Combined MRI, high-resolution manometry and a randomised trial of bisacodyl versus hyoscine show the significance of an enlarged colon in constipation: the RECLAIM study.

BACKGROUND: Colonic motility in constipation can be assessed non-invasively using MRI. OBJECTIVE: To compare MRI with high-resolution colonic manometry (HRCM) for predicting treatment response. DESIGN: Part 1: 44 healthy volunteers (HVs), 43 patients with irritable bowel syndrome with constipation (IBS-C) and 37 with functional constipation (FC) completed stool diaries and questionnaires and underwent oral macrogol (500-1000 mL) challenge. Whole gut transit time (WGTT), segmental colonic volumes (CV), MRI-derived Motility Index and chyme movement by 'tagging' were assessed using MRI and time to defecation after macrogol recorded. Left colonic HRCM was recorded before and after a 700 kcal meal. Patients then proceeded to Part 2: a randomised cross-over study of 10-days bisacodyl 10 mg daily versus hyoscine 20 mg three times per day, assessing daily pain and constipation. RESULTS: Part 1: Total CVs median (range) were significantly greater in IBS-C (776 (595-1033)) and FC (802 (633-951)) vs HV (645 (467-780)), p<0.001. Patients also had longer WGTT and delayed evacuation after macrogol. IBS-C patients showed significantly reduced tagging index and less propagated pressure wave (PPW) activity during HRCM versus HV. Compared with FC, IBS-C patients were more anxious and reported more pain. Abnormally large colons predicted significantly delayed evacuation after macrogol challenge (p<0.02), impaired manometric meal response and reduced pain with bisacodyl (p<0.05).Part 2: Bisacodyl compared with hyoscine increased bowel movements but caused more pain in both groups (p<0.03). CONCLUSION: An abnormally large colon is an important feature in constipation which predicts impaired manometric response to feeding and treatment responses. HRCM shows that IBS-C patients have reduced PPW activity. TRIAL REGISTRATION NUMBER: The study was preregistered on ClinicalTrials.gov, Reference: NCT03226145.

Cerebral Creatine Deficiency Affects the Timing of Oligodendrocyte Myelination.

Cerebral creatine deficiency syndrome (CCDS) is an inborn error of metabolism characterized by intellectual delays, seizures, and autistic-like behavior. However, the role of endogenously synthesized creatine on CNS development and function remains poorly understood. Here, magnetic resonance spectroscopy of adult mouse brains from both sexes revealed creatine synthesis is dependent on the expression of the enzyme, guanidinoacetate methyltransferase (GAMT). To identify Gamt-expressed cells, and how Gamt affects postnatal CNS development, we generated a mouse line by knocking-in a GFP, which is expressed on excision of Gamt We found that Gamt is expressed in mature oligodendrocytes during active myelination in the developing postnatal CNS. Homozygous deletion of Gamt resulted in significantly reduced mature oligodendrocytes and delayed myelination in the corpus callosum. Moreover, the absence of endogenous creatine resulted in altered AMPK signaling in the brain, reduced brain creatine kinase expression in cortical neurons, and signs of axonal damage. Experimental demyelination in mice after tamoxifen-induced conditional deletion of Gamt in oligodendrocyte lineage cells resulted in delayed maturation of oligodendrocytes and myelin coverage in lesions. Moreover, creatine and cyclocreatine supplementation can enhance remyelination after demyelination. Our results suggest endogenously synthesized creatine controls the bioenergetic demand required for the timely maturation of oligodendrocytes during postnatal CNS development, and that delayed myelination and altered CNS energetics through the disruption of creatine synthesis might contribute to conditions, such as CCDS.SIGNIFICANCE STATEMENT Cerebral creatine deficiency syndrome is a rare disease of inborn errors in metabolism, which is characterized by intellectual delays, seizures, and autism-like behavior. We found that oligodendrocytes are the main source of endogenously synthesized creatine in the adult CNS, and the loss of endogenous creatine synthesis led to delayed myelination. Our study suggests impaired cerebral creatine synthesis affects the timing of myelination and may impact brain bioenergetics.

