Microbial Indoles: Key Regulators of Organ Growth and Metabolic Function.

Gut microbes supporting body growth are known but the mechanisms are less well documented. Using the microbial tryptophan metabolite indole, known to regulate prokaryotic cell division and metabolic stress conditions, we mono-colonized germ-free (GF) mice with indole-producing wild-type Escherichia coli (E. coli) or tryptophanase-encoding tnaA knockout mutant indole-non-producing E. coli. Indole mutant E. coli mice showed multiorgan growth retardation and lower levels of glycogen, cholesterol, triglycerides, and glucose, resulting in an energy deficiency despite increased food intake. Detailed analysis revealed a malfunctioning intestine, enlarged cecum, and reduced numbers of enterochromaffin cells, correlating with a metabolic phenotype consisting of impaired gut motility, diminished digestion, and lower energy harvest. Furthermore, indole mutant mice displayed reduction in serum levels of tricarboxylic acid (TCA) cycle intermediates and lipids. In stark contrast, a massive increase in serum melatonin was observed-frequently associated with accelerated oxidative stress and mitochondrial dysfunction. This observational report discloses functional roles of microbe-derived indoles regulating multiple organ functions and extends our previous report of indole-linked regulation of adult neurogenesis. Since indoles decline by age, these results imply a correlation with age-linked organ decline and levels of indoles. Interestingly, increased levels of indole-3-acetic acid, a known indole metabolite, have been shown to correlate with younger biological age, further supporting a link between biological age and levels of microbe-derived indole metabolites. The results presented in this resource paper will be useful for the future design of food intervention studies to reduce accelerated age-linked organ decline.

The impact of stapled compared to handsewn repair on anastomotic outcomes in trauma patients: a systematic review and meta-analysis.

BACKGROUND: Approach to enteric anastomotic technique has been a subject of debate, with no clear consensus as to whether handsewn or stapled techniques are superior in trauma settings, which are influenced by unique perturbances to important processes such as immune function, coagulation, wound healing and response to infection. This systematic review and meta-analysis compares the risk of anastomotic complications in trauma patients with gastrointestinal injury requiring restoration of continuity with handsewn versus staples approaches. METHODS: A comprehensive computer assisted search of electronic databases Medline, Embase and Cochrane Central was performed. Comparative studies evaluating stapled versus handsewn gastrointestinal anastomoses in trauma patients were included in this review. All anastomoses involving small intestine to small intestine, small to large intestine, and large intestine to large intestine were eligible. Anastomosis to the rectum was excluded. Outcomes evaluated were (1) anastomotic leak (AL) (2) a composite anastomotic complication (CAC) end point consisting of AL, enterocutaneous fistula (ECF) and deep abdominal abscess. RESULTS: Eight studies involving 931 patients were included and of these patients, data from 790 patients were available for analysis. There was no significant difference identified for anastomotic leak between the two groups (OR = 0.77; 95% CI 0.24-2.45; P = 0.66). There was no significant improvement in composite anastomotic complication; defined as a composite of anastomotic leak, deep intra-abdominal abscess and intra-abdominal fistula, in the stapled anastomosis group (OR = 1.05; 95% CI 0.53-2.09; P = 0.90). Overall, there was limited evidence to suggest superiority with handsewn or stapled anastomosis for improving AL or CAC, however this was based on studies of moderate to high risk of bias with poor control for confounders. DISCUSSION: This meta-analysis demonstrates no superiority improvement in anastomotic outcomes with handsewn or stapled repair. These findings may represent no effect in anastomotic outcome by technique for all situations. However, considering the paucity of information on potential confounders, perhaps there is a difference in outcome with overall technique or for specific subgroups that have not been described due to limited sample size and data on confounders. Currently, there is insufficient evidence to recommend an anastomotic technique in trauma.

Whole blood transcriptomics reveals granulocyte colony-stimulating factor as a mediator of cardiopulmonary bypass-induced systemic inflammatory response syndrome.

