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The influence of X chromosome genetic variation on blood lipids and coronary heart disease (CHD) is not well understood. Here, the authors analyse X chromosome sequencing data across 65,322 multi-ancestry individuals, identifying associations of the Xq23 locus with lipid changes and reduced risk of CHD and diabetes mellitus.

Existing tumor markers for testicular germ cell tumor (TGCT) cannot detect the presence of pure teratoma. Serum miRNAs have strong performance detecting other subtypes of TGCT. Previous reports suggest high levels of miR-375 expression in teratoma tissue. The purpose of this study was to explore the role of serum miRNA, including miR-375, in detecting the presence of teratoma at postchemotherapy retroperitoneal lymph node dissection (PC-RPLND).We prospectively collected presurgical serum from 40 TGCT patients undergoing PC-RPLND (21 with teratoma at RPLND and 19 with no evidence of disease). We examined the utility of serum miR-375-3p and miR-375-5p by quantitative polymerase chain reaction, and searched for other putative serum miRNAs with small RNA sequencing. The area under the receiver operating characteristic curve (AUC) and univariate analyses were utilized to evaluate test characteristics and predictors of teratoma.Both serum miR-375-3p and miR-375-5p exhibited poor performance (miR-375-3p: 86% sensitivity, 32% specificity, AUC: 0.506; miR-375-5p: 55% sensitivity, 67% specificity, AUC: 0.556). Teratoma at orchiectomy was the only predictor of PC-RPLND teratoma. Small RNA sequencing identified three potentially discriminatory miRNAs, but further validation demonstrated no utility. Our results confirm prior reports that serum miR-375 cannot predict teratoma, and suggest that there may not exist a predictive serum miRNA for teratoma. Patient summary: We found that serum miR-375 cannot detect the presence of teratoma at postchemotherapy retroperitoneal lymph node dissection (PC-RPLND). We are also unable to find any other serum miRNAs predictive of pure teratoma at PC-RPLND. Hence, the lack of a reliable circulating marker of teratoma remains a critical clinical need.

Background: With increasing interest in stereotactic body radiotherapy (SBRT) for unresectable pancreatic cancer, quality improvement (QI) initiatives to develop integrated clinical workflows are crucial to ensure quality assurance (QA) when introducing this challenging technique into radiation practices.Materials/Methods: In 2017, we used the Plan, Do, Study, Act (PDSA) QI methodology to implement a new pancreas SBRT program in an integrated community radiation oncology satellite. A unified integrated information technology infrastructure was used to virtually integrate the planned workflow into the community radiation oncology satellite network (P – Plan/D – Do). This workflow included multiple prospective quality assurance (QA) measures including multidisciplinary evaluation, prospective scrutiny of radiation target delineation, prospective radiation plan evaluation, and monitoring of patient outcomes. Institutional review board approval was obtained to retrospectively study and report outcomes of patients treated in this program (S – Study).Results:There were 12 consecutive patients identified who were treated in this program from 2017 to 2020 with a median follow-up of 27 months. The median survival was 13 months, median local failure free survival was 12 months and median progression free survival was 6 months from SBRT. There were no acute or late Common Terminology Criteria for Adverse Effects (CTCAE) version 5 toxicities ≥ Grade 3.Conclusion:We report the successful implementation of a community pancreas SBRT program involving multiple prospective QA measures, providing the groundwork to safely expand access to pancreas SBRT in our community satellite network (A – Act).

Microglia are resident macrophages of the brain, performing roles related to brain homeostasis, including modulation of synapses, trophic support, phagocytosis of apoptotic cells and debris, as well as brain protection and repair. Studies assessing morphological and transcriptional features of microglia found regional differences as well as sex differences in some investigated brain regions. However, markers used to isolate microglia in many previous studies are not expressed exclusively by microglia or cannot be used to identify and isolate microglia in all contexts. Here, fluorescent activated cell sorting was used to isolate cells expressing the microglia-specific marker TMEM119 from prefrontal cortex (PFC), striatum, and midbrain in mice. RNA-sequencing was used to assess the transcriptional profile of microglia, focusing on brain region and sex differences. We found striking brain region differences in microglia-specific transcript expression. Most notable was the distinct transcriptional profile of midbrain microglia, with enrichment for pathways related to immune function; these midbrain microglia exhibited a profile similar to disease-associated or immune-surveillant microglia. Transcripts more highly expressed in PFC isolated microglia were enriched for synapse-related pathways while microglia isolated from the striatum were enriched for pathways related to microtubule polymerization. We also found evidence for a gradient of expression of microglia-specific transcripts across the rostral-to-caudal axes of the brain, with microglia extracted from the striatum exhibiting a transcriptional profile intermediate between that of the PFC and midbrain. We also found sex differences in expression of microglia-specific transcripts in all 3 brain regions, with many selenium-related transcripts more highly expressed in females across brain regions. These results suggest that the transcriptional profile of microglia varies between brain regions under homeostatic conditions, suggesting that microglia perform diverse roles in different brain regions and even based on sex.

Summary: Bromocriptine is approved as a diabetes therapy, yet its therapeutic mechanisms remain unclear. Though bromocriptine’s actions have been mainly attributed to the stimulation of brain dopamine D2 receptors (D2R), bromocriptine also targets the pancreas. Here, we employ bromocriptine as a tool to elucidate the roles of catecholamine signaling in regulating pancreatic hormone secretion. In β-cells, bromocriptine acts on D2R and α2A-adrenergic receptor (α2A-AR) to reduce glucose-stimulated insulin secretion (GSIS). Moreover, in α-cells, bromocriptine acts via D2R to reduce glucagon secretion. α2A-AR activation by bromocriptine recruits an ensemble of G proteins with no β-arrestin2 recruitment. In contrast, D2R recruits G proteins and β-arrestin2 upon bromocriptine stimulation, demonstrating receptor-specific signaling. Docking studies reveal distinct bromocriptine binding to α2A-AR versus D2R, providing a structural basis for bromocriptine’s dual actions on β-cell α2A-AR and D2R. Together, joint dopaminergic and adrenergic receptor actions on α-cell and β-cell hormone release provide a new therapeutic mechanism to improve dysglycemia.

The sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA) pump is responsible for the transport of Ca2+ from the cytosol into the sarcoplasmic reticulum at the expense of ATP, making it a regulator of both muscle relaxation and muscle-based energy expenditure. Neurogranin (Ng) is a small protein that negatively regulates calcineurin signaling. Calcineurin is Ca2+/calmodulin dependent phosphatase that promotes the oxidative fibre type in skeletal muscle and regulates muscle-based energy expenditure. A recent study has shown that calcineurin activation reduces SERCA Ca2+ transport efficiency, ultimately raising energy expenditure. Since the biomedical view of obesity states that it arises as an imbalance between energy intake and expenditure which favors the former, we questioned whether heterozygous Ng deletion (Ng+/-) would reduce SERCA efficiency and increase energy expenditure in female mice fed a high-fat diet (HFD). Young (3–4-month-old) female wild type (WT) and Ng+/- mice were fed a HFD for 12 weeks with their metabolic profile being analyzed using metabolic cages and DXA scanning, while soleus SERCA efficiency was measured using SERCA specific Ca2+ uptake and ATPase activity assays. Ng+/- mice showed significantly less cage ambulation compared to WT mice but this did not lead to any added weight gain nor changes in daily energy expenditure, glucose or insulin tolerance despite a similar level of food intake. Furthermore, we observed significant reductions in SERCA’s apparent coupling ratio which were associated with significant reductions in SERCA1 and phospholamban content. Thus, our results show that Ng regulates SERCA pump efficiency, and future studies should further investigate the potential cellular mechanisms.

# Background Percussive therapy is hypothesized to speed recovery by delivering gentle, rhythmic pulses to soft tissue. However, patients often present with a differential soreness response after percussive therapy, which may lead to altered clinical outcomes. # Purpose To compare the acute effects of percussion therapy on passive range of motion (ROM) and tissue-specific ultrasound measures (pennation angle \[PA\] and muscle thickness \[MT\]) between healthy individuals responding positively vs. negatively to percussive therapy performed on the dominant arm posterior rotator cuff. # Study Design Cross-sectional laboratory study # Methods Fifty-five healthy individuals were assessed on a subjective soreness scale before and after a five-minute percussive therapy session on the dominant arm posterior rotator cuff muscles. Participants with no change or a decrease in muscle soreness were assigned to the positive response group and participants who reported an increase in muscle soreness were assigned to the negative response group. Passive internal rotation (IR) and external rotation (ER) ROM and strength, and muscle architecture of the infraspinatus and teres minor were measured via ultrasound on the dominant shoulder. All dependent variables were collected before percussive therapy, and 20 minutes following percussive therapy. # Results The positive response group had greater improvements than the negative response group in dominant arm IR ROM (2.3° positive vs. -1.3° negative, p=0.021) and IR strength (1.1 lbs vs. -1.2 lbs, p=0.011) after percussive therapy. No differences in ER strength or ROM were observed between groups. Regarding muscle architecture, the positive group had a lesser change in teres minor MT (0.00 mm vs. 0.11 mm, p=0.019) after percussive therapy. All other muscle architecture changes were not statistically different between groups. # Conclusion Participants with a positive response to percussive therapy had increased dominant arm IR ROM and IR strength, and decreased teres minor MT, after percussive therapy compared to the negative response participants. # Level of Evidence III

Opioid use disorder (OUD) and deaths from drug overdoses have reached unprecedented levels. Given the enormous impact of the opioid crisis on public health, a more thorough, in-depth understanding of the consequences of opioids on the brain is required to develop novel interventions and pharmacological therapeutics. In the brain, the effects of opioids are far reaching, from genes to cells, synapses, circuits, and ultimately behavior. Accumulating evidence implicates a primary role for the extracellular matrix (ECM) in opioid-induced plasticity of synapses and circuits, and the development of dependence and addiction to opioids. As a network of proteins and polysaccharides, including cell adhesion molecules, proteases, and perineuronal nets, the ECM is intimately involved in both the formation and structural support of synapses. In the human brain, recent findings support an association between altered ECM signaling and OUD, particularly within the cortical and striatal circuits involved in cognition, reward, and craving. Furthermore, the ECM signaling proteins, including matrix metalloproteinases and proteoglycans, are directly involved in opioid seeking, craving, and relapse behaviors in rodent opioid models. Both the impact of opioids on the ECM and the role of ECM signaling proteins in opioid use disorder, may, in part, depend on biological sex. Here, we highlight the current evidence supporting sex-specific roles for ECM signaling proteins in the brain and their associations with OUD. We emphasize knowledge gaps and future directions to further investigate the potential of the ECM as a therapeutic target for the treatment of OUD.

Objective: The effect of cardiac arrest (CA) on cerebral transcriptomics and metabolomics is unknown. We previously demonstrated hemodynamic-directed CPR (HD-CPR) improves survival with favorable neurologic outcomes versus standard CPR (Std-CPR). We hypothesized HD-CPR would preserve the cerebral transcriptome and metabolome compared to Std-CPR. Design: Randomized pre-clinical animal trial. Setting: Large animal resuscitation laboratory at an academic children’s hospital. Subjects: Four-week-old female piglets (8–11 kg). Interventions: Pigs (1-month-old), three groups: 1) HD-CPR (compression depth to systolic BP 90 mmHg, vasopressors to coronary perfusion pressure 20 mmHg); 2) Std-CPR and 3) shams (no CPR). HD-CPR and Std-CPR underwent asphyxia, induced ventricular fibrillation, 10–20 min of CPR and post-resuscitation care. Primary outcomes at 24 h in cerebral cortex: 1) transcriptomic analysis (n = 4 per treatment arm, n = 8 sham) of 1727 genes using differential gene expression and 2) metabolomic analysis (n = 5 per group) of 27 metabolites using one-way ANOVA, post-hoc Tukey HSD. Measurements and main results: 65 genes were differentially expressed between HD-CPR and Std-CPR and 72 genes between Std-CPR and sham, but only five differed between HD-CPR and sham. Std-CPR increased the concentration of five AA compared to HD-CPR and sham, including the branched chain amino acids (BCAA), but zero metabolites differed between HD-CPR and sham. Conclusions: In cerebral cortex 24 h post CA, Std-CPR resulted in a different transcriptome and metabolome compared with either HD-CPR or sham. HD-CPR preserves the transcriptome and metabolome, and is neuroprotective. Global molecular analyses may be a novel method to assess efficacy of clinical interventions and identify therapeutic targets. Institutional protocol number: IAC 16-001023.

Fusel alcohol mixtures containing ethanol, isobutanol, isopentanol, and 2-phenylethanol have been shown to be a promising means to maximize renewable fuel yield from various biomass feedstocks and waste streams. We hypothesized that use of these fusel alcohol mixtures as a blending agent with gasoline can significantly lower the greenhouse gas emissions from the light-duty fleet. Since the composition of fusel alcohol mixtures derived from fermentation is dependent on a variety of factors such as biocatalyst selection and feedstock composition, multi-objective optimization was performed to identify optimal fusel alcohol blends in gasoline that simultaneously maximize thermodynamic efficiency gain and energy density. Pareto front analysis combined with fuel property predictions and a Merit Score-based metric led to prediction of optimal fusel alcohol-gasoline blends over a range of blending volumes. The optimal fusel blends were analyzed based on a Net Fuel Economy Improvement Potential metric for volumetric blending in a gasoline base fuel. The results demonstrate that various fusel alcohol blends provide the ability to maximize efficiency improvement while minimizing increases to blending vapor pressure and decreases to energy density compared to an ethanol-only bioblendstock. Fusel blends exhibit predicted Net Fuel Economy Improvement Potential comparable to neat ethanol when blended with gasoline in all scenarios, with increased improvement over ethanol at moderate to high bio-blendstock blending levels. The optimal fusel blend that was identified was a mixture of 90% v/v isobutanol and 10% v/v 2-phenylethanol, blended at 45% v/v with gasoline, yielding a predicted 4.67% increase in Net Fuel Economy Improvement Potential. These findings suggest that incorporation of fusel alcohols as a gasoline bioblendstock can improve both fuel performance and the net fuel yield of the bioethanol industry.

