns in the most important radiomic features. Conclusions: Our study highlights the potential of novel image analysis techniques in extracting quantitative information beyond calcification in the identification of CAD. Though further work is required, the transition of these novel techniques into clinical practice may eventually facilitate better stroke risk stratification.

Fludrocortisone dose-response relationship in septic shock: a randomised phase II trial.

BACKGROUND: The combination of intravenous hydrocortisone and enteral fludrocortisone may reduce mortality in patients with septic shock. The optimal dose and reliability of absorption of fludrocortisone in critically ill patients are unclear. METHODS: In a multi-centre, open label, phase II randomized clinical trial, intravenous hydrocortisone alone or in combination with one of three doses of enteral fludrocortisone (50 µg, 100 µg or 200 µg daily) for 7 days was compared in patients with septic shock. The primary outcome was time to shock resolution. We conducted pharmacokinetic studies to assess absorption. RESULTS: Out of 153 enrolled patients, 38 (25%) received hydrocortisone alone, 42 (27%) received additional 50 µg, 36 (24%) received 100 µg and 37 (24%) received 200 µg fludrocortisone. Plasma concentrations of fludrocortisone were detected in 97% of patients at 3 h-median (interquartile range [IQR]) 261 (156-334) ng/L. There was no significant difference in the time to shock resolution between groups with median (IQR) of 3 (2.5-4.5), 3 (2-4), 3 (2-6) and 3 (2-5.5) days in the hydrocortisone alone, 50 µg, 100 µg and 200 µg fludrocortisone groups, respectively. The corresponding 28-day mortality rates were 9/38 (24%), 7/42 (17%), 4/36 (11%) and 4/37 (11%), respectively. There were no significant differences between groups with respect to, recurrence of shock, indices of organ failure or other secondary outcomes. CONCLUSIONS: Enteral fludrocortisone resulted in detectable plasma fludrocortisone concentrations in the majority of critically ill patients with septic shock, although they varied widely indicating differing absorption and bioavailability. Its addition to hydrocortisone was not associated with shorter time to shock resolution.

Impact of Different Packaging Configurations on A Topical Cream Product.

PURPOSE: The objective of this study was to investigate whether different dispensing processes can alter the physicochemical and structural (Q3) attributes of a topical cream product, and potentially alter its performance. METHODS: Acyclovir cream, 5% (Zovirax®) is sold in the UK and other countries in a tube and a pump packaging configurations. The structural attributes of the cream dispensed from each packaging configuration were analyzed by optical microscopy, confocal Raman microscopy and cryo-scanning electron microscopy. Rheological behavior of the products was also evaluated. Product performance (rate and extent of skin delivery) was assessed by in vitro permeation tests (IVPT) using heat-separated human epidermis mounted in static vertical (Franz-type) diffusion cells. RESULTS: Differences in Q3 attributes and IVPT profiles were observed with creams dispensed from the two packaging configurations, even though the product inside each packaging appeared to be the same in Q3 attributes. Visible globules were recognized in the sample dispensed from the pump, identified as dimethicone globules by confocal Raman microscopy. Differences in rheological behaviour could be attributed to these globules as products not dispensed through the pump, demonstrated a similar rheological behaviour. Further, IVPT confirmed a reduced rate and extent to delivery across human epidermis from the product dispensed through a pump. CONCLUSIONS: Different methods of dispensing topical semisolid products can result in metamorphosis and Q3 changes that may have the potential to alter the bioavailability of an active ingredient. These findings have potential implications for product developers and regulators, related to the manufacturing and comparative testing of reference standard and prospective generic products dispensed from different packaging configurations.

Skeletal muscle myosin heavy chain fragmentation as a potential marker of protein degradation in response to resistance training and disuse atrophy.