Objectives: Systemic inflammatory response syndrome (SIRS) is a frequent complication of cardiopulmonary bypass (CPB). SIRS is associated with significant morbidity and mortality, but its pathogenesis remains incompletely understood, and as a result, biomarkers are lacking and treatment remains expectant and supportive. This study aimed to understand the pathophysiological mechanisms driving SIRS induced by CPB and identify novel therapeutic targets that might reduce systemic inflammation and improve patient outcomes. Methods: Twenty-one patients undergoing cardiac surgery and CPB were recruited, and blood was sampled before, during and after surgery. SIRS was defined using the American College of Chest Physicians/Society of Critical Care Medicine criteria. We performed immune cell profiling and whole blood transcriptomics and measured individual mediators in plasma/serum to characterise SIRS induced by CPB. Results: Nineteen patients fulfilled criteria for SIRS, with a mean duration of 2.7 days. Neutrophil numbers rose rapidly with CPB and remained elevated for at least 48 h afterwards. Transcriptional signatures associated with neutrophil activation and degranulation were enriched during CPB. We identified a network of cytokines governing these transcriptional changes, including granulocyte colony-stimulating factor (G-CSF), a regulator of neutrophil production and function. Conclusions: We identified neutrophils and G-CSF as major regulators of CPB-induced systemic inflammation. Short-term targeting of G-CSF could provide a novel therapeutic strategy to limit neutrophil-mediated inflammation and tissue damage in SIRS induced by CPB.

G-CSF reshapes the cytosolic PCNA scaffold and modulates glycolysis in neutrophils.

Cytosolic proliferating cell nuclear antigen (PCNA) is involved in neutrophil survival and function, in which it acts as a scaffold and associates with proteins involved in apoptosis, NADPH oxidase activation, cytoskeletal dynamics, and metabolism. While the PCNA interactome has been characterized in neutrophils under homeostatic conditions, less is known about neutrophil PCNA in pathophysiological contexts. Granulocyte colony-stimulating factor (G-CSF) is a cytokine produced in response to inflammatory stimuli that regulates many aspects of neutrophil biology. Here, we used isolated normal-density neutrophils from G-CSF-treated haemopoietic stem cell donors (GDs) as a model to understand the role of PCNA during inflammation. Proteomic analysis of the neutrophil cytosol revealed significant differences between GDs and healthy donors (HDs). PCNA was one of the most upregulated proteins in GDs, and the PCNA interactome was significantly different in GDs compared with HDs. Importantly, while PCNA associated with almost all enzymes involved in glycolysis in HDs, these associations were decreased in GDs. Functionally, neutrophils from GDs had a significant increase in glycolysis compared with HDs. Using p21 competitor peptides, we showed that PCNA negatively regulates neutrophil glycolysis in HDs but had no effect on GD neutrophils. These data demonstrate that G-CSF alters the PCNA scaffold, affecting interactions with key glycolytic enzymes, and thus regulates glycolysis, the main energy pathway utilized by neutrophils. By this selective control of glycolysis, PCNA can organize neutrophils functionality in parallel with other PCNA mechanisms of prolonged survival. PCNA may therefore be instrumental in the reprogramming that neutrophils undergo in inflammatory or tumoral settings.

PAK1-dependent mechanotransduction enables myofibroblast nuclear adaptation and chromatin organization during fibrosis.

Myofibroblasts are responsible for scarring during fibrosis. The scar propagates mechanical signals inducing a radical transformation in myofibroblast cell state and increasing profibrotic phenotype. Here, we show mechanical stress from progressive scarring induces nuclear softening and de-repression of heterochromatin. The parallel loss of H3K9Me3 enables a permissive state for distinct chromatin accessibility and profibrotic gene regulation. Integrating chromatin accessibility profiles with RNA expression provides insight into the transcription network underlying the switch in profibrotic myofibroblast states, emphasizing mechanoadaptive regulation of PAK1 as key drivers. Through genetic manipulation in liver and lung fibrosis, loss of PAK1-dependent signaling impairs the mechanoadaptive response in vitro and dramatically improves fibrosis in vivo. Moreover, we provide human validation for mechanisms underpinning PAK1-mediated mechanotransduction in liver and lung fibrosis. Collectively, these observations provide insight into the nuclear mechanics driving the profibrotic chromatin landscape in fibrosis, highlighting actomyosin-dependent mechanisms as potential therapeutic targets in fibrosis.