Abstract Dopamine (DA) and norepinephrine (NE) are catecholamines primarily studied in the central nervous system that also act in the pancreas as peripheral regulators of metabolism. Pancreatic catecholamine signaling has also been increasingly implicated as a mechanism responsible for the metabolic disturbances produced by antipsychotic drugs (APDs). Critically, however, the mechanisms by which catecholamines modulate pancreatic hormone release are not completely understood. We show that human and mouse pancreatic α- and β-cells express the catecholamine biosynthetic and signaling machinery, and that α-cells synthesize DA de novo. This locally-produced pancreatic DA signals via both α- and β-cell adrenergic and dopaminergic receptors with different affinities to regulate glucagon and insulin release. Significantly, we show DA functions as a biased agonist at α2A-adrenergic receptors, preferentially signaling via the canonical G protein-mediated pathway. Our findings highlight the interplay between DA and NE signaling as a novel form of regulation to modulate pancreatic hormone release. Lastly, pharmacological blockade of DA D2-like receptors in human islets with APDs significantly raises insulin and glucagon release. This offers a new mechanism where APDs act directly on islet α- and β-cell targets to produce metabolic disturbances.

Abstract Estuaries regulate transport of dissolved organic carbon (DOC) from land to ocean. Export of terrestrial DOC from coastal watersheds is exacerbated by increasing major rainfall and storm events and human activities, leading to pulses of DOC that are shunted through rivers downstream to estuaries. Despite an upward trend of extreme events, the fate of the pulsed terrestrial DOC in estuaries remains unclear. We analyzed the effects of seven major tropical cyclones (TC) from 1999 to 2017 on the quantity and fate of DOC in the Neuse River Estuary (NC, USA). Significant TC‐induced increases in DOC were observed throughout the estuary; the increase lasting from around 50 d at head‐of‐tide to over 6 months in lower estuary. Our results suggest that pulsed terrestrial DOC associated with TCs temporarily overwhelms the estuarine filter's abiotic and biotic degradation capacity under such high flow events, enhancing the shunt of terrestrial carbon to the coastal ocean.

Abstract Background Diametrically opposed positions exist regarding the deleterious effects of elevated lactate. There are data suggesting that it is a detrimental proxy for tissue hypoperfusion and anaerobic metabolism in sepsis and an alternative viewpoint is that some of the hyperlactatemia produced maybe adaptive. This study was conducted to explore the relationship between serum lactate levels, mean arterial blood pressure (MAP), and sympathetic stimulation in patients with sepsis. Methods Retrospective analysis of prospectively collected clinical data from four community-based hospitals and one academic medical center. 8173 adults were included. Heart rate (HR) was used as a surrogate marker of sympathetic stimulation. HR, MAP, and lactate levels were measured upon presentation. Results MAP and HR interacted to affect lactate levels with the highest levels observed in patients with low MAP and high HR (3.6 mmol/L) and the lowest in patients with high MAP and low HR (2.2 mmol/L). The overall mortality rate was 12.4%. Each 10 beats/min increase in HR increased the odds of death 6.0% (95% CI 2.6% to 9.4%), each 1 mmol/L increase in lactate increased the odds of death 20.8% (95% CI 17.4% to 24.2%), whereas each 10 mmHg increase in MAP reduced the odds of death 12.3% (95% CI 9.2% to 15.4%). However, HR did not moderate or mediate the association between lactate and death. Conclusions In septic patients, lactate production was associated with increased sympathetic activity (HR ≥ 90) and hypotension (MAP

Abstract Neurologic injury is a leading cause of morbidity and mortality following pediatric cardiac arrest. In this study, we assess the feasibility of quantitative, non-invasive, frequency-domain diffuse optical spectroscopy (FD-DOS) neuromonitoring during cardiopulmonary resuscitation (CPR), and its predictive utility for return of spontaneous circulation (ROSC) in an established pediatric swine model of cardiac arrest. Cerebral tissue optical properties, oxy- and deoxy-hemoglobin concentration ([HbO2], [Hb]), oxygen saturation (StO2) and total hemoglobin concentration (THC) were measured by a FD-DOS probe placed on the forehead in 1-month-old swine (8–11 kg; n = 52) during seven minutes of asphyxiation followed by twenty minutes of CPR. ROSC prediction and time-dependent performance of prediction throughout early CPR (

Abstract Circadian variability is driven by genetics and Diversity Outbred (DO) mice is a powerful tool for examining the genetics of complex traits because their high genetic and phenotypic diversity compared to conventional mouse crosses. The DO population combines the genetic diversity of eight founder strains including five common inbred and three wild-derived strains. In DO mice and their founders, we established a high-throughput system to measure cellular rhythms using in vitro preparations of skin fibroblasts. Among the founders, we observed strong heritability for rhythm period, robustness, phase and amplitude. We also found significant sex and strain differences for these rhythms. Extreme differences in period for molecular and behavioral rhythms were found between the inbred A/J strain and the wild-derived CAST/EiJ strain, where A/J had the longest period and CAST/EiJ had the shortest. In addition, we measured cellular rhythms in 329 DO mice, which displayed far greater phenotypic variability than the founders—80% of founders compared to only 25% of DO mice had periods of ~ 24 h. Collectively, our findings demonstrate that genetic diversity contributes to phenotypic variability in circadian rhythms, and high-throughput characterization of fibroblast rhythms in DO mice is a tractable system for examining the genetics of circadian traits.

Aquatic habitats in the Canadian Arctic are expected to come under increasing stress due to projected effects of climate change. There is a need for community-based biomonitoring programs to observe and understand the effects of these stressors on the environment. Here we present results from a 5 year annual sampling program of benthic invertebrates from lakes in the Mackenzie Delta, Northwest Territories, using a rapid bioassessment protocol. Connectivity between the deltaic lakes and main channels is a major driver of lake function and is expected to be substantially impacted by climate change. Lakes were selected along a gradient of connectivity based on sill elevation above the river. Using multivariate analyses of community structure, we determined that benthic assemblages responded to differences in connection time among lakes. This response was detected using a coarse taxonomic level that could be applied by community groups or volunteers but was stronger when invertebrates were identified to the family and genus levels. A secondary gradient was observed that corresponded to productivity gradients in lakes that are isolated from the river during summer. We show that benthic assemblages have potential use as sensitive indicators of climate-mediated changes to the hydrology of lakes in the Mackenzie Delta.