We examined how resistance exercise (RE), cycling exercise and disuse atrophy affect myosin heavy chain (MyHC) protein fragmentation. The 1boutRE study involved younger men (n = 8; 5 ± 2 years of RE experience) performing a lower body RE bout with vastus lateralis (VL) biopsies being obtained prior to and acutely following exercise. With the 10weekRT study, VL biopsies were obtained in 36 younger adults before and 24 h after their first/naïve RE bout. Participants also engaged in 10 weeks of resistance training and donated VL biopsies before and 24 h after their last RE bout. VL biopsies were also examined in an acute cycling study (n = 7) and a study involving 2 weeks of leg immobilization (n = 20). In the 1boutRE study, fragmentation of all MyHC isoforms (MyHCTotal) increased 3 h post-RE (∼200%, P = 0.018) and returned to pre-exercise levels by 6 h post-RE. Interestingly, a greater magnitude increase in MyHC type IIa versus I isoform fragmentation occurred 3 h post-RE (8.6 ± 6.3-fold vs. 2.1 ± 0.7-fold, P = 0.018). In 10weekRT participants, the first/naïve and last RE bouts increased MyHCTotal fragmentation 24 h post-RE (+65% and +36%, P < 0.001); however, the last RE bout response was attenuated compared to the first bout (P = 0.045). Although cycling exercise did not alter MyHCTotal fragmentation, ∼8% VL atrophy with 2 weeks of leg immobilization increased MyHCTotal fragmentation (∼108%, P < 0.001). Mechanistic C2C12 myotube experiments indicated that MyHCTotal fragmentation is likely due to calpain proteases. In summary, RE and disuse atrophy increase MyHC protein fragmentation. Research into how ageing and disease-associated muscle atrophy affect these outcomes is needed. HIGHLIGHTS: What is the central question of this study? How different exercise stressors and disuse affect skeletal muscle myosin heavy chain fragmentation. What is the main finding and its importance? This investigation is the first to demonstrate that resistance exercise and disuse atrophy lead to skeletal muscle myosin heavy chain protein fragmentation in humans. Mechanistic in vitro experiments provide additional evidence that MyHC fragmentation occurs through calpain proteases.

Utilization of Telemedicine to Supervise Medical Students in the Post-Acute/Long-Term Care Setting.

OBJECTIVES: Telemedicine has become a widely accepted alternative to face-to-face patient encounters. Although there have been several peer-reviewed journal articles on incorporating telemedicine into the medical school curriculum, particularly during the COVID-19 pandemic, assessments of the effectiveness of remote supervision of medical students have not been reported. This prospective cohort study of student subjects using observational survey data evaluated the efficacy of telemedicine as an educational resource by comparing learning outcomes between osteopathic medical students receiving direct (physically present) supervision with a group who received remote (telemedicine) supervision by clinical faculty within a post-acute/long-term care (PA/LTC) setting. Learning outcomes in the domains of patient rapport, attitudes, knowledge, and behavior were measured using standardized survey instruments. DESIGN: Prospective cohort study of student subjects using observational survey data. SETTING AND PARTICIPANTS: A total of 167 fourth-year osteopathic medical students at a teaching nursing home (TNH). METHODS: A total of 167 fourth-year osteopathic medical students (OMS-4s) were randomly assigned face-to-face PA/LTC patient encounters at the TNH. The encounters were follow-up visits to residents of the TNH that were supervised by faculty geriatricians. Half were accompanied by the physician and the other half were supervised by the physician through telemedicine. Evaluation using validated survey instruments measured patient rapport, verbal communication, and physical examination skills as well as attitudes, knowledge, and behaviors of the student/subjects. RESULTS: A nonparametric statistical analysis of 4 dependent variables measuring patient rapport, attitudes, knowledge and behavior showed no significant difference between the 2 teaching modalities. CONCLUSIONS AND IMPLICATIONS: The results of this prospective cohort study indicate that telemedicine supervision is comparable (noninferior) to direct supervision of medical student trainees in a PA/LTC setting.

Androgen receptor markers do not differ between nonresponders and responders to resistance training-induced muscle hypertrophy.