Dysregulation of neutrophil oxidant production and interleukin-1-related cytokines in granulomatosis with polyangiitis.

OBJECTIVES: Neutrophils play a key role in ANCA-associated vasculitis, both as targets of autoimmunity and facilitators of vascular damage. In granulomatosis with polyangiitis (GPA), data regarding the production of reactive oxygen species (ROS) in neutrophils are unclear. Further, recent data suggests that ROS production could have an anti-inflammatory effect through the regulation of the inflammasome and IL-1-related cytokines. We aimed to analyse the ROS production in neutrophils from patients with GPA and investigate its association with IL-1-related cytokines and the autoantigen proteinase 3 (PR3). METHODS: Seventy-two GPA patients with disease flare were included in the NEUTROVASC prospective cohort study. ROS production was evaluated in whole blood of patients with active GPA and compared with the same patients in remission or healthy controls. Associations between ROS production, PR3 membrane expression on neutrophils, serum levels of IL-1-related cytokines as well as inflammasome-related proteins were analyzed. RESULTS: We observed a robust defect in ROS production by neutrophils from patients with active GPA compared with healthy controls, independent of glucocorticoid treatment. Serum levels of IL-1-related cytokines were significantly increased in GPA patients, particularly in patients with kidney involvement, and levels of these cytokines returned to normal after patients achieved remission. Further, inflammasome-related proteins were significantly dysregulated in the cytosol of neutrophils as well as the serum from GPA patients. CONCLUSION: Our data suggests that ROS production and regulation of the inflammasome in neutrophils from patients with GPA are disturbed and may be a potential therapeutic target. CLINICAL TRIAL REGISTRATION NUMBER: NCT01862068, clinicaltrials.gov, https://www.clinicaltrials.gov.

Risks of opioid overdose among New York State Medicaid recipients with chronic pain before and during the COVID-19 pandemic.

OBJECTIVE: The COVID-19 pandemic contributed to healthcare disruptions for patients with chronic pain. Following initial disruptions, national policies were enacted to expand access to long-term opioid therapy (LTOT) for chronic pain and opioid use disorder (OUD) treatment services, which may have modified risk of opioid overdose. We examined associations between LTOT and/or OUD with fatal and non-fatal opioid overdoses, and whether the pandemic moderated overdose risk in these groups. METHODS: We analyzed New York State Medicaid claims data (3/1/2019-12/31/20) of patients with chronic pain (N = 236,391). We used generalized estimating equations models to assess associations between LTOT and/or OUD (neither LTOT or OUD [ref], LTOT only, OUD only, and LTOT and OUD) and the pandemic (03/2020-12/2020) with opioid overdose. RESULTS: The pandemic did not significantly (ns) affect opioid overdose among patients with LTOT and/or OUD. While patients with LTOT (vs. no LTOT) had a slight increase in opioid overdose during the pandemic (pre-pandemic: aOR:1.65, 95% CI:1.05, 2.57; pandemic: aOR:2.43, CI:1.75,3.37, ns), patients with OUD had a slightly attenuated odds of overdose during the pandemic (pre-pandemic: aOR:5.65, CI:4.73, 6.75; pandemic: aOR:5.16, CI:4.33, 6.14, ns). Patients with both LTOT and OUD also experienced a slightly reduced odds of opioid overdose during the pandemic (pre-pandemic: aOR:5.82, CI:3.58, 9.44; pandemic: aOR:3.70, CI:2.11, 6.50, ns). CONCLUSIONS: Findings demonstrated no significant effect of the pandemic on opioid overdose among people with chronic pain and LTOT and/or OUD, suggesting pandemic policies expanding access to chronic pain and OUD treatment services may have mitigated the risk of opioid overdose.