Background: Contemporary studies note sustained clinical benefit and decreasing complications after reverse total shoulder arthroplasty (RTSA), which warrant a comparison with the standard anatomic total shoulder arthroplasty (ATSA). The purpose of this study is to evaluate and compare differences in midterm survivorship between ATSA and RTSA patients treated with a single platform shoulder prosthesis. Secondary objectives include a comparison of the clinical outcomes and complication profile for each procedure. Methods: A prospective analysis of all primary ATSA and RTSA performed by 3 surgeons between 2007 and 2012 was conducted. Selection of the ATSA or RTSA implant configuration was determined by the surgeons per their clinical understanding of each individual patient's glenoid morphology, rotator cuff, and patient expectations. All 778 procedures were performed using a single platform shoulder system. Results: Survivorship for ATSA was similar to that for RTSA at all time points; ATSA at 2 and 8 years was 98.5% and 96.0%, whereas RTSA at 2 and 8 years was 98.7% and 96.0%, respectively ( P= .392). All postoperative range of motion scores for ATSA patients were greater than those for RTSA patients. The overall rate of complications between the ATSA and RTSA groups was similar (6.3% vs. 4.9%, P= .414). Conclusions: On the basis of this cohort comparison, both ATSA and RTSA demonstrated similar survivorship at 8 years after surgery with multiple surgeons practicing in different countries. Our results demonstrate that the RTSA and ATSA implants have comparable results and can be expected to provide similar implant longevity over the midterm with excellent functional outcomes.

Abstract Picophytoplankton (PicoP) are increasingly recognized as significant contributors to primary productivity and phytoplankton biomass in coastal and estuarine systems. Remarkably though, PicoP composition is unknown or not well-resolved in several large estuaries including the semi-lagoonal Neuse River Estuary (NRE), a tributary of the second largest estuary-system in the lower USA, the Pamlico-Albemarle Sound. The NRE is impacted by extreme weather events, including recent increases in precipitation and flooding associated with tropical cyclones. Here we examined the impacts of moderate to extreme (Hurricane Florence, September 2018) precipitation events on NRE PicoP abundances and composition using flow cytometry, over a 1.5 year period. Phycocyanin-rich Synechococcus-like cells were the most dominant PicoP, reaching ~ 106 cells mL−1, which highlights their importance as key primary producers in this relatively long residence-time estuary. Ephemeral “blooms” of picoeukaryotic phytoplankton (PEUK) during spring and after spikes in river flow were also detected, making PEUK periodically major contributors to PicoP biomass (up to ~ 80%). About half of the variation in PicoP abundance was explained by measured environmental variables. Temperature explained the most variation (24.5%). Change in total dissolved nitrogen concentration, an indication of increased river discharge, explained the second-most variation in PicoP abundance (15.9%). The short-term impacts of extreme river discharge from Hurricane Florence were particularly evident as PicoP biomass was reduced by ~ 100-fold for more than 2 weeks. We conclude that precipitation is a highly influential factor on estuarine PicoP biomass and composition, and show how ‘wetter’ future climate conditions will have ecosystem impacts down to the smallest of phytoplankton.

In many different infectious syndromes, most notably several viral conditions, time to therapy initiation from symptom onset has been identified as a critical component contributing to the success of therapy. Regarding COVID-19, several therapeutic antivirals, both repurposed and novel, have been evaluated for overall safety and efficacy. As the literature related to these therapies has expanded recently, a wide array of trial designs, time to therapy initiation thresholds, and clinical outcomes in regard to time to initiation have been reported. We describe the potential effects of time to therapy initiation on outcomes in patients with COVID-19 and detail the existing data surrounding this topic in relation to remdesivir, convalescent plasma, lopinavir/ritonavir, and hydroxychloroquine.

Hereditary hemorrhagic telangiectasia (HHT; also known as Osler-Weber-Rendu syndrome) is an inherited vascular disorder with a spectrum of clinical manifestations depending on lesion distribution. Epistaxis, mucocutaneous telangiectasia, and gastrointestinal bleeding are most common. Patients with pulmonary arteriovenous malformations are at serious risk of cerebral embolic stroke and abscess due to paradoxical embolism, indicating the need for early diagnosis and intervention. Herein, we report a 14-year-old boy who presented to his pediatrician's office with hypoxemia and personal history of epistaxis, family history of HHT, and radiologic workup demonstrating pulmonary and cerebral arteriovenous malformations. He was diagnosed with HHT and treated by endovascular embolization.

Abstract Marine dissolved organic matter (DOM) is a massive elemental pool on Earth and is thought to consist of a chemically complex mixture of molecules. Part of marine DOM is fluorescent (FDOM) and includes humic‐like compounds. The chemical composition of, and biochemical pathways that yield, autochthonous humic‐like FDOM in the ocean is largely unknown. Inspired by medical and biochemical research detailing the formation of colored and fluorescent dityrosine via peroxidase mediated reactions, we used fluorometry and spectroscopy and found dityrosine exhibits humic‐like fluorescence similar to that of marine FDOM. Investigating its recalcitrance, we conducted short‐term nutrient‐addition and light exposure experiments with dityrosine and found it is resistant to respiration or assimilation by marine microbial communities, yet readily photodegraded. The formation and characteristics of dityrosine newly points to polymerization via reactive oxygen quenching, under aphotic and putatively photic conditions, as an explanation for autochthonous, humic‐like, (semi‐)recalcitrant DOM in the ocean.

