To study the prevalence of exocrine pancreas insufficiency (EPI) at a population level and the subsequent risk of pancreatic ductal adenocarcinoma (PDAC). Using TriNetX (a database of over 79 million US residents), we included patients ≥18 years with EPI (identified via ICD-10 codes) and continuous follow-up from 2016-2022. Patients with prior pancreas resection and PDAC before an EPI diagnosis were excluded. The primary outcome was EPI prevalence. Secondary outcomes included imaging utilization, PDAC risk and, pancreas enzyme replacement therapy (PERT) utilization. We performed 1:1 propensity score matching of patients with EPI vs. patients without an EPI diagnosis. Adjusted odds ratio (aOR) and hazard ratios (aHR) with 95% confidence intervals were reported. The population prevalence of EPI was 0.8% (n = 24,080) with a mean age of 55.6 years at diagnosis. After propensity score matching, PDAC risk among patients with EPI was twice as high compared to patients without EPI (AHR 1.97, 95% confidence interval [CI] 1.66-2.36). This risk persisted even after excluding patients with a history of acute or chronic pancreatitis (aOR: 4.25, 95% CI 2.99-6.04). Only 58% (n = 13, 390) of patients with EPI received PERT with a mean treatment duration of 921 days. No difference was observed in PDAC risk between patients with EPI treated with PERT vs. those that did not receive PERT (AHR 1.10, 95% CI 0.95-1.26, p = 0.17). Despite a low prevalence, patients with EPI may have a higher risk of PDAC and many of these patients with EPI were not on PERT. PERT did not appear to impact incident PDAC risk after an EPI diagnosis.

Nasal intermittent positive pressure ventilation (NIPPV) has been shown to be superior to nasal continuous positive airway pressure (CPAP) postextubation in preterm neonates. However, studies have not permitted high CPAP pressures or rescue with other modes. We hypothesized that if CPAP pressures >8 cmH2O and rescue with other modes were permitted, CPAP would be noninferior to NIPPV. We conducted a pragmatic, comparative-effectiveness, noninferiority study utilizing network-based real-world data from 22 Canadian NICUs. Centers self-selected CPAP or NIPPV as their standard postextubation mode for preterm neonates <29 weeks' gestation. The primary outcome was failure of the initial mode ≤72 hours. Secondary outcomes included failure ≤7 days, and reintubation ≤72 hours and ≤7 days. Groups were compared using a noninferiority adjusted risk-difference (aRD) margin of 0.05, and margin of no difference. A total of 843 infants extubated to CPAP and 974 extubated to NIPPV were included. CPAP was not noninferior (and inferior) to NIPPV for failure of the initial mode ≤72 hours (33.0% vs 26.3%; aRD 0.07 [0.03 to 0.12], Pnoninferiority(NI) = .86), and ≤7 days (40.7% vs 35.8%; aRD 0.09 [0.05 to 0.13], PNI = 0.97). However, CPAP was noninferior (and equivalent) to NIPPV for reintubation ≤72 hours (13.2% vs 16.1%; aRD 0.01 [-0.05 to 0.02], PNI < .01), and noninferior (and superior) for reintubation ≤7 days (16.4% vs 22.8%; aRD -0.04 [-0.07 to -0.001], PNI < .01). CPAP was not noninferior to NIPPV for failure ≤72 hours postextubation; however, it was noninferior to NIPPV for reintubation ≤72 hours and ≤7 days. This suggests CPAP may be a reasonable initial postextubation mode if alternate rescue strategies are available.