Utilization and disparities in medication treatment for opioid use disorder among patients with comorbid opioid use disorder and chronic pain during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic's impact on utilization of medications for opioid use disorder (MOUD) among patients with opioid use disorder (OUD) and chronic pain is unclear. METHODS: We analyzed New York State (NYS) Medicaid claims from pre-pandemic (August 2019-February 2020) and pandemic (March 2020-December 2020) periods for beneficiaries with and without chronic pain. We calculated monthly proportions of patients with OUD diagnoses in 6-month-lookback windows utilizing MOUD and proportions of treatment-naïve patients initiating MOUD. We used interrupted time series to assess changes in MOUD utilization and initiation rates by medication type and by race/ethnicity. RESULTS: Among 20,785 patients with OUD and chronic pain, 49.3% utilized MOUD (versus 60.3% without chronic pain). The pandemic did not affect utilization in either group but briefly disrupted initiation among patients with chronic pain (ß=-0.009; 95% CI [-0.015, -0.002]). Overall MOUD utilization was not affected by the pandemic for any race/ethnicity but opioid treatment program (OTP) utilization was briefly disrupted for non-Hispanic Black individuals (ß=-0.007 [-0.013, -0.001]). The pandemic disrupted overall MOUD initiation in non-Hispanic Black (ß=-0.007 [-0.012, -0.002]) and Hispanic individuals (ß=-0.010 [-0.019, -0.001]). CONCLUSIONS: Adults with chronic pain who were enrolled in NYS Medicaid before the COVID-19 pandemic had lower MOUD utilization than those without chronic pain. MOUD initiation was briefly disrupted, with disparities especially in racial/ethnic minority groups. Flexible MOUD policy initiatives may have maintained overall treatment utilization, but disparities in initiation and care continuity remain for patients with chronic pain, and particularly for racial/ethnic minoritized subgroups.

Coeliac artery avulsion secondary to high velocity blunt abdominal trauma: a case report.

Coeliac artery (CA) injuries are an extremely rare subset of blunt abdominal trauma with a reported incidence of only 0.01%. Patterns of CA injury include intimal tear, dissection, thrombosis and pseudoaneurysm, with the most rare being complete CA avulsion. These complex injuries pose a treatment challenge due to rapid blood loss and anatomical difficultly in achieving proximal and multiple points of distal vascular control. To our knowledge, this case of CA avulsion from blunt polytrauma is only the 7th case reported in the literature. To assist in management, we report a case of blunt traumatic CA avulsion managed successfully with open ligation following endovascular balloon occlusion of the juxta-coeliac aorta for haemorrhage control.

The evolution of antimicrobial peptides in Chiroptera.

High viral tolerance coupled with an extraordinary regulation of the immune response makes bats a great model to study host-pathogen evolution. Although many immune-related gene gains and losses have been previously reported in bats, important gene families such as antimicrobial peptides (AMPs) remain understudied. We built an exhaustive bioinformatic pipeline targeting the major gene families of defensins and cathelicidins to explore AMP diversity and analyze their evolution and distribution across six bat families. A combination of manual and automated procedures identified 29 AMP families across queried species, with α-, ß-defensins, and cathelicidins representing around 10% of AMP diversity. Gene duplications were inferred in both α-defensins, which were absent in five species, and three ß-defensin gene subfamilies, but cathelicidins did not show significant shifts in gene family size and were absent in Anoura caudifer and the pteropodids. Based on lineage-specific gains and losses, we propose diet and diet-related microbiome evolution may determine the evolution of α- and ß-defensins gene families and subfamilies. These results highlight the importance of building species-specific libraries for genome annotation in non-model organisms and shed light on possible drivers responsible for the rapid evolution of AMPs. By focusing on these understudied defenses, we provide a robust framework for explaining bat responses to pathogens.

A common human MLKL polymorphism confers resistance to negative regulation by phosphorylation.