Innovative nursing employment initiatives to strengthen and sustain the health workforce in Canada.

Health systems worldwide are at a critical juncture due to an increasing demand for health services and a diminishing pool of health human resources. While COVID-19 exacerbated nursing deficits, the need to strengthen and sustain the health workforce in Canada was evident decades prior and supported by numerous studies that warned of significant shortages. Post pandemic, building health system capacity has become paramount. This article examines innovative nursing employment initiatives in Canada. It provides a snapshot of federal, provincial and territorial approaches, with a particular focus on Internationally Educated Nurses (IENs) due to burgeoning interest in and competition for their skills and services. However, recognizing that health human resource planning is a persistent challenge, further initiatives are suggested. These include complementary policy development to improve retention and policy frameworks that support proactive long-term strategies to address the cyclical shortage of nurses.

Allosteric Regulation of Glycogen Phosphorylase by Order/Disorder Transition of the 250' and 280s Loops.

Allostery is a fundamental mechanism of protein activation, yet the precise dynamic changes that underlie functional regulation of allosteric enzymes, such as glycogen phosphorylase (GlyP), remain poorly understood. Despite being the first allosteric enzyme described, its structural regulation is still a challenging problem: the key regulatory loops of the GlyP active site (250' and 280s) are weakly stable and often missing density or have large b-factors in structural models. This led to the longstanding hypothesis that GlyP regulation is achieved through gating of the active site by (dis)order transitions, as first proposed by Barford and Johnson. However, testing this requires a quantitative measurement of weakly stable local structure which, to date, has been technically challenging in such a large protein. Hydrogen-deuterium-exchange mass spectrometry (HDX-MS) is a powerful tool for studying protein dynamics, and millisecond HDX-MS has the ability to measure site-localized stability differences in weakly stable structures, making it particularly valuable for investigating allosteric regulation in GlyP. Here, we used millisecond HDX-MS to measure the local structural perturbations of glycogen phosphorylase b (GlyPb), the phosphorylated active form (GlyPa), and the inhibited glucose-6 phosphate complex (GlyPb:G6P) at near-amino acid resolution. Our results support the Barford and Johnson hypothesis for GlyP regulation by providing insight into the dynamic changes of the key regulatory loops.

Online Fully Automated System for Hydrogen/Deuterium-Exchange Mass Spectrometry with Millisecond Time Resolution.

Amide hydrogen/deuterium-exchange mass spectrometry (HDX-MS) is a powerful tool for analyzing the conformational dynamics of proteins in a solution. Current conventional methods have a measurement limit starting from several seconds and are solely reliant on the speed of manual pipetting or a liquid handling robot. Weakly protected regions of polypeptides, such as in short peptides, exposed loops and intrinsically disordered the protein exchange on the millisecond timescale. Typical HDX methods often cannot resolve the structural dynamics and stability in these cases. Numerous academic laboratories have demonstrated the considerable utility of acquiring HDX-MS data in the sub-second regimes. Here, we describe the development of a fully automated HDX-MS apparatus to resolve amide exchange on the millisecond timescale. Like conventional systems, this instrument boasts automated sample injection with software selection of labeling times, online flow mixing and quenching, while being fully integrated with a liquid chromatography-MS system for existing standard "bottom-up" workflows. HDX-MS's rapid exchange kinetics of several peptides demonstrate the repeatability, reproducibility, back-exchange, and mixing kinetics achieved with the system. Comparably, peptide coverage of 96.4% with 273 peptides was achieved, supporting the equivalence of the system to standard robotics. Additionally, time windows of 50 ms-300 s allowed full kinetic transitions to be observed for many amide groups; especially important are short time points (50-150 ms) for regions that are likely highly dynamic and solvent- exposed. We demonstrate that information on structural dynamics and stability can be measured for stretches of weakly stable polypeptides in small peptides and in local regions of a large enzyme, glycogen phosphorylase.