Abstract Background Despite controversies, epinephrine remains a mainstay of cardiopulmonary resuscitation (CPR). Recent animal studies have suggested that epinephrine may decrease cerebral blood flow (CBF) and cerebral oxygenation, possibly potentiating neurological injury during CPR. We investigated the cerebrovascular effects of intravenous epinephrine in a swine model of pediatric in-hospital cardiac arrest. The primary objectives of this study were to determine if (1) epinephrine doses have a significant acute effect on CBF and cerebral tissue oxygenation during CPR and (2) if the effect of each subsequent dose of epinephrine differs significantly from that of the first. Methods One-month-old piglets (n = 20) underwent asphyxia for 7 min, ventricular fibrillation, and CPR for 10–20 min. Epinephrine (20 mcg/kg) was administered at 2, 6, 10, 14, and 18 min of CPR. Invasive (laser Doppler, brain tissue oxygen tension [PbtO2]) and noninvasive (diffuse correlation spectroscopy and diffuse optical spectroscopy) measurements of CBF and cerebral tissue oxygenation were simultaneously recorded. Effects of subsequent epinephrine doses were compared to the first. Results With the first epinephrine dose during CPR, CBF and cerebral tissue oxygenation increased by > 10%, as measured by each of the invasive and noninvasive measures (p

Aims: COVID-19 necessitated abrupt changes in trauma service delivery. We compare the demographics and outcomes of patients treated during lockdown to a matched period from 2019. Findings have important implications for service development. Methods: A split-site service was introduced, with a COVID-19 free site treating the majority of trauma patients. Polytrauma, spinal, and paediatric trauma patients, plus COVID-19 confirmed or suspicious cases, were managed at another site. Prospective data on all trauma patients undergoing surgery at either site between 16 March 2020 and 31 May 2020 was collated and compared with retrospective review of the same period in 2019. Patient demographics, injury, surgical details, length of stay (LOS), COVID-19 status, and outcome were compared. Results: There were 1,004 urgent orthopaedic trauma patients (604 in 2019; 400 in 2020). Significant reductions in time to theatre and LOS stay were observed. COVID-19 positive status was confirmed in 4.5% (n = 18). The COVID-19 mortality rate was 1.8% (n = 7). Day-case surgery comprised 47.8% (n = 191), none testing positive for COVID-19 or developing clinically significant COVID-19 symptoms requiring readmission, at a minimum of 17 days follow-up. Conclusion: The novel split-site service, segregating suspected or confirmed COVID-19 cases, minimized onward transmission and demonstrated improved outcomes regarding time to surgery and LOS, despite altered working patterns and additional constraints. Day-surgery pathways appear safe regarding COVID-19 transmission. Lessons learned require dissemination and should be sustained in preparation for a potential second wave or, the return of a “normal” non-COVID workload.

Ornamental bedding plant operations transitioning to leafy greens and herb production must decide whether to invest in new hydroponic equipment or modify existing culture systems for edible crops. In addition, common practices used to increase space-use and production efficiencies during bedding plant production may be modified for hydroponic leafy greens and herbs, such as purchasing large seedlings for transplant. The objective of the first experiment was to evaluate plant growth in a modified and novel shallow aggregate ebb-and-flood (SAEF) system intended for bedding plant growers with an emphasis on comparing yield across four basil (Ocimum basilicum) cultivars grown in the SAEF system to those grown using the traditional nutrient film technique (NFT) and deep water culture (DWC) hydroponic systems. The second experiment objective was to evaluate basil seedling size and the time of transplant to NFT hydroponic systems to determine effects on the final yield. ‘Genovese’ basil seedlings were grown in trays with cell counts of 32, 50, 72, 105, and 162 cells with corresponding root volumes per plant of 98.1, 50.2, 38.5, 19.6, and 16.3 cm3, respectively. Seedlings were transplanted to NFT systems at 14, 21, and 28 days after sowing and were harvested at 35 days. In the first experiment, overall basil shoot fresh and dry weights per plant were intermediate in the SAEF system (90.4 and 8.3 g) compared with the DWC (102.6 and 9.1 g) and NFT (75.8 and 6.6 g) hydroponic systems. In the second experiment, final shoot fresh and dry weight per plant increased as seedling root volume increased from 16.3 cm3 [72.8 and 5.5 g (162-cell tray)] to 98.1 cm3 [148.5 and 12.2 g (32-cell tray)]. Transplanting seedlings at later dates decreased yield across tray size and root volume treatments. Differences in yield between culture systems may have resulted from differences in nutrient supply and availability for plant uptake. Transplant of large seedling plugs to hydroponic culture was not shown to increase space-use efficiency after transplant without compromising yield, likely because root zone factors limited growth during seedling production. Further investigation into maximizing plant growth during seedling production and evaluating the effects of seedling size and transplant practices are needed to determine the potential for increasing space-use and production efficiencies.

Abstract Background The coronavirus disease 2019 (COVID-19) pandemic places healthcare workers at risk of exposure to the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Emergency department (ED) staff are particularly vulnerable when managing patients with acute respiratory distress due to the aerosolization of the virus during endotracheal intubation. A simple and innovative intubation tent was designed with the intent of decreasing the risk of accidental viral transmission from emergent intubations during the COVID-19 pandemic. Presentation of technique The materials and assembly process of the novel “Corona Curtain” are described in technical detail, with the intent of allowing other providers to template the concept at their respective facilities. Results A total of 36 intubation tents were mounted in the ED at the Medical Center of Aurora, Colorado, on April 7, 2020, and thereafter consistently used for all intubations during the ongoing COVID-19 outbreak. The cost of raw materials and labor for the initial assembly averaged US $ 8.00 per construct. The price of the single-use plastic cover is variable depending on the vendor source. Conclusion The new “Corona Curtain” was designed to improve the safety of ED staff when performing urgent/emergent intubations during the current COVID-19 pandemic. The concept can easily be adopted to other patient care areas, including perioperative and intensive care units. Future validation studies are needed to determine the safety and efficacy of the intubation tents by quantifying the pre−/post-intubation exposure through “point-of-care” SARS-CoV-2 testing once these resources are more widely available.

Abstract Plastids are morphologically and functionally diverse organelles that are dependent on nuclear-encoded, plastid-targeted proteins for all biochemical and regulatory functions. However, how plastid proteomes vary temporally, spatially, and taxonomically has been historically difficult to analyze at a genome-wide scale using experimental methods. A bioinformatics workflow was developed and evaluated using a combination of fast and user-friendly subcellular prediction programs to maximize performance and accuracy for chloroplast transit peptides and demonstrate this technique on the predicted proteomes of 15 sequenced plant genomes. Gene family grouping was then performed in parallel using modified approaches of reciprocal best BLAST hits (RBH) and UCLUST. A total of 628 protein families were found to have conserved plastid targeting across angiosperm species using RBH, and 828 using UCLUST. However, thousands of clusters were also detected where only one species had predicted plastid targeting, most notably in Panicum virgatum which had 1,458 proteins with species-unique targeting. An average of 45% overlap was found in plastid-targeted protein-coding gene families compared with Arabidopsis, but an additional 20% of proteins matched against the full Arabidopsis proteome, indicating a unique evolution of plastid targeting. Neofunctionalization through subcellular relocalization is known to impart novel biological functions but has not been described before on a genome-wide scale for the plastid proteome. Further work to correlate these predicted novel plastid-targeted proteins to transcript abundance and high-throughput proteomics will uncover unique aspects of plastid biology and shed light on how the plastid proteome has evolved to influence plastid morphology and biochemistry.

People often prioritize their own interests, but also like to see themselves as moral. Here the authors show how distortions in memory might resolve this tension by demonstrating that people tend to remember being more generous in the past than they actually were.