Across the globe, 2-3% of humans carry the p.Ser132Pro single nucleotide polymorphism in MLKL, the terminal effector protein of the inflammatory form of programmed cell death, necroptosis. Here we show that this substitution confers a gain in necroptotic function in human cells, with more rapid accumulation of activated MLKLS132P in biological membranes and MLKLS132P overriding pharmacological and endogenous inhibition of MLKL. In mouse cells, the equivalent Mlkl S131P mutation confers a gene dosage dependent reduction in sensitivity to TNF-induced necroptosis in both hematopoietic and non-hematopoietic cells, but enhanced sensitivity to IFN-ß induced death in non-hematopoietic cells. In vivo, MlklS131P homozygosity reduces the capacity to clear Salmonella from major organs and retards recovery of hematopoietic stem cells. Thus, by dysregulating necroptosis, the S131P substitution impairs the return to homeostasis after systemic challenge. Present day carriers of the MLKL S132P polymorphism may be the key to understanding how MLKL and necroptosis modulate the progression of complex polygenic human disease.

The small-molecule formyl peptide receptor biased agonist, compound 17b, is a vasodilator and anti-inflammatory in mouse precision-cut lung slices.

BACKGROUND AND PURPOSE: Pulmonary arterial hypertension (PAH), a rare fatal disorder characterised by inflammation, vascular remodelling and vasoconstriction. Current vasodilator therapies reduce pulmonary arterial pressure but not mortality. The G-protein coupled formyl peptide receptors (FPRs) mediates vasodilatation and resolution of inflammation, actions possibly beneficial in PAH. We investigated dilator and anti-inflammatory effects of the FPR biased agonist compound 17b in pulmonary vasculature using mouse precision-cut lung slices (PCLS). EXPERIMENTAL APPROACH: PCLS from 8-week-old male and female C57BL/6 mice, intrapulmonary arteries were pre-contracted with 5-HT for concentration-response curves to compound 17b and 43, and standard-of-care drugs, sildenafil, iloprost and riociguat. Compound 17b-mediated relaxation was assessed with FPR antagonists or inhibitors and in PCLS treated with TNF-α or LPS. Cytokine release from TNF-α- or LPS-treated PCLS ± compound 17b was measured. KEY RESULTS: Compound 17b elicited concentration-dependent vasodilation, with potencies of iloprost > compound 17b = riociguat > compound 43 = sildenafil. Compound 17b was inhibited by the FPR1 antagonist cyclosporin H but not by soluble guanylate cyclase, nitric oxide synthase or cyclooxygenase inhibitors. Under inflammatory conditions, the efficacy and potency of compound 17b were maintained, while iloprost and sildenafil were less effective. Additionally, compound 17b inhibited secretion of PAH-relevant cytokines via FPR2. CONCLUSIONS AND IMPLICATIONS: Vasodilation to compound 17b but not standard-of-care vasodilators, is maintained under inflammatory conditions, with additional inhibition of PAH-relevant cytokine release. This provides the first evidence that targeting FPR, with biased agonist, simultaneously targets vascular function and inflammation, supporting the development of FPR-based pharmacotherapy to treat PAH.

Evaluating chronic pain as a risk factor for COVID-19 complications among New York State Medicaid beneficiaries: a retrospective claims analysis.

OBJECTIVE: To assess whether chronic pain increases the risk of COVID-19 complications and whether opioid use disorder (OUD) differentiates this risk among New York State Medicaid beneficiaries. DESIGN, SETTING, AND SUBJECTS: This was a retrospective cohort study of New York State Medicaid claims data. We evaluated Medicaid claims from March 2019 through December 2020 to determine whether chronic pain increased the risk of COVID-19 emergency department (ED) visits, hospitalizations, and complications and whether this relationship differed by OUD status. We included beneficiaries 18-64 years of age with 10 months of prior enrollment. Patients with chronic pain were propensity score-matched to those without chronic pain on demographics, utilization, and comorbidities to control for confounders and were stratified by OUD. Complementary log-log regressions estimated hazard ratios (HRs) of COVID-19 ED visits and hospitalizations; logistic regressions estimated odds ratios (ORs) of hospital complications and readmissions within 0-30, 31-60, and 61-90 days. RESULTS: Among 773 880 adults, chronic pain was associated with greater hazards of COVID-related ED visits (HR = 1.22 [95% CI: 1.16-1.29]) and hospitalizations (HR = 1.19 [95% CI: 1.12-1.27]). Patients with chronic pain and OUD had even greater hazards of hospitalization (HR = 1.25 [95% CI: 1.07-1.47]) and increased odds of hepatic- and cardiac-related events (OR = 1.74 [95% CI: 1.10-2.74]). CONCLUSIONS: Chronic pain increased the risk of COVID-19 ED visits and hospitalizations. Presence of OUD further increased the risk of COVID-19 hospitalizations and the odds of hepatic- and cardiac-related events. Results highlight intersecting risks among a vulnerable population and can inform tailored COVID-19 management.

