The 3-chymotrypsin-like cysteine protease (3CLpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is considered a major target for the discovery of direct antiviral agents. We ...previously reported the evaluation of SARS-CoV-2 3CLpro inhibitors in a novel self-assembled monolayer desorption ionization mass spectrometry (SAMDI-MS) enzymatic assay (Gurard-Levin et al., 2020). The assay was further improved by adding the rhinovirus HRV3C protease to the same well as the SARS-CoV-2 3CLpro enzyme. High substrate specificity for each enzyme allowed the proteases to be combined in a single assay reaction without interfering with their individual activities. This novel duplex assay was used to profile a diverse set of reference protease inhibitors. The protease inhibitors were grouped into three categories based on their relative potency against 3CLpro and HRV3C including those that are: equipotent against 3CLpro and HRV3C (GC376 and calpain inhibitor II), selective for 3CLpro (PF-00835231, calpain inhibitor XII, boceprevir), and selective for HRV3C (rupintrivir). Structural analysis showed that the combination of minimal interactions, conformational flexibility, and limited bulk allows GC376 and calpain inhibitor II to potently inhibit both enzymes. In contrast, bulkier compounds interacting more tightly with pockets P2, P3, and P4 due to optimization for a specific target display a more selective inhibition profile. Consistently, the most selective viral protease inhibitors were relatively weak inhibitors of human cathepsin L. Taken together, these results can guide the design of cysteine protease inhibitors that are either virus-specific or retain a broad antiviral spectrum against coronaviruses and rhinoviruses.
•A novel single-well assay was developed to monitor the enzymatic activities of both SARS-CoV-2 3CLpro and rhinovirus HRV3C.•Reference protease inhibitors were either equipotent against 3CLpro and HRV3C, selective for 3CLpro, or selective for HRV3C.•GC376 had broad antiviral spectrum but also potently inhibited human cathepsin L.•PF-00835231 was selective for SARS-CoV-2 3CLpro and only weakly inhibited cathepsin L.
To examine rates and predictors of receiving a psychosocial service before initiating antipsychotic treatment among young people in the Medicaid program.
A retrospective new-user cohort study of 8 ...state Medicaid programs focused on children and adolescents 0 to 20 years, initiating antipsychotic treatment (N = 24,372). The proportion receiving a psychosocial service in the 3 months before initiating antipsychotic treatment was calculated and stratified by socio-demographic and diagnostic characteristics arranged in 9 hierarchical groups, as follows: developmental, psychotic/bipolar, disruptive, attention-deficit/hyperactivity, obsessive-compulsive, stress, major depressive, anxiety, and other disorders.
Less than one-half of youth received a psychosocial service before initiating antipsychotic treatment (48.8%). Compared to younger adolescents (12–17 years) initiating antipsychotic treatment (51.5%), corresponding younger children (0–5 years; 39.2%) and older adolescents (18–20 years; 40.1%), but not older children (6–11 years; 51.5%), were significantly less likely to have received a psychosocial service. In relation to youth diagnosed with psychotic or bipolar disorder (52.7%), those diagnosed with attention-deficit/hyperactivity (43.3%), developmental (41.4%), depressive (46.5%), or anxiety (35.6%) disorder were significantly less likely to have received a psychosocial service during the 3 months before antipsychotic initiation. By contrast, youth diagnosed with stress disorders (61.2%) were significantly more likely than those diagnosed with psychotic or bipolar disorders (52.7%) to have received a psychosocial service before starting an antipsychotic.
A majority of Medicaid-insured youth initiating antipsychotic treatment have not received a psychosocial service in the preceding 3 months. This service pattern highlights a critical gap in access to psychosocial services.