The aim of this study was to investigate whether baseline values and acute and chronic changes in androgen receptors (AR) markers, including total AR, cytoplasmic (cAR), and nuclear (nAR) fractions, as well as DNA-binding activity (AR-DNA), are involved in muscle hypertrophy responsiveness by comparing young nonresponder and responder individuals. After 10 wk of resistance training (RT), participants were identified as nonresponders using two typical errors (TE) obtained through two muscle cross-sectional area (mCSA) ultrasound measurements (2 × TE; 4.94%), and the highest responders within our sample were numerically matched. Muscle biopsies were performed at baseline, 24 h after the first RT session (acute responses), and 96 h after the last session (chronic responses). AR, cAR, and nAR were analyzed using Western blotting, and AR-DNA was analyzed using an ELISA-oligonucleotide assay. Twelve participants were identified as nonresponders (ΔmCSA: -1.32%) and 12 as responders (ΔmCSA: 21.35%). There were no baseline differences between groups in mCSA, AR, cAR, nAR, or AR-DNA (P > 0.05). For acute responses, there was a significant difference between nonresponders (+19.5%) and responders (-14.4%) in AR-DNA [effect size (ES) = -1.39; 95% confidence interval (CI): -2.53 to -0.16; P = 0.015]. There were no acute between-group differences in any other AR markers (P > 0.05). No significant differences between groups were observed in chronic responses across any AR markers (P > 0.05). Nonresponders and responders presented similar baseline, acute, and chronic results for the majority of the AR markers. Thus, our findings do not support the influence of AR markers on muscle hypertrophy responsiveness to RT in untrained individuals.NEW & NOTEWORTHY We explored, for the first time, the influence of androgen receptor (AR) through the separation of cytoplasmic and nuclear cell fractions [i.e., cytoplasmic androgen receptor (cAR), nuclear androgen receptor (nAR), and androgen receptor DNA-binding activity (AR-DNA)] on muscle hypertrophy responsiveness to resistance training. The absence of muscle hypertrophy in naïve individuals does not seem to be explained by baseline values, and acute or chronic changes in AR markers.

BP1003 Decreases STAT3 Expression and Its Pro-Tumorigenic Functions in Solid Tumors and the Tumor Microenvironment.

Overexpression and aberrant activation of signal transducer and activator of transcription 3 (STAT3) contribute to tumorigenesis, drug resistance, and tumor-immune evasion, making it a potential cancer therapeutic target. BP1003 is a neutral liposome incorporated with a nuclease-resistant P-ethoxy antisense oligodeoxynucleotide (ASO) targeting the STAT3 mRNA. Its unique design enhances BP1003 stability, cellular uptake, and target affinity. BP1003 efficiently reduces STAT3 expression and enhances the sensitivity of breast cancer cells (HER2+, triple negative) and ovarian cancer cells (late stage, invasive ovarian cancer) to paclitaxel and 5-fluorouracil (5-FU) in both 2D and 3D cell cultures. Similarly, ex vivo and in vivo patient-derived models of pancreatic ductal adenocarcinoma (PDAC) show reduced tissue viability and tumor volume with BP1003 and gemcitabine combination treatments. In addition to directly affecting tumor cells, BP1003 can modulate the tumor microenvironment. Unlike M1 differentiation, monocyte differentiation into anti-inflammatory M2 macrophages is suppressed by BP1003, indicating its potential contribution to immunotherapy. The broad anti-tumor effect of BP1003 in numerous preclinical solid tumor models, such as breast, ovarian, and pancreatic cancer models shown in this work, makes it a promising cancer therapeutic.

The utility-and limitations-of the rodent synergist ablation model in examining mechanisms of skeletal muscle hypertrophy.

In this issue, Burke et al. discuss the utility of the rodent synergist ablation (SA) model for examining mechanisms associated with skeletal muscle hypertrophy. In this invited perspective, we aim to complement their original perspective by discussing limitations to the model along with alternative mechanical overload models that have strengths and limitations.

Relative rDNA copy number is not associated with resistance training-induced skeletal muscle hypertrophy and does not affect myotube anabolism in vitro.