Development of an Efficient, Effective, and Economical Technology for Proteome Analysis.

Proteomics experiments have typically high economic and technical barriers to broad biomedical scientists, which not only result in costly supplies and accessories for sample preparation but also the reluctance to adapt new techniques. In the present study, we present an effective and efficient, yet economical technology, which we call E3technology, for proteomics sample preparation. By immobilizing silica microparticles into a polytetrafluoroethylene (PTFE) matrix, we developed a novel medium, which could be used as a robust and reliable proteomics platform to generate LCMS-friendly samples in a rapid and low-cost fashion. Using different formats of E3technology, including E3tip, E3filter, E3cartridge, and E3plate, we explored a variety of sample types in varied complexity, quantity, volume, and size, including bacterial, fungi, mammalian cells, mouse tissue, and human body fluids. We benchmark their performance against several established approaches. Our data suggest that E3technology outperforms many of the currently available techniques in terms of proteome identification and quantitation. It is widely applicable, highly reproducible, readily scalable and automatable, and is user-friendly and stress-free to non-expert proteomics laboratories. It does not require specialized expertise and equipment, and significantly lowers the technical and economical barrier to proteomics experiments. An enhanced version, E4technology, also opens new avenues to sample preparation for low input and/or low-cell proteomics analysis. The presented technologies by our study represent a breakthrough innovation in biomedical science, and we anticipate widespread adoption by the proteomics community.

Largest comparative analysis: Novel large spot size 595 nm, high-energy, pulsed dye laser reduces number of treatments for improvement of adult and pediatric port wine birthmarks.

OBJECTIVE: Port wine birthmarks (PWBs) are vascular malformations affecting 0.3%-0.5% of newborns with the tendency to persist into adulthood without adequate treatment of the heterogenous ectatic vessels. This study compares treatment outcomes and parameters of the prior generation pulsed dye laser (PPDL) and the larger spot novel generation pulsed dye laser (NPDL) to establish whether a larger spot size laser provides greater clearance with fewer treatments. METHODS: One hundred and sixty patients were treated with either the PPDL (80 patients) and NPDL (80 patients) with retrospective review of age, body site, laser treatment parameters, number of treatments, and improvement following laser therapy. RESULTS: Patients treated with PPDL were older on average than patients treated with NPDL (mean 24.8 ± 19.7 vs. mean 17.1± 19.3 years, p < 0.05). The majority of lesions treated with PPDL were located on the face and neck, whereas truncal and extremity sites were more frequently treated with the NPDL. Use of NPDL was associated with a mean maximum spot size of 13.1 mm and mean maximum fluence of 7.3 J/cm2 with pulse durations of 0.45-3 ms, whereas use of the PPDL was associated with a mean spot size of 10.8 mm and mean maximum fluence of 8.8 J/cm2 with pulse durations of 0.45-6 ms. Fifty percent improvement was seen with 8.8 PPDL treatments compared to 4.3 NPDL treatments (p ≤ 0.01) with no significant difference in overall mean improvement between both devices at the chosen parameters. Multiple regression analysis showed that device type, not age or lesion location, was the only statistically significant independent variable to affect the endpoint of at least 50% improvement of the lesion. CONCLUSIONS: Use of the larger spot NPDL is associated with achieving 50% improvement with fewer treatments.