Immunodepletion of MDSC by AMV564, a novel bivalent, bispecific CD33/CD3 T cell engager, ex vivo in MDS and melanoma.

We have reported previously that CD33hi myeloid-derived suppressor cells (MDSCs) play a direct role in the pathogenesis of myelodysplastic syndromes (MDSs) and that their sustained activation contributes to hematopoietic and immune impairment, including modulation of PD1/PDL1. MDSCs can also limit the clinical activity of immune checkpoint inhibition in solid malignancies. We hypothesized that depletion of MDSCs may ameliorate resistance to checkpoint inhibitors and, hence, targeted them with AMV564 combined with anti-PD1 in MDS bone marrow (BM) mononuclear cells (MNCs) enhanced activation of cytotoxic T cells. AMV564 was active in vivo in a leukemia xenograft model when co-administered with healthy donor peripheral blood MNCs (PBMCs). Our findings provide a strong rationale for clinical investigation of AMV564 as a single agent or in combination with an anti-PD1 antibody and in particular for treatment of cancers resistant to checkpoint inhibitors.

The magnitude and impact of the 431 CE Tierra Blanca Joven eruption of Ilopango, El Salvador.

The Tierra Blanca Joven (TBJ) eruption from Ilopango volcano deposited thick ash over much of El Salvador when it was inhabited by the Maya, and rendered all areas within at least 80 km of the volcano uninhabitable for years to decades after the eruption. Nonetheless, the more widespread environmental and climatic impacts of this large eruption are not well known because the eruption magnitude and date are not well constrained. In this multifaceted study we have resolved the date of the eruption to 431 ± 2 CE by identifying the ash layer in a well-dated, high-resolution Greenland ice-core record that is >7,000 km from Ilopango; and calculated that between 37 and 82 km3 of magma was dispersed from an eruption coignimbrite column that rose to ∼45 km by modeling the deposit thickness using state-of-the-art tephra dispersal methods. Sulfate records from an array of ice cores suggest stratospheric injection of 14 ± 2 Tg S associated with the TBJ eruption, exceeding those of the historic eruption of Pinatubo in 1991. Based on these estimates it is likely that the TBJ eruption produced a cooling of around 0.5 °C for a few years after the eruption. The modeled dispersal and higher sulfate concentrations recorded in Antarctic ice cores imply that the cooling would have been more pronounced in the Southern Hemisphere. The new date confirms the eruption occurred within the Early Classic phase when Maya expanded across Central America.

Preparing for success in final summative medical specialist examinations: The case for RACE.

BACKGROUND: Failure rates on medical specialist final summative examinations in Australia are high, regardless of speciality. Examination failure can have detrimental psycho-social, financial and job security effects on the trainee, while delays in completion of training adversely impacts workforce growth and health outcomes for the community. The study aimed to explore the preparation factors that contribute to ophthalmology trainee success in their final summative examination. METHODS: Semi-structured in-depth interviews were conducted with 29 participants via telephone or Zoom with ophthalmology trainees and Fellows. To be eligible, interviewees had to have sat the Royal Australian and New Zealand College of Ophthalmologists Advanced Clinical Examination (RACE) within the past five years or were providing supervision to trainees preparing for RACE. Interviews were audio-recorded, transcribed and thematically analysed. RESULTS: Examination success was underpinned by six themes relating to preparation: (i) 'Those who fail to plan, plan to fail', which related to development and adherence to a study plan; (ii) 'It takes a village' encompassed trainees establishing and activating personal and professional supports; (iii) 'Get to know your opponent', which encompassed developing an understanding of the examination construct, format and requirements; (iv) 'There is no substitute for hard work', which related to intensive study over a period of 12-18 months; (v) 'Keep pace with the herd', which referred to benchmarking preparation efforts and progress against peers; and (vi) 'Don't jump the gun', which related to ensuring readiness to sit. CONCLUSIONS: Maximising medical specialist examination pass rates is in the best interest of trainees, training Colleges, health care systems and communities. Recognising and facilitating preparation approaches that foster success in final summative examinations are the collective responsibility of trainees, specialist training Colleges, training networks and health systems. Trainees need to plan for examination success, be self-determined to commit to intensive study over an extended time period and be realistic about their readiness to sit.