Ribosomal DNA (rDNA) copies exist across multiple chromosomes, and interindividual variation in copy number is speculated to influence the hypertrophic response to resistance training. Thus, we examined if rDNA copy number was associated with resistance training-induced skeletal muscle hypertrophy. Participants (n = 53 male, 21 ± 1 yr old; n = 29 female, 21 ± 2 yr old) performed 10-12 wk of full-body resistance training. Hypertrophy outcomes were determined, as was relative rDNA copy number from preintervention vastus lateralis (VL) biopsies. Pre- and postintervention VL biopsy total RNA was assayed in all participants, and mRNA/rRNA markers of ribosome content and biogenesis were also assayed in the 29 female participants before training, 24 h following training bout 1, and in the basal state after 10 wk of training. Across all participants, no significant associations were evident between relative rDNA copy number and training-induced changes in whole body lean mass (r = -0.034, P = 0.764), vastus lateralis thickness (r = 0.093, P = 0.408), mean myofiber cross-sectional area (r = -0.128, P = 0.259), or changes in muscle RNA concentrations (r = 0.026, P = 0.818), and these trends were similar when examining each gender. However, all Pol-I regulon mRNAs as well as 45S pre-rRNA, 28S rRNA, and 18S rRNA increased 24 h following the first training bout in female participants. Follow-up studies using LHCN-M2 myotubes demonstrated that a reduction in relative rDNA copy number induced by bisphenol A did not significantly affect insulin-like-growth factor-induced myotube hypertrophy. These findings suggest that relative rDNA copy number is not associated with myofiber hypertrophy.NEW & NOTEWORTHY We examined ribosomal DNA (rDNA) copy numbers in men and women who resistance trained for 10-12 wk and found no significant associations with skeletal muscle hypertrophy outcomes. These data, along with in vitro data in immortalized human myotubes whereby rDNA copy number was reduced, provide strong evidence that relative rDNA copy number is not associated with anabolism.

Recent methodological advances in federated learning for healthcare.

For healthcare datasets, it is often impossible to combine data samples from multiple sites due to ethical, privacy, or logistical concerns. Federated learning allows for the utilization of powerful machine learning algorithms without requiring the pooling of data. Healthcare data have many simultaneous challenges, such as highly siloed data, class imbalance, missing data, distribution shifts, and non-standardized variables, that require new methodologies to address. Federated learning adds significant methodological complexity to conventional centralized machine learning, requiring distributed optimization, communication between nodes, aggregation of models, and redistribution of models. In this systematic review, we consider all papers on Scopus published between January 2015 and February 2023 that describe new federated learning methodologies for addressing challenges with healthcare data. We reviewed 89 papers meeting these criteria. Significant systemic issues were identified throughout the literature, compromising many methodologies reviewed. We give detailed recommendations to help improve methodology development for federated learning in healthcare.

NHS-Reimbursed Cannabis Flowers for Cancer Palliative Care and the Management of Chemotherapy-Induced Nausea and Vomiting: An Autobiographical Case Report.

Chemotherapy-induced nausea and vomiting (CINV) is a debilitating side effect of cancer treatment, affecting many patients. Cannabinoid agonists, such as nabilone and Δ9-tetrahydrocannabinol (THC), the main psychoactive component of Cannabis sativa L., have shown efficacy as antiemetics. Here, we report the case of Michael Roberts (MR), who we believe is the first British patient reimbursed by the National Health Service (NHS) England for the cost of medicinal cannabis flowers to manage CINV. Medical data were obtained from NHS records and individual funding request (IFR) forms. Patient-reported outcome measures (PROMs) were collected using validated questionnaires as part of the standard of care at the specialized private clinics where the prescription of medicinal cannabis was initiated. The patient presented with rectosigmoid adenocarcinoma with lung metastases. He received FOLFIRI (folinic acid, fluorouracil, and irinotecan) chemotherapy and underwent an emergency Hartmann's procedure with subsequent second-line FOLFOX (folinic acid, fluorouracil, and oxaliplatin) chemotherapy and lung ablation. MR reported severe nausea and vomiting associated with the initial FOLFIRI treatment. Antiemetics metoclopramide and aprepitant demonstrated moderated efficacy. Antiemetics ondansetron, levomepromazine, and nabilone were associated with intolerable side effects. Inhalation of THC-predominant cannabis flowers in association with standard medication improved CINV, anxiety, sleep quality, appetite, overall mood, and quality of life. Our results add to the available evidence suggesting that medicinal cannabis flowers may offer valuable support in cancer palliative care integrated with standard-of-care oncology treatment. The successful individual funding request in this case demonstrates a pathway for other patients to gain access to these treatments, advocating for broader awareness and integration of cannabis-based medicinal products in national healthcare services.