Rare causes of abdominal pain: a primer for the admitting general surgeon.

The broad uptake of the acute surgical unit (ASU) model of surgical care in Australia has resulted in general surgeons becoming increasingly involved in the management of patients with acute abdominal pain (AAP), some of whom will be labelled as having non-specific abdominal pain (NSAP) (Kinnear N, Jolly S, Herath M, et al. The acute surgical unit: An updated systematic review and meta-analysis. review. Int. J. Surg. 2021;94:106109; Lehane CW, Jootun RN, Bennett M, Wong S, Truskett P. Does an acute care surgical model improve the management and outcome of acute cholecystitis? ANZ J. Surg. 2010;80:438-42). NSAP patients lack a clear diagnosis of surgical pathology based on standard clinical, laboratory and imaging work-up, although they may require ASU admission for pain control and assessment. This article provides a review of uncommon conditions, presenting as AAP, that could possibly be mis-labelled as NSAP, with a focus on aspects of the presentation that may aid diagnosis and management including specific demographic features, clinical findings, key investigations and initial treatment priorities for ASU clinicians. Ultimately, most of the conditions discussed will not require surgical intervention, however, they require a diagnosis to be made and initial treatment planning before on-referral to the appropriate specialty. For the on-call general surgeon, some knowledge of these conditions and an index of suspicion are invaluable for the prompt diagnosis and efficient management of these patients.

Impact of COVID-19 pandemic on delivery of pediatric radiotherapy: A critical review.

The COVID-19 pandemic has prevented the timely diagnosis and treatment of many diseases, including pediatric cancer. Its impact on pediatric oncologic treatments warrants investigation. As radiotherapy is an integral component of cancer care, we reviewed the published data regarding the impact of COVID-19 on the delivery of pediatric radiotherapy to inform actions for future global events. We found that disruptions in radiotherapy were reported amongst interruptions in other therapies. Disruptions were more common in low-income countries (78%) and low middle-income countries (68%) compared with upper middle-income countries (46%) and high-income countries (10%). Several papers included recommendations for mitigation strategies. Altered treatment regimens were common, including increasing the use of active surveillance and systemic therapy to delay local therapies, and accelerated/hypofractionated dose delivery. Our findings suggest that COVID-19 has impacted radiotherapy delivery in the pediatric population globally. Countries with limited resources may be more affected. Various mitigation strategies have been developed. The efficacy of mitigation measures warrants further investigation.

Forested watersheds provide the highest water quality among all land cover types, but the benefit of this ecosystem service depends on landscape context.

Conversion of natural land cover can degrade water quality in water supply watersheds and increase treatment costs for Public Water Systems (PWSs), but there are few studies that have fully evaluated land cover and water quality relationships in mixed use watersheds across broad hydroclimatic settings. We related upstream land cover (forest, other natural land covers, development, and agriculture) to observed and modeled water quality across the southeastern US and specifically at 1746 PWS drinking water intake facilities. While there was considerable complexity and variability in the relationship between land cover and water quality, results suggest that Total Nitrogen (TN), Total Phosphorus (TP) and Suspended Sediment (SS) concentrations decrease significantly with increasing forest cover, and increase with increasing developed or agricultural cover. Catchments with dominant (>90 %) agricultural land cover had the greatest export rates for TN, TP, and SS based on SPARROW model estimates, followed by developed-dominant, then forest- and other-natural-dominant catchments. Variability in modeled TN, TP, and SS export rates by land cover type was driven by variability in natural background sources and catchment characteristics that affected water quality even in forest-dominated catchments. Both intake setting (i.e., run-of-river or reservoir) and upstream land cover were important determinants of water quality at PWS intakes. Of all PWS intakes, 15 % had high raw water quality, and 85 % of those were on reservoirs. Of the run-of-river intakes with high raw water quality, 75 % had at least 50 % forest land cover upstream. In addition, PWS intakes obtaining surface water supply from smaller upstream catchments may experience the largest losses of natural land cover based on projections of land cover in 2070. These results illustrate the complexity and variability in the relationship between land cover and water quality at broad scales, but also suggest that forest conservation can enhance the resilience of drinking water supplies.