Parental Perspectives on Impact of Parental Presence Restrictions in the Neonatal Intensive Care Unit During the COVID-19 pandemic: A Cross-Sectional Study.

PURPOSE: To describe parental experiences in the neonatal intensive care unit (NICU) during the COVID-19 restrictions. We explore what parents found most challenging, the impact these restrictions had on them and their infant, and how they coped. METHODS: A cross-sectional online survey was completed by parents of infants who required care in a Canadian NICU during the early period of the COVID-19 pandemic. Data from 3 questions were coded using thematic analysis. RESULTS: Participants ( n = 161) were primarily mothers (93%), with an average length of stay of 32.1 days. Three themes were identified from responses: (1) emotional and physical closeness of the parents to their infant; (2) physical and psychosocial well-being of the infant and parent; and (3) how parents coped, and strategies for moving forward. Parents reported that parental restriction policies adversely impacted their perceived physical and emotional closeness with their infant and their infant's physical and psychosocial well-being. Parents reported that being able to be present with their infant, having their partner able to be present with them, and effective communication helped them cope. CONCLUSION: Despite the need for some restrictive policies to control the spread of the virus, the benefits and risks to the overall well-being of the parents and infants must be weighed.

Staff perceptions following a training programme about reducing psychotropic medication use in adults with intellectual disability: The need for a realistic professional practice framework.

BACKGROUND: Adults with intellectual disability are at higher risk of being administered psychotropic medications. The UK-developed SPECTROM (Short-term PsychoEducation for Carers To Reduce Over Medication of people with intellectual disabilities) training programme educates disability support workers on psychotropic medications and alternatives to these medications. METHOD: Interviews were conducted with 10 participants who took part in the pilot SPECTROM training programme to elicit their views on the programme and its appropriateness in an Australian context. RESULTS: The key theme was 'Need for a psychotropic medication practice framework'. Four sub-themes were Broad satisfaction with the SPECTROM training programme; Disability support workers acknowledging the limitations of their scope of practice; Empowering training through prescriptive and reflective methods and; Need for future mentoring from Multi-Disciplinary Team members in the application of new knowledge. CONCLUSIONS: Participants felt that whilst they could improve their knowledge and attitudes surrounding psychotropic medication administration for behaviours of concern through SPECTROM training, a national practice framework is needed to execute its goals at scale.

Beyond the 'big smoke': Enabling supervision of ophthalmology trainees in regional, rural and remote Australia.

OBJECTIVE: Expansion of opportunities for ophthalmology training beyond the 'big smoke' is anticipated to support the future distribution of ophthalmologists in regional, rural and remote areas of Australia. However, little is known about what enables supervision outside of metropolitan tertiary hospital settings that would contribute to positive training experiences for specialist medical trainees and encourage them to leave the 'big smoke' once qualified. The aim of this study was therefore to explore the perceived enablers of ophthalmology trainee supervision in regional, rural and remote health settings across Australia. SETTING: Australia. PARTICIPANTS: Ophthalmologists working in regional, rural or remote health settings with experience and/or interest in supervising ophthalmology trainees (n = 16). DESIGN: Qualitative design involving semistructured interviews. RESULTS: Seven key enablers of ophthalmology trainee supervision in regional, rural and remote health settings were identified: adequate physical infrastructure, resources and funding to host a trainee; availability of online curriculum and teaching resources so as to ensure equity of training opportunities; pre-established training posts, driven by supervision 'champions'; a critical mass of ophthalmologists to help share the supervisory load; relationships and support between training posts, the training network and the Specialist Medical College; alignment of trainee competence and attitude with the needs of the training setting; and the recognition of reciprocal benefits for supervisors through supporting trainees, including workforce support and renewal. CONCLUSION: With training experiences beyond the 'big smoke' anticipated to influence future ophthalmology workforce distribution, implementation of enablers of trainee supervision should occur in regional, rural and remote health settings wherever possible.