B-vitamins are essential micronutrients for marine plankton. Additionally, we now know many marine plankton cannot synthesize B-vitamins de novo (from scratch) and thus are reliant on external supplies. Details of B-vitamin exchange, whether ‘active’ or ‘passive’ (i.e. through cell secretion or mortality), are lacking and as a result we struggle to predict microbial physiology, community composition and biogeochemistry. We argue that significant advances in understanding of the impact of B-vitamin exchange and cycling on marine community structure and biogeochemistry can be made by focusing on unknowns related to the ‘in’s and out’s’ of B-vitamin transport, exchange between plankton, and ecosystem scale processing/transformation of B-vitamins. We point out that it is particularly necessary to reach beyond traditional categorization of populations as B-vitamin auxotrophs (requiring supplied vitamin) or prototrophs (de novo vitamin synthesizers) and begin addressing which populations are net ‘providers’ and/or ‘consumers’. This is a particularly interesting problem as organisms cannot be confidently categorized as net ‘providers’ and/or ‘consumers’ based on genome-based prediction, and it is possible the two roles may change over time and environmental conditions. We posit that greater knowledge of B-vitamin exchange, e.g. cross-feeding, acquisition and secretion systems, environmental triggers of ‘provision’ and ‘consumption’, will reveal unforeseen networking and novel niches across marine planktonic communities. Last, we advocate for further experiments tracking the responses of isolates or natural communities relative to vitamin availability, tracing flow of B-vitamins between cells using novel approaches (e.g. isotopic, fluorometric), and greater consideration of altered B-vitamin exchange and cycling under future climate scenarios.

In many vertebrates, courtship occurs through the performance of elaborate behavioral displays that are as spectacular as they are complex. The question of how sexual selection acts upon these animals’ neuromuscular systems to transform a repertoire of pre-existing movements into such remarkable (if not unusual) display routines has received relatively little research attention. This is a surprising gap in knowledge, given that unraveling this extraordinary process is central to understanding the evolution of behavioral diversity and its neural control. In many vertebrates, courtship displays often push the limits of neuromuscular performance, and often in a ritualized manner. These displays can range from songs that require rapid switching between two independently controlled ‘voice boxes’ to precisely choreographed acrobatics. Here, we propose a framework for thinking about how the brain might not only control these displays, but also shape their evolution. Our framework focuses specifically on a major midbrain area, which we view as a likely important node in the orchestration of the complex neural control of behavior used in the courtship process. This area is the periaqueductal grey (PAG), as studies suggest that it is both necessary and sufficient for the production of many instinctive survival behaviors, including courtship vocalizations. Thus, we speculate about why the PAG, as well as its key inputs, might serve as targets of sexual selection for display behavior. In doing so, we attempt to combine core ideas about the neural control of behavior with principles of display evolution. Our intent is to spur research in this area and bring together neurobiologists and behavioral ecologists to more fully understand the role that the brain might play in behavioral innovation and diversification.

Abstract The sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA) restores intracellular Ca2+ ([Ca2+]i) to resting levels after muscle contraction, ultimately eliciting relaxation. SERCA pumps are highly susceptible to tyrosine (T)‐nitration, impairing their ability to take up Ca2+ resulting in reduced muscle function and increased [Ca2+]i and cellular damage. The mitochondrial antioxidant enzyme, superoxide dismutase 2 (SOD2), converts superoxide radicals into less reactive H2O2. Heterozygous deletion of SOD2 (Sod2+/−) in mice increases mitochondrial oxidative stress; however, the consequences of reduced SOD2 expression in skeletal and cardiac muscle, specifically the effect on SERCA pumps, has yet to be investigated. We obtained soleus, extensor digitorum longus (EDL), and left ventricle (LV) muscles from 6 to 7 month‐old wild‐type (WT) and Sod2+/− female C57BL/6J mice. Ca2+‐dependent SERCA activity assays were performed to assess SERCA function. Western blotting was conducted to examine the protein content of SERCA, phospholamban, and sarcolipin; and immunoprecipitation experiments were done to assess SERCA2a‐ and SERCA1a‐specific T‐nitration. Heterozygous SOD2 deletion did not alter SERCA1a or SERCA2a expression in the soleus or LV but reduced SERCA2a in the EDL compared with WT, though this was not statistically significant. Soleus muscles from Sod2+/− mice showed a significant reduction in SERCA’s apparent affinity for Ca2+ when compared to WT, corresponding with significantly elevated SERCA2a T‐nitration in the soleus. No effect was seen in the EDL or the LV. This is the first study to investigate the effects of SOD2 deficiency on muscle SERCA function and shows that it selectively impairs SERCA function in the soleus.

Drenching and injection are two pesticide application methods that are particularly effective in controlling some of the most troublesome insect pests of ornamental landscape trees. This 4-page document describes the equipment and procedures you will need to carry out either of these methods. Written by Frederick M. Fishel and published by the UF/IFAS Agronomy Department, January 2018. http://edis.ifas.ufl.edu/pi274 This new revision by Ryan Klein and Adam Dale expands and updates the original 2018 version by Fred Fishel. Original version: Fishel, Frederick M. 2018. “Pesticide Injection and Drenching: PI274, 1/2018”. EDIS 2018 (1).

Wildfire smoke events are increasing in British Columbia (BC), Canada and environmental and public health agencies are responsible for communicating the health-related risks and mitigation strategies. To evaluate and identify opportunities for improving public communications about wildfire smoke and associated health risks we collaborated with end-users and developed a 32-question online survey. The survey was deployed province-wide from 29 September to 31 December 2020 following a severe wildfire smoke episode, which impacted large parts of BC. Using a convenience sample, we disseminated the survey through email lists, radio advertisements, a provincial research platform, and snowball methods. There were 757 respondents, who were generally representative of provincial demographics. Respondents indicated that they receive wildfire smoke messages from diverse sources, including: websites, social media, radio, and television. Radio was identified as the most important source of information for populations that may have increased exposure or health risks, including Indigenous respondents and those working in the trades. Respondents with lower educational attainment expressed that messaging should be simplified. Environmental and public health agencies should continue to share wildfire smoke messages using diverse methods, ideally tailoring the messages and methods to specific populations at risk for exposure and health effects.

Atopic disorders, including atopic dermatitis, food and environmental allergies, and asthma, are increasingly prevalent diseases. Atopic disorders are often associated with eosinophilia, driven by T helper type 2 (Th2) immune responses, and triggered by disrupted barrier function leading to abnormal immune priming in a susceptible host. Immune deficiencies, in contrast, occur with a significantly lower incidence, but are associated with greater morbidity and mortality. A subset of atopic disorders with eosinophilia and elevated IgE are associated with monogenic inborn errors of immunity (IEI). In this review, we discuss current knowledge of IEI that are associated with atopy and the lessons these immunologic disorders provide regarding the fundamental mechanisms that regulate type 2 immunity in humans. We also discuss further mechanistic insights provided by animal models.