Impact of Age on Overall Survival Among Children With Wilms Tumor: A Population-based Registry Analysis.

OBJECTIVES: International trials have reported conflicting findings on whether the association between age and worse overall survival (OS) among children with Wilms tumor (WT) is due to age as an independent prognostic factor or the observation of more advanced disease at older ages. We sought to further elucidate this relationship using a population-based registry analysis. METHODS: The Surveillance, Epidemiology, and End Results database was queried for all patients diagnosed with WT under the age of 20. The association between age and OS was assessed using multivariable Cox proportional hazards regression. RESULTS: In this study, 3463 patients (54% female) were diagnosed with WT between 1975 and 2016. More advanced stage, larger primary tumor size, lymph node involvement, disease requiring radiotherapy, and omission of surgery were associated with worse OS ( P <0.05). More advanced stage, larger primary tumor size, and disease requiring radiotherapy were also associated with older age, whereas bilateral disease was associated with younger age ( P <0.001). On average, each year of age conferred an incremental hazard ratio (HR) of 1.07 (95% CI, 1.01 to 1.12, P =0.018) independent of relevant covariates. The rise in adjusted OS HR was most pronounced after the transitions in diagnosis age from 2 to 3 (HR age 3-15 vs. 0-2 1.77, 95% CI, 1.11 to 2.82, P =0.016) and from 15 to 16 (HR age 16-19 vs. 3-15 2.58, 95% CI, 1.06 to 6.25, P =0.036). CONCLUSIONS: Diagnosis of pediatric WT at an older age was found to be independently associated with worse OS. Although additional prospective studies are warranted to examine tumor biology and other potential correlates, more aggressive treatment of older children based on age, especially as they approach early adulthood, may be considered in the multidisciplinary management of WT.

Naloxone expansion is not associated with increases in adolescent heroin use and injection drug use: Evidence from 44 US states.

BACKGROUND: Naloxone distribution is central to ongoing efforts to address the opioid overdose crisis. Some critics contend that naloxone expansion may inadvertently promote high-risk substance use behaviors among adolescents, but this question has not been directly investigated. METHODS: We examined relationships between naloxone access laws and pharmacy naloxone distribution with lifetime heroin and injection drug use (IDU), 2007-2019. Models generating adjusted odds ratios (aOR) and 95% confidence intervals (CI) included year and state fixed effects, controlled for demographics and sources of variation in opioid environments (e.g., fentanyl penetration), as well as additional policies expected to impact substance use (e.g., prescription drug monitoring). Exploratory and sensitivity analyses further examined naloxone law provisions (e.g., third-party prescribing) and applied e-value testing to assess vulnerability to unmeasured confounding. RESULTS: Adoption of any naloxone law was not associated with changes in adolescent lifetime heroin or IDU. For pharmacy dispensing, we observed a small decrease in heroin use (aOR: 0.95 [CI: 0.92, 0.99]) and a small increase in IDU (aOR: 1.07 [CI: 1.02, 1.11]). Exploratory analyses of law provisions suggested that third-party prescribing (aOR: 0.80, [CI: 0.66, 0.96]) and non-patient-specific dispensing models (aOR: 0.78, [CI: 0.61, 0.99]) were associated with decreased heroin use but not decreased IDU. Small e-values associated with the pharmacy dispensing and provision estimates indicate that unmeasured confounding may explain observed findings. CONCLUSION: Naloxone access laws and pharmacy naloxone distribution were more consistently associated with decreases rather than increases in lifetime heroin and IDU among adolescents. Our findings therefore do not support concerns that naloxone access promotes high-risk adolescent substance use behaviors. As of 2019, all US states have adopted legislation to improve naloxone access and facilitate use. However, further removal of adolescent naloxone access barriers is an important priority given that the opioid epidemic continues to affect people of all ages.