Benefits and challenges to ophthalmology training via the Specialist Training Program.

INTRODUCTION: The Specialist Training Program (STP) is a commonwealth funding initiative to support specialist medical training positions in regional, rural and remote areas, and in private settings. The program helps to improve the skills and distribution of the specialist medical workforce by providing trainees experience of a broader range of healthcare settings. OBJECTIVE: To examine the benefits and challenges of ophthalmology training delivered by the STP in regional, rural, remote, and/or private settings across Australia. DESIGN: Qualitative design involving semi-structured in-depth interviews with thirty-two participants experienced in the delivery of ophthalmology training at STP posts including ophthalmology trainees (n = 8), STP supervisors and clinical tutors (n = 16), and other stakeholders (n = 8). FINDINGS: Training delivered at STP posts was reportedly beneficial for ophthalmology trainees, their supervisors and the broader community given it enabled exposure to regional, rural, remote and private settings, access to unique learning opportunities, provided workforce support and renewal, and affordable ophthalmic care. However, all participants also reported challenges including difficulties achieving work/life balance, unmet training expectations, a lack of professional support, and financial and administrative burden. Malalignment between trainee preferences for STP posts, low STP literacy and limited regional, rural and remote training experiences were also seen as missed opportunities to foster future rural ophthalmic workforce development. DISCUSSION: The STP improves access to ophthalmic care in underserved populations while enabling valuable rural and/or private practice exposure for medical specialist trainees and workforce support for supervising ophthalmologists. CONCLUSION: Efforts are needed to improve the quality of training experiences provided at STP posts and post sustainability. Although research is needed to investigate the longer-term benefits of the STP to rural and/or private workforce recruitment and retention, RANZCO should develop further regional, rural and remote STP posts to help realise future rural practice intention amongst ophthalmology trainees.

LungMAP Portal Ecosystem: Systems-Level Exploration of the Lung.

An improved understanding of the human lung necessitates advanced systems models informed by an ever-increasing repertoire of molecular omics, cellular, imaging, and pathological datasets. To centralize and standardize information across broad lung research efforts we expanded the LungMAP.net website into a new gateway portal. This portal connects a broad spectrum of research networks, bulk and single-cell multi-omics data and a diverse collection of image data that span mammalian lung development, and disease. The data are standardized across species and technologies using harmonized data and metadata models that leverage recent advances including those from the Human Cell Atlas, diverse ontologies, and the LungMAP CellCards initiative. To cultivate future discoveries, we have aggregated a diverse collection of single-cell atlases for multiple species (human, rhesus, mouse), to enable consistent queries across technologies, cohorts, age, disease, and drug treatment. These atlases are provided as independent and integrated queryable datasets, with an emphasis on dynamic visualization, figure generation, re-analysis, cell-type curation, and automated reference-based classification of user-provided single-cell genomics datasets (Azimuth). As this resource grows, we intend to increase the breadth of available interactive interfaces, supported data types, data portals and datasets from LungMAP and external research efforts.

Dietary fat composition shapes bile acid metabolism and severity of liver injury in a pig model of pediatric NAFLD.