Corynebacterium glutamicum has been successfully employed for the industrial production of amino acids and other bioproducts, partially due to its native ability to utilize a wide range of carbon substrates. We demonstrated C. glutamicum as an efficient microbial host for utilizing diverse carbon substrates present in biomass hydrolysates, such as glucose, arabinose, and xylose, in addition to its natural ability to assimilate lignin-derived aromatics. As a case study to demonstrate its bioproduction capabilities, L-lactate was chosen as the primary fermentation end product along with acetate and succinate. C. glutamicum was found to grow well in different aromatics (benzoic acid, cinnamic acid, vanillic acid, and p-coumaric acid) up to a concentration of 40 mM. Besides, 13C-fingerprinting confirmed that carbon from aromatics enter the primary metabolism via TCA cycle confirming the presence of β-ketoadipate pathway in C. glutamicum. 13C-fingerprinting in the presence of both glucose and aromatics also revealed coumarate to be the most preferred aromatic by C. glutamicum contributing 74 and 59% of its carbon for the synthesis of glutamate and aspartate respectively. 13C-fingerprinting also confirmed the activity of ortho-cleavage pathway, anaplerotic pathway, and cataplerotic pathways. Finally, the engineered C. glutamicum strain grew well in biomass hydrolysate containing pentose and hexose sugars and produced L-lactate at a concentration of 47.9 g/L and a yield of 0.639 g/g from sugars with simultaneous utilization of aromatics. Succinate and acetate co-products were produced at concentrations of 8.9 g/L and 3.2 g/L, respectively. Our findings open the door to valorize all the major carbon components of biomass hydrolysate by using C. glutamicum as a microbial host for biomanufacturing.

# Background Higher postoperative quadriceps function has been positively associated with surgical outcomes after anterior cruciate ligament reconstruction (ACLR). However, the impact of autograft harvest and/or a concomitant meniscal procedure on the recovery of quadriceps strength is not well defined. # Purpose To describe postoperative recovery of quadriceps strength following ACLR related to autograft selection, meniscal status, and sex. # Study Design Retrospective Cohort. # Methods One hundred and twenty-five participants who underwent ACLR with either a hamstring tendon (HT), bone-patellar tendon-bone (BPTB) or quadriceps tendon (QT) autograft were included. At postoperative months 3, 6 and 9, each participant completed an isometric quadriceps strength testing protocol at 90-degrees of knee flexion. Participants’ quadriceps average peak torque (Q-AvgPKT), average peak torque relative to body weight (Q-RPKT), and calculated limb symmetry index (Q-LSI) were collected and used for data analysis. Patients were placed in groups based on sex, graft type, and whether they had a concomitant meniscal procedure at the time of ACLR. At each time point, One-way ANOVAs, independent samples t-test and chi-square analyses were used to test for any between-group differences in strength outcomes. # Results At three months after ACLR, Q-RPKT was significantly higher in those with the HT compared to the QT. At all time points, males had significantly greater Q-RPKT than females and HT Q-LSI was significantly higher than BPTB and QT. A concomitant meniscal procedure at the time of ACLR did not significantly affect Q-LSI or Q-RPKT at any testing point. # Conclusion This study provides outcomes that are procedure specific as well as highlights the objective progression of quadriceps strength after ACLR. This information may help better-define the normal recovery of function, as well as guide rehabilitation strategies after ACLR. # Level of Evidence 3

Abstract This study pursued the hypothesis that wild plant germplasm accessions carrying alleles of interest can be identified using available single nucleotide polymorphism (SNP) genotypes for particular alleles of other (unlinked) genes that contribute to the trait of interest. The soybean cyst nematode (SCN, Heterodera glycines [HG]) resistance locus Rhg1 is widely used in farmed soybean [Glycine max (L.) Merr.]. The two known resistance‐conferring haplotypes, rhg1‐a and rhg1‐b, typically contain three or seven to 10 tandemly duplicated Rhg1 segments, respectively. Each Rhg1 repeat carries four genes, including Glyma.18G022500, which encodes unusual isoforms of the vesicle‐trafficking chaperone α‐SNAP. Using SoySNP50K data for NSFRAN07 allele presence, we discovered a new Rhg1 haplotype, rhg1‐ds, in six accessions of wild soybean, Glycine soja Siebold & Zucc. (0.5% of the ∼1,100 G. soja accessions in the USDA collection). The α‐SNAP encoded by rhg1‐ds is unique at an important site of amino acid variation and shares with the rhg1‐a and rhg1‐b α‐SNAP proteins the traits of cytotoxicity and altered N‐ethylmaleimide sensitive factor (NSF) protein interaction. Copy number assays indicate three repeats of rhg1‐ds. G. soja PI 507613 and PI 507623 exhibit resistance to HG type 2.5.7 SCN populations, in part because of contributions from other loci. In a segregating F2 population, rhg1‐b and rhg1‐ds made statistically indistinguishable contributions to resistance to a partially virulent HG type 2.5.7 SCN population. Hence, the unusual multigene copy number variation Rhg1 haplotype was present but rare in ancestral G. soja and was present in accessions that offer multiple traits for SCN resistance breeding. The accessions were initially identified for study based on an unlinked SNP.

Infective endocarditis (IE) is a rare but increasingly prevalent disease with high morbidity and mortality, requiring antimicrobials and at times surgical intervention. Through the decades of healthcare professionals’ experience with managing IE, certain dogmas and uncertainties have arisen around its pharmacotherapy. The introduction of new antimicrobials and novel combinations are exciting developments but also further complicate IE treatment choices. In this review, we provide and evaluate the relevant evidence focused around contemporary debates in IE treatment pharmacotherapy, including beta-lactam choice in MSSA IE, combination therapies (aminoglycosides, ceftaroline), the use of oral antimicrobials, the role of rifamycins, and long-acting lipoglycopeptides.