Mitigating skeletal muscle wasting in unloading and augmenting subsequent recovery.

Skeletal muscle wasting is the hallmark pathophysiological adaptation to unloading or disuse that demonstrates the dependency on frequent mechanical stimulation (e.g. muscle activation and subsequent loading) for homeostasis of normally load-bearing muscles. In the absence of mitigation strategies, no mammalian organism is resistant to muscle atrophy driven by unloading. Given the profound impact of unloading-induced muscle wasting on physical capacity, metabolic health and immune function; mitigation strategies during unloading and/or augmentation approaches during recovery have broad healthcare implications in settings of bed-bound hospitalization, cast immobilization and spaceflight. This topical review aims to: (1) provide a succinct, state-of-the-field summary of seminal and recent findings regarding the mechanisms of unloading-induced skeletal muscle wasting; (2) discuss unsuccessful vs. promising mitigation and recovery augmentation strategies; and (3) identify knowledge gaps ripe for future research. We focus on the rapid muscle atrophy driven by relatively short-term mechanical unloading/disuse, which is in many ways mechanistically distinct from both hypermetabolic muscle wasting and denervation-induced muscle atrophy. By restricting this discussion to mechanical unloading during which all components of the nervous system remain intact (e.g. without denervation models), mechanical loading requiring motor and sensory neural circuits in muscle remain viable targets for both mitigation and recovery augmentation. We emphasize findings in humans with comparative discussions of studies in rodents which enable elaboration of key mechanisms. We also discuss what is currently known about the effects of age and sex as biological factors, and both are highlighted as knowledge gaps and novel future directions due to limited research.

Correcting common OCT artifacts enhances plaque classification and identification of higher-risk plaque features.

BACKGROUND: Optical coherence tomography (OCT) is used widely to guide stent placement, identify higher-risk plaques, and assess mechanisms of drug efficacy. However, a range of common artifacts can prevent accurate plaque classification and measurements, and limit usable frames in research studies. We determined whether pre-processing OCT images corrects artifacts and improves plaque classification. METHODS: We examined both ex-vivo and clinical trial OCT pullbacks for artifacts that prevented accurate tissue identification and/or plaque measurements. We developed Fourier transform-based software that reconstructed images free of common OCT artifacts, and compared corrected and uncorrected images. RESULTS: 48 % of OCT frames contained image artifacts, with 62 % of artifacts over or within lesions, preventing accurate measurement in 12 % frames. Pre-processing corrected >70 % of all artifacts, including thrombus, macrophage shadows, inadequate flushing, and gas bubbles. True tissue reconstruction was achieved in 63 % frames that would otherwise prevent accurate clinical measurements. Artifact correction was non-destructive and retained anatomical lumen and plaque parameters. Correction improved accuracy of plaque classification compared against histology and retained accurate assessment of higher-risk features. Correction also changed plaque classification and prevented artifact-related measurement errors in a clinical study, and reduced unmeasurable frames to <5 % ex-vivo and ~1 % in-vivo. CONCLUSIONS: Fourier transform-based pre-processing corrects a wide range of common OCT artifacts, improving identification of higher-risk features and plaque classification, and allowing more of the whole dataset to be used for clinical decision-making and in research. Pre-processing can augment OCT image analysis systems both for stent optimization and in natural history or drug studies.

Lineage-tracing reveals an expanded population of NPY neurons in the inferior colliculus.