The objective of this study was to investigate the effect of dietary fatty acid (FA) composition on bile acid (BA) metabolism in a pig model of NAFLD, by using a multiomics approach combined with histology and serum biochemistry. Thirty 20-day-old Iberian pigs pair-housed in pens were randomly assigned to receive 1 of 3 hypercaloric diets for 10 wk: 1) lard-enriched (LAR; n = 5 pens), 2) olive oil-enriched (OLI; n = 5), and 3) coconut oil-enriched (COC; n = 5). Animals were euthanized on week 10 after blood sampling, and liver, colon, and distal ileum (DI) were collected for histology, metabolomics, and transcriptomics. Data were analyzed by multivariate and univariate statistics. Compared with OLI and LAR, COC increased primary and secondary BAs in liver, plasma, and colon. In addition, both COC and OLI reduced circulating fibroblast growth factor 19, increased hepatic necrosis, composite lesion score, and liver enzymes in serum, and upregulated genes involved in hepatocyte proliferation and DNA repair. The severity of liver disease in COC and OLI pigs was associated with increased levels of phosphatidylcholines, medium-chain triacylglycerides, trimethylamine-N-oxide, and long-chain acylcarnitines in the liver, and the expression of profibrotic markers in DI, but not with changes in the composition or size of BA pool. In conclusion, our results indicate a role of dietary FAs in the regulation of BA metabolism and progression of NAFLD. Interventions that aim to modify the composition of dietary FAs, rather than to regulate BA metabolism or signaling, may be more effective in the treatment of NAFLD.NEW & NOTEWORTHY Bile acid homeostasis and signaling is disrupted in NAFLD and may play a central role in the development of the disease. However, there are no studies addressing the impact of diet on bile acid metabolism in patients with NAFLD. In juvenile Iberian pigs, we show that fatty acid composition in high-fat high-fructose diets affects BA levels in liver, plasma, and colon but these changes were not associated with the severity of the disease.

Differential Responses to Targeting Matrix Metalloproteinase 9 in Idiopathic Pulmonary Fibrosis.

Rationale: Aberrant lung remodeling in idiopathic pulmonary fibrosis (IPF) is characterized by elevated MMP9 (matrix metalloproteinase 9) expression, but the precise role of this matrix metalloproteinase in this disease has yet to be fully elucidated.Objectives: To evaluate antifibrotic effects of MMP9 inhibition on IPF.Methods: Quantitative genomic, proteomic, and functional analyses both in vitro and in vivo were used to determine MMP9 expression in IPF cells and the effects of MMP9 inhibition on profibrotic mechanisms.Measurements and Main Results: In the present study, we demonstrate that MMP9 expression was increased in airway basal cell (ABC)-like cells from IPF lungs compared with ABC cells from normal lungs. The inhibition of MMP9 activity with an anti-MMP9 antibody, andecaliximab, blocked TGF-ß1 (transforming growth factor ß1)-induced Smad2 phosphorylation. However, in a subset of cells from patients with IPF, TGF-ß1 activation in their ABC-like cells was unaffected or enhanced by MMP9 blockade (i.e., nonresponders). Further analysis of nonresponder ABC-like cells treated with andecaliximab revealed an association with type 1 IFN expression, and the addition of IFNα to these cells modulated both MMP9 expression and TGF-ß1 activation. Finally, the inhibition of MMP9 ameliorated pulmonary fibrosis induced by responder lung cells but not a nonresponder in a humanized immunodeficient mouse model of IPF.Conclusions: Together, these data demonstrate that MMP9 regulates the activation of ABC-like cells in IPF and that targeting this MMP might be beneficial to a subset of patients with IPF who show sufficient expression of type 1 IFNs.

Tracking the evolution of CNS remyelinating lesion in mice with neutral red dye.

Animal models of central nervous system (CNS) demyelination, including toxin-induced focal demyelination and immune-mediated demyelination through experimental autoimmune encephalomyelitis (EAE), have provided valuable insights into the mechanisms of neuroinflammation and CNS remyelination. However, the ability to track changes in transcripts, proteins, and metabolites, as well as cellular populations during the evolution of a focal lesion, has remained challenging. Here, we developed a method to label CNS demyelinating lesions by the intraperitoneal injection of a vital dye, neutral red (NR), into mice before killing. We demonstrate that NR-labeled lesions can be easily identified on the intact spinal cord in both lysolecithin- and EAE-mediated demyelination models. Using fluorescence microscopy, we detected NR in activated macrophages/microglia and astrocytes, but not in oligodendrocytes present in lesions. Importantly, we successfully performed RT-qPCR, Western blot, flow cytometry, and mass spectrometry analysis of precisely dissected NR-labeled lesions at 5, 10, and 20 d postlesion (dpl) and found differential changes in transcripts, proteins, cell populations, and metabolites in lesions over the course of remyelination. Therefore, NR administration is a simple and powerful method to track and analyze the detailed molecular, cellular, and metabolic changes that occur within the lesion microenvironment over time following CNS injury. Furthermore, this method can be used to identify molecular and metabolic pathways that regulate neuroinflammation and remyelination and facilitate the development of therapies to promote repair in demyelinating disorders such as multiple sclerosis.