Managing nutrients in recirculating solutions can be challenging in hydroponic production, and poor management practices can rapidly result in root zone nutrient imbalances in reduced yield. Using mass balance principles to formulate hydroponic replenishment solutions is a proposed strategy to reduce nutrient imbalances and the need to periodically replace the hydroponic solution. Objectives were to (1) formulate species-specific nutrient replenishment solutions for arugula (Eruca sativa L.) and basil (Ocimum basilicum L.) using mass balance principles and (2) evaluate the effects of using these replenishment solutions on plant growth and root zone nutrients over time. In the first experiment, arugula and basil tissues were analyzed over 42 d for macronutrient concentrations which were used to custom formulate species-specific replenishment solutions for both species. In the second experiment, nutrients were resupplied for hydroponic arugula and basil over time using either the species-specific or a standard commercial hydroponic replenishment solution. Species-specific replenishment solutions resulted in decreased solution EC and concentrations of most macronutrients over time for both species. In contrast, replenishment with the standard hydroponic solution resulted in increased solution EC and concentrations of calcium, magnesium, and sulfate and decreased nitrogen, phosphorus, and potassium. Replenishment treatment had no effect on yield for arugula and basil; however, results suggested root zone imbalances may have still occurred eventually for both treatments and species. Species-specific replenishment solutions would be most effective in scenarios where solutions could be formulated for a specific crop, mixed using high-quality irrigation water, and where environmental conditions are controlled and stable, such as indoor farming systems. This study highlighted several practical challenges and considerations regarding the formulation of hydroponic solutions using mass balance.

ABSTRACT The fish external microbiota competitively excludes primary pathogens and prevents the proliferation of opportunists. A shift from healthy microbiota composition, known as dysbiosis, may be triggered by environmental stressors and increases host susceptibility to disease. The Deepwater Horizon (DWH) oil spill was a significant stressor event in the Gulf of Mexico. Despite anecdotal reports of skin lesions on fishes following the oil spill, little information is available on the impact of dispersed oil on the fish external microbiota. In this study, juvenile red snapper (Lutjanus campechanus) were exposed to a chemically enhanced water-accommodated fraction (CEWAF) of Corexit 9500/DWH oil (CEWAF) and/or the bacterial pathogen Vibrio anguillarum in treatments designed to detect changes in and recovery of the external microbiota. In fish chronically exposed to CEWAF, immunoglobulin M (IgM) expression significantly decreased between 2 and 4 weeks of exposure, coinciding with elevated liver total polycyclic aromatic hydrocarbons (PAHs). Dysbiosis was detected on fish chronically exposed to CEWAF compared to seawater controls, and addition of a pathogen challenge altered the final microbiota composition. Dysbiosis was prevented by returning fish to clean seawater for 21 days after 1 week of CEWAF exposure. Four fish exhibited lesions during the trial, all of which were exposed to CEWAF but not all of which were exposed to V. anguillarum. This study indicates that month-long exposure to dispersed oil leads to dysbiosis in the external microbiota. As the microbiota is vital to host health, these effects should be considered when determining the total impacts of pollutants in aquatic ecosystems. IMPORTANCE Fish skin is an immunologically active tissue. It harbors a complex community of microorganisms vital to host homeostasis as, in healthy fish, they competitively exclude pathogens found in the surrounding aquatic environment. Crude oil exposure results in immunosuppression in marine animals, altering the relationship between the host and its microbial community. An alteration of the healthy microbiota, a condition known as dysbiosis, increases host susceptibility to pathogens. Despite reports of external lesions on fishes following the DWH oil spill and the importance of the external microbiota to fish health, there is little information on the effect of dispersed oil on the external microbiota of fishes. This research provides insight into the impact of a stressor event such as an oil spill on dysbiosis and enhances understanding of long-term sublethal effects of exposure to aid in regulatory decisions for protecting fish populations during recovery.

Summary: In clinical trials, oral supplementation with nicotinamide riboside (NR) fails to increase muscle mitochondrial respiratory capacity and insulin sensitivity but also does not increase muscle NAD+ levels. This study tests the feasibility of chronically elevating skeletal muscle NAD+ in mice and investigates the putative effects on mitochondrial respiratory capacity, insulin sensitivity, and gene expression. Accordingly, to improve bioavailability to skeletal muscle, we developed an experimental model for administering NR repeatedly through a jugular vein catheter. Mice on a Western diet were treated with various combinations of NR, pterostilbene (PT), and voluntary wheel running, but the metabolic effects of NR and PT treatment were modest. We conclude that the chronic elevation of skeletal muscle NAD+ by the intravenous injection of NR is possible but does not affect muscle respiratory capacity or insulin sensitivity in either sedentary or physically active mice. Our data have implications for NAD+ precursor supplementation regimens.

OBJECTIVES:. A recent study suggests that Multisystem Inflammatory Syndrome in Children (MIS-C) is triggered by gastrointestinal breach of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral particles from the gut lumen into systemic circulation. The virus remains in the gut weeks to months after respiratory infection, causing zonulin release from the intestinal epithelial cells. Zonulin loosens tight junctions, permitting trafficking of highly inflammatory viral particles into circulation. Current MIS-C treatments target the subsequent immune hyperactivation, not the causative loss of mucosal barrier integrity. Larazotide, a zonulin inhibitor, prevents breakdown of tight junctions, limiting antigen trafficking. DESIGN:. Children with MIS-C were treated with larazotide as an adjuvant to steroid/intravenous immunoglobulin therapy. Clinical outcomes, SARS-CoV-2 antigenemia, and cytokine profiles are reported. Outcomes were compared with children with MIS-C receiving steroids and/or IVIG therapy alone. PATIENTS:. Four children with MIS-C, ages 3–17 years, were enrolled. INTERVENTIONS:. Patients were treated with open label larazotide 10 mcg/kg (maximum 500 mcg/dose) orally four times daily for 21 days. MEASUREMENTS AND MAIN RESULTS:. All four patients tolerated larazotide without adverse effects and displayed reduction in Spike antigenemia to undetectable levels. When compared with 22 children with MIS-C receiving steroids and/or intravenous immunoglobulin therapy alone, larazotide-treated patients reported significantly improved time to resolution of gastrointestinal symptoms (p = 0.03), and time to clearance of Spike antigenemia (p = 0.04), plus a trend towards shorter length of stay. CONCLUSIONS:. Larazotide appears safe and well-tolerated and may offer potential benefit as an adjuvant to immune-targeted therapies. Expansion of clinical trials is urgently needed to ascertain the clinical impact of larazotide on MIS-C.

Background: Chondral pathology is frequently encountered during knee arthroscopies with a prevalence rate of 63% to 66%. Prior studies have demonstrated that unaddressed or excised fragments result in poor knee function and arthritis. As a result, chondral-related procedures have increased in popularity, and now more than 200,000 procedures are performed annually. Indications: We present a case of an active 32-year-old woman, prior collegiate basketball player, with persistent left knee pain noted to have a full-thickness patellar articular cartilage defect and maltracking. Technique: A patellar autologous matrix-induced chondrocyte is implanted with a concomitant tibial tubercle osteotomy (TTO) and lateral retinacular lengthening. Results: At 9 weeks, the patient had no knee pain with full range of motion symmetric to the contralateral side while slowly progressing with quadriceps strengthening. Discussion/Conclusion: Successful outcomes addressing large patellar chondral defects and maltracking can be achieved with matrix autologous chondrocyte implantation and concomitant TTO with lateral retinacular lengthening.