RationaleAcute respiratory distress syndrome (ARDS) is a life-threatening critical care syndrome commonly associated with infections such as COVID-19, influenza, and bacterial pneumonia. Ongoing research aims to improve our understanding of ARDS, including its molecular mechanisms, individualized treatment options, and potential interventions to reduce inflammation and promote lung repair.ObjectiveTo map and compare metabolic phenotypes of different infectious causes of ARDS to better understand the metabolic pathways involved in the underlying pathogenesis.MethodsWe analyzed metabolic phenotypes of 3 ARDS cohorts caused by COVID-19, H1N1 influenza, and bacterial pneumonia compared to non-ARDS COVID-19-infected patients and ICU-ventilated controls. Targeted metabolomics was performed on plasma samples from a total of 150 patients using quantitative LC–MS/MS and DI-MS/MS analytical platforms.ResultsDistinct metabolic phenotypes were detected between different infectious causes of ARDS. There were metabolomics differences between ARDSs associated with COVID-19 and H1N1, which include metabolic pathways involving taurine and hypotaurine, pyruvate, TCA cycle metabolites, lysine, and glycerophospholipids. ARDSs associated with bacterial pneumonia and COVID-19 differed in the metabolism of D-glutamine and D-glutamate, arginine, proline, histidine, and pyruvate. The metabolic profile of COVID-19 ARDS (C19/A) patients admitted to the ICU differed from COVID-19 pneumonia (C19/P) patients who were not admitted to the ICU in metabolisms of phenylalanine, tryptophan, lysine, and tyrosine. Metabolomics analysis revealed significant differences between C19/A, H1N1/A, and PNA/A vs ICU-ventilated controls, reflecting potentially different disease mechanisms.ConclusionDifferent metabolic phenotypes characterize ARDS associated with different viral and bacterial infections.

Although not approved for the treatment of anxiety disorders (except trifluoperazine) there is ongoing off-label, unapproved use of first-generation antipsychotics (FGAs) and second-generation antipsychotics (SGAs) for anxiety disorders. There have been systematic reviews and meta-analyses on the use of antipsychotics in anxiety disorders, most of which focused on SGAs. The specific aims of this umbrella review are to: (1) Evaluate the evidence of efficacy of FGAs and SGAs in anxiety disorders as an adjunctive treatment to traditional antidepressant treatments and other nonantipsychotic medications; (2) Compare monotherapy with antipsychotics to first-line treatments for anxiety disorders in terms of effectiveness, risks, and side effects. The review protocol is registered on PROSPERO (CRD42021237436). An initial search was undertaken to identify systematic reviews and meta-analyses from inception until 2020, with an updated search completed August 2021 and January 2023. The searches were conducted in PubMed, MEDLINE (Ovid), EMBASE (Ovid), APA PsycInfo (Ovid), CINAHL Complete (EBSCOhost), and the Cochrane Library through hand searches of references of included articles. Review quality was measured using the AMSTAR-2 (A MeaSurement Tool to Assess Systematic Reviews) scale. The original and updated searches yielded 1796 and 3744 articles respectively, of which 45 were eligible. After final review, 25 systematic reviews and meta-analyses were included in the analysis. Most of the systematic reviews and meta-analyses were deemed low-quality through AMSTAR-2 with only one review being deemed high-quality. In evaluating the monotherapies with antipsychotics compared with first-line treatments for anxiety disorder there was insufficient evidence due to flawed study designs (such as problems with randomization) and small sample sizes within studies. There was limited evidence suggesting efficacy of antipsychotic agents in anxiety disorders other than quetiapine in generalized anxiety disorder (GAD). This umbrella review indicates a lack of high-quality studies of antipsychotics in anxiety disorders outside of the use of quetiapine in GAD. Although potentially effective for anxiety disorders, FGAs and SGAs may have risks and side effects that outweigh their efficacy, although there were limited data. Further long-term and larger-scale studies of antipsychotics in anxiety disorders are needed.

BackgroundRecent data from the randomized SUSTAIN CSX trial could not confirm clinical benefits from perioperative selenium treatment in high-risk cardiac surgery patients. Underlying reasons may involve inadequate biosynthesis of glutathione peroxidase (GPx3), which is a key mediator of selenium's antioxidant effects. This secondary analysis aimed to identify patients with an increase in GPx3 activity following selenium treatment. We hypothesize that these responders might benefit from perioperative selenium treatment.MethodsPatients were selected based on the availability of selenium biomarker information. Four subgroups were defined according to the patient's baseline status, including those with normal kidney function, reduced kidney function, selenium deficiency, and submaximal GPx3 activity.ResultsTwo hundred and forty-four patients were included in this analysis. Overall, higher serum concentrations of selenium, selenoprotein P (SELENOP) and GPx3 were correlated with less organ injury. GPx3 activity at baseline was predictive of 6-month survival (AUC 0.73; p = 0.03). While selenium treatment elevated serum selenium and SELENOP concentrations but not GPx3 activity in the full patient cohort, subgroup analyses revealed that GPx3 activity increased in patients with reduced kidney function, selenium deficiency and low to moderate GPx3 activity. Clinical outcomes did not vary between selenium treatment and placebo in any of these subgroups, though the study was not powered to conclusively detect differences in outcomes. ConclusionsThe identification of GPx3 responders encourages further refined investigations into the treatment effects of selenium in high-risk cardiac surgery patients.Graphical