Growing evidence suggests that neuropeptide signaling shapes auditory computations. We previously showed that neuropeptide Y (NPY) is expressed in the inferior colliculus (IC) by a population of GABAergic stellate neurons and that NPY regulates the strength of local excitatory circuits in the IC. NPY neurons were initially characterized using the NPY-hrGFP mouse, in which humanized renilla green fluorescent protein (hrGFP) expression indicates NPY expression at the time of assay, i.e., an expression-tracking approach. However, studies in other brain regions have shown that NPY expression can vary based on several factors, suggesting that the NPY-hrGFP mouse might miss NPY neurons not expressing NPY on the experiment date. Here, we hypothesized that neurons with the ability to express NPY represent a larger population of IC GABAergic neurons than previously reported. To test this hypothesis, we used a lineage-tracing approach to irreversibly tag neurons that expressed NPY at any point prior to the experiment date. We then compared the physiological and anatomical features of neurons labeled with this lineage-tracing approach to our prior data set, revealing a larger population of NPY neurons than previously found. In addition, we used optogenetics to test the local connectivity of NPY neurons and found that NPY neurons provide inhibitory synaptic input to other neurons in the ipsilateral IC. Together, our data expand the definition of NPY neurons in the IC, suggest that NPY expression might be dynamically regulated in the IC, and provide functional evidence that NPY neurons form local inhibitory circuits in the IC.NEW & NOTEWORTHY Across brain regions, neuropeptide Y (NPY) expression is dynamic and influenced by extrinsic and intrinsic factors. We previously showed that NPY is expressed by a class of inhibitory neurons in the auditory midbrain. Here, we find that this neuron class also includes neurons that previously expressed NPY, suggesting that NPY expression is dynamically regulated in the auditory midbrain. We also provide functional evidence that NPY neurons contribute to local inhibitory circuits in the auditory midbrain.

Clinical toxicology of acute glyphosate self-poisoning: impact of plasma concentrations of glyphosate, its metabolite and polyethoxylated tallow amine surfactants on the toxicity.

INTRODUCTION: Common major co-formulants in glyphosate-based herbicides, polyethoxylated tallow amine surfactants, are suspected of being more toxic than glyphosate, contributing to the toxicity in humans. However, limited information exists on using polyethoxylated tallow amine concentrations to predict clinical outcomes. We investigated if plasma concentrations of glyphosate, its metabolite and polyethoxylated tallow amines can predict acute kidney injury and case fatality in glyphosate poisoning. METHODS: We enrolled 151 patients with acute glyphosate poisoning between 2010 and 2013. Plasma concentrations of glyphosate, its metabolite, aminomethylphosphonic acid, and polyethoxylated tallow amines were determined in 2020 using liquid chromatography-tandem mass spectrometry. Associations between exposure and poisoning severity were assessed. RESULTS: Plasma concentrations of glyphosate and aminomethylphosphonic acid demonstrated good and moderate performances in predicting acute kidney injury (≥2), with an area under the receiver operating characteristic curve of 0.83 (95% CI 0.69-0.97) and 0.76 (95% CI 0.59-0.94), respectively. Polyethoxylated tallow amines were detected in one-fifth of symptomatic patients, including one of four fatalities and those with unsaturated tallow moieties being good indicators of acute kidney injury (area under the receiver operating characteristic curve ≥0.7). As the number of repeating ethoxylate units in tallow moieties decreased, the odds of acute kidney injury increased. Glyphosate and aminomethylphosphonic acid concentrations were excellent predictors of case fatality (area under the receiver operating characteristic curve >0.9). DISCUSSION: The 2.7% case fatality rate with 49% acute, albeit mild, acute kidney injury following glyphosate poisoning is consistent with previously published data. A population approach using model-based metrics might better explore the relationship of exposure to severity of poisoning. CONCLUSIONS: Plasma concentrations of glyphosate and its metabolite predicted the severity of clinical toxicity in glyphosate poisoning. The co-formulated polyethoxylated tallow amine surfactants were even more strongly predictive of acute kidney injury but were only detected in a minority of patients.