Rethinking Remdesivir: Synthesis, Antiviral Activity, and Pharmacokinetics of Oral Lipid Prodrugs.

Remdesivir (RDV; GS-5734) is currently the only FDA-approved antiviral drug for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The drug is approved for use in adults or children 12 years or older who are hospitalized for the treatment of COVID-19 on the basis of an acceleration of clinical recovery for inpatients with this disease. Unfortunately, the drug must be administered intravenously, restricting its use to those requiring hospitalization for relatively advanced disease. RDV is also unstable in plasma and has a complex activation pathway which may contribute to its highly variable antiviral efficacy in SARS-CoV-2-infected cells. Potent orally bioavailable antiviral drugs for early treatment of SARS-CoV-2 infection are urgently needed, and several, including molnupiravir and PF-07321332, are currently in clinical development. We focused on making simple, orally bioavailable lipid analogs of remdesivir nucleoside (RVn; GS-441524) that are processed to RVn monophosphate, the precursor of the active RVn triphosphate, by a single-step intracellular cleavage. In addition to high oral bioavailability, stability in plasma, and simpler metabolic activation, new oral lipid prodrugs of RVn had submicromolar anti-SARS-CoV-2 activity in a variety of cell types, including Vero E6, Calu-3, Caco-2, human pluripotent stem cell (PSC)-derived lung cells, and Huh7.5 cells. In Syrian hamsters, oral treatment with 1-O-octadecyl-2-O-benzyl-glycero-3-phosphate RVn (ODBG-P-RVn) was well tolerated and achieved therapeutic levels in plasma above the 90% effective concentration (EC90) for SARS-CoV-2. The results suggest further evaluation as an early oral treatment for SARS-CoV-2 infection to minimize severe disease and reduce hospitalizations.

Consumption of High-Fructose Corn Syrup Compared with Sucrose Promotes Adiposity and Increased Triglyceridemia but Comparable NAFLD Severity in Juvenile Iberian Pigs.

BACKGROUND: Fructose consumption has been linked to nonalcoholic fatty liver disease (NAFLD) in children. However, the effect of high-fructose corn syrup (HFCS) compared with sucrose in pediatric NAFLD has not been investigated. OBJECTIVES: We tested whether the isocaloric substitution of dietary sucrose by HFCS would increase the severity of NAFLD in juvenile pigs, and whether this effect would be associated with changes in gut histology, SCFA production, and microbial diversity. METHODS: Iberian pigs, 53-d-old and pair-housed in pens balanced for weight and sex, were randomly assigned to receive a mash diet top-dressed with increasing amounts of sucrose (SUC; n = 3 pens; 281.6-486.8 g/kg diet) or HFCS (n = 4; 444.3-724.8 g/kg diet) during 16 wk. Diets exceeded the animal's energy requirements by providing sugars in excess, but met the requirements for all other nutrients. Animals were killed at 165 d of age after blood sampling, and liver, muscle, and gut were collected for histology, metabolome, and microbiome analyses. Data were analyzed by multivariate and univariate statistics. RESULTS: Compared with SUC, HFCS increased subcutaneous fat, triacylglycerides in plasma, and butyrate in colon (P ≤ 0.05). In addition, HFCS decreased UMP and short-chain acyl carnitines in liver, and urea nitrogen and creatinine in serum (P ≤ 0.05). Microbiome analysis showed a 24.8% average dissimilarity between HFCS and SUC associated with changes in SCFA-producing bacteria. Body weight gain, intramuscular fat, histological and serum markers of liver injury, and circulating hormones, glucose, and proinflammatory cytokines did not differ between diets. CONCLUSIONS: Fructose consumption derived from HFCS promoted butyrate synthesis, triglyceridemia, and subcutaneous lipid deposition in juvenile Iberian pigs, but did not increase serum and histological markers of NAFLD compared with a sucrose-enriched diet. Longer studies could be needed to observe differences in liver injury among sugar types.