Many COVID-19 survivors have post-COVID-19 conditions, and females are at a higher risk. We sought to determine (1) how protein levels change from acute to post-COVID-19 conditions, (2) whether females have a plasma protein signature different from that of males, and (3) which biological pathways are associated with COVID-19 when compared to restrictive lung disease. We measured protein levels in 74 patients on the day of admission and at 3 and 6 months after diagnosis. We determined protein concentrations by multiple reaction monitoring (MRM) using a panel of 269 heavy-labeled peptides. The predicted forced vital capacity (FVC) and diffusing capacity of the lungs for carbon monoxide (DLCO) were measured by routine pulmonary function testing. Proteins associated with six key lipid-related pathways increased from admission to 3 and 6 months; conversely, proteins related to innate immune responses and vasoconstriction-related proteins decreased. Multiple biological functions were regulated differentially between females and males. Concentrations of eight proteins were associated with FVC, %, and they together had c-statistics of 0.751 (CI:0.732-0.779); similarly, concentrations of five proteins had c-statistics of 0.707 (CI:0.676-0.737) for DLCO, %. Lipid biology may drive evolution from acute to post-COVID-19 conditions, while activation of innate immunity and vascular regulation pathways decreased over that period. (ProteomeXchange identifiers: PXD041762, PXD029437).

BackgroundIn 2012, the Brazilian government launched a radiotherapy (RT) expansion plan (PER-SUS) to install 100 linear accelerators. This study assesses the development of this program after eight years. MethodsOfficial reports from the Ministry of Health (MoH) were reviewed. RT centres projects status, timeframes, and cost data (all converted to US dollars) were extracted. The time analysis was divided into seven phases, and for cost evaluation, there were five stages. The initial predicted project time (IPPT) and costs (estimated by the MoH) for each phase were compared between the 18 operational RT centres (able to treat patients) and 30 non-operational RT centres using t-tests, ANOVA, and the Mann-Whitney U. A p-value < 0.05 indicates statistical significance. ResultsA significant delay was observed when comparing the IPPT with the overall time to conclude each 48 RT centres project (p < 0.001), with considerable delays in the first five phases (p < 0.001 for all). Moreover, the median time to conclude the first 18 operational RT centres (77.4 months) was shorter compared with the 30 non-operational RT centres (94.0 months), p < 0.001. The total cost of 48 RT services was USD 82,84 millions (mi) with a significant difference in the per project median total cost between 18 operational RT centres, USD1,34 mi and 30 non-operational RT centres USD2,11 mi, p < 0.001. All phases had a higher cost when comparing 30 non-operational RT centres to 18 operational RT centres, p < 0.001. The median total cost for expanding existing RT centres was USD1,30 mi versus USD2,18 mi for new RT services, p < 0.0001. ConclusionAfter eight years, the PER-SUS programs showed a substantial delay in most projects and their phases, with increased costs over time. Policy summaryOur findings indicate a need to act to increase the success of this plan. This study may provide a benchmark for other developing countries trying to expand RT capacity.

ABSTRACTCongenital heart disease (CHD) is the most common congenital anomaly. Non-canonical splice-disrupting variants are not routinely evaluated by clinical tests. Algorithms including SpliceAI predict such variants, but are not specific to cardiac-expressed genes. Whole genome (WGS) (n=1083) and myocardial RNA-Sequencing (RNA-Seq) (n=114) of CHD cases was used to identify splice-disrupting variants. Using features of variants confirmed to affect splicing in myocardial RNA, we trained a machine learning model that outperformed SpliceAI for predicting cardiac-specific splice-disrupting variants (AUC 0.92 vs 0.66), and was independently validated in 43 cardiomyopathy probands (AUC 0.88 vs 0.64). Application of this model to 971 CHD WGS samples identified 9% patients with splice-disrupting variants in CHD genes. Forty-one% of predicted splice-disrupting variants were deeply intronic. The burden of variants in CHD genes was higher in cases compared with 2,570 controls. Our model improved genetic yield by identifying splice-disrupting variants that are not evaluated by routine tests.