Incidence of Serum Creatinine Monitoring and Outpatient Visit Follow-Up among Acute Kidney Injury Survivors after Discharge: A Population-Based Cohort Study.

INTRODUCTION: Acute kidney injury (AKI) affects 20% of hospitalized patients and worsens outcomes. To limit complications, post-discharge follow-up and kidney function testing are advised. The objective of this study was to evaluate the frequency of follow-up after discharge among AKI survivors. METHODS: This was a population-based cohort study of adult Olmsted County residents hospitalized with an episode of stage II or III AKI between 2006 and 2014. Those dismissed from the hospital on dialysis, hospice, or who died within 30 days after discharge were excluded. The frequency and predictors of follow-up, defined as an outpatient serum creatinine (SCr) level or an in-person healthcare visit after discharge were described. RESULTS: In the 627 included AKI survivors, the 30-day cumulative incidence of a follow-up outpatient SCr was 80% (95% confidence interval [CI]: 76% and 83%), a healthcare visit was 82% (95% CI: 79 and 85%), or both was 70% (95% CI: 66 and 73%). At 90 days and 1 year after discharge, the cumulative incidences of meeting both follow-up criteria rose to 82 and 91%, respectively. Independent predictors of receiving both an outpatient SCr assessment and healthcare visit within 30 days included lower estimated glomerular filtration rate at discharge, higher comorbidity burden, longer length of hospitalization, and greater maximum AKI severity. Age, sex, race/ethnicity, education level, and socioeconomic status did not predict follow-up. CONCLUSIONS: Among patients with moderate to severe AKI, 30% did not have follow-up with a SCr and healthcare visit in the 30-day post-discharge interval. Follow-up was associated with higher acuity of illness rather than demographic or socioeconomic factors.

A revised AMS and tephra chronology for the Late Middle to Early Upper Paleolithic occupations of Ortvale Klde, Republic of Georgia.

The nature and timing of the shift from the Late Middle Paleolithic (LMP) to the Early Upper Paleolithic (EUP) varied geographically, temporally, and substantively across the Near East and Eurasia; however, the result of this process was the archaeological disappearance of Middle Paleolithic technologies across the length and breadth of their geographic distribution. Ortvale Klde rockshelter (Republic of Georgia) contains the most detailed LMP-EUP archaeological sequence in the Caucasus, an environmentally and topographically diverse region situated between southwest Asia and Europe. Tephrochronological investigations at the site reveal volcanic ash (tephra) from various volcanic sources and provide a tephrostratigraphy for the site that will facilitate future correlations in the region. We correlate one of the cryptotephra layers to the large, caldera-forming Nemrut Formation eruption (30,000 years ago) from Nemrut volcano in Turkey. We integrate this tephrochronological constraint with new radiocarbon dates and published ages in an OxCal Bayesian age model to produce a revised chronology for the site. This model increases the ages for the end of the LMP (∼47.5-44.2 ka cal BP) and appearance of the EUP (∼46.7-43.6 ka cal BP) at Ortvale Klde, which are earlier than those currently reported for other sites in the Caucasus but similar to estimates for specific sites in southwest Asia and eastern Europe. These data, coupled with archaeological, stratigraphic, and taphonomic observations, suggest that at Ortvale Klde, (1) the appearance of EUP technologies of bone and stone has no technological roots in the preceding LMP, (2) a LMP population vacuum likely preceded the appearance of these EUP technologies, and (3) the systematic combination of tephra correlations and absolute dating chronologies promises to substantially improve our inter-regional understanding of this critical time interval of human evolution and the potential interconnectedness of hominins at different sites.