The issue of whether viruses are subject to restriction by endogenous microRNAs (miRNAs) and/or by virus-induced small interfering RNAs (siRNAs) in infected human somatic cells has been ...controversial. Here, we address this question in two ways. First, using deep sequencing, we demonstrate that infection of human cells by the RNA virus dengue virus (DENV) or West Nile virus (WNV) does not result in the production of any virus-derived siRNAs or viral miRNAs. Second, to more globally assess the potential of small regulatory RNAs to inhibit virus replication, we used gene editing to derive human cell lines that lack a functional Dicer enzyme and that therefore are unable to produce miRNAs or siRNAs. Infection of these cells with a wide range of viruses, including DENV, WNV, yellow fever virus, Sindbis virus, Venezuelan equine encephalitis virus, measles virus, influenza A virus, reovirus, vesicular stomatitis virus, human immunodeficiency virus type 1, or herpes simplex virus 1 (HSV-1), failed to reveal any enhancement in the replication of any of these viruses, although HSV-1, which encodes at least eight Dicer-dependent viral miRNAs, did replicate somewhat more slowly in the absence of Dicer. We conclude that most, and perhaps all, human viruses have evolved to be resistant to inhibition by endogenous human miRNAs during productive replication and that dependence on a cellular miRNA, as seen with hepatitis C virus, is rare. How viruses have evolved to avoid inhibition by endogenous cellular miRNAs, which are generally highly conserved during metazoan evolution, remains to be determined. Importance: Eukaryotic cells express a wide range of small regulatory RNAs, including miRNAs, that have the potential to inhibit the expression of mRNAs that show sequence complementarity. Indeed, previous work has suggested that endogenous miRNAs have the potential to inhibit viral gene expression and replication. Here, we demonstrate that the replication of a wide range of pathogenic viruses is not enhanced in human cells engineered to be unable to produce miRNAs, indicating that viruses have evolved to be resistant to inhibition by miRNAs. This result is important, as it implies that manipulation of miRNA levels is not likely to prove useful in inhibiting virus replication. It also focuses attention on the question of how viruses have evolved to resist inhibition by miRNAs and whether virus mutants that have lost this resistance might prove useful, for example, in the development of attenuated virus vaccines.
Purpose: To determine if pain screening and functional assessment results are associated with new diagnoses and treatment for pain in primary care. Patients and Methods: Observational study at 13 ...primary care sites of a statewide federally qualified health center that implemented routine screening and functional assessment for all adults in primary care. The study group included 10,091 adults aged 18+ who had an in-person visit between July 2, 2018, and June 1, 2019, where they screened positive for chronic pain and completed a 3-question functional assessment with the PEG (Pain, Enjoyment of Life, General Activity). Multivariate logistic regressions quantified associations between pain frequency, diagnosis and treatment, sociodemographics, comorbidities, and self-reported severe pain impairment with pain diagnoses and treatment documented after screening. Results: Patients were mostly women (60.3%), Latinx (41.1%), English-speaking (80.1%), and Medicaid-insured (62.0%); they averaged 49.1 years old (SD = 13.7 years). Patients with severe pain impairment or who were Latinx were more likely to get a newly documented pain diagnosis (absolute risk difference ARD: 13.2% and 8.6%, ps < 0.0001), while patients with mental health/substance use or medical comorbidities were less likely (ARDs: -20.0% to -6.2%, ps < 0.001). Factors most consistently associated with treatment were prior treatment of the same modality (4 of 7 treatments, ARDs = 27.3% to 44.1%, ps <0.0001), new pain diagnosis (5 of 7, ARDs = 3.2% to 27.4%, ps <0.001), and severe impairment (4 of 7, ARDs = 2.6% to 6.5%, ps < 0.0001). A new diagnosis had the strongest association with non-opioid pain analgesics and physical medicine (ARD = 27.0% and 27.4%, p < 0.0001). Latinx patients were less likely to receive opioid analgesics and mental health/substance use medications and counseling (ARDs = -3.3% to 7.5%, ps <0.0001). Conclusion: Screening and assessment with patient-reported tools may influence pain care. Care for Latinx patients differed from non-Latinx white patients. Keywords: PEG, chronic pain, primary care, patient-reported outcome measures, federally qualified health center, equity
Riociguat in Patients with Symptomatic Pulmonary Hypertension associated with Idiopathic Interstitial Pneumonias (RISE-IIP), a randomized, controlled, phase 2b trial of riociguat for pulmonary ...hypertension associated with idiopathic interstitial pneumonia, was terminated early due to increased mortality in riociguat-treated patients. Baseline characteristics of enrolled patients demonstrated a low diffusing capacity of the lung for carbon monoxide (DLCO) with preserved lung volumes at baseline, suggesting the presence of combined pulmonary fibrosis and emphysema (CPFE) in some patients. This post hoc analysis of RISE-IIP was undertaken to explore lung morphology, assessed by high-resolution computed tomography, and associated clinical outcomes.
Available baseline/pre-baseline high-resolution computed tomography scans were reviewed centrally by 2 radiologists. The extent of emphysema and fibrosis was retrospectively scored and combined to provide the total CPFE score.
Data were available for 65/147 patients (44%), including 15/27 fatal cases (56%). Of these, 41/65 patients (63%) had CPFE. Mortality was higher in patients with CPFE (12/41; 29%) than those without (3/24; 13%). Fourteen patients with CPFE had emphysema > fibrosis (4 died). No relationship was observed between CPFE score, survival status, and treatment assignment. A low DLCO, short 6-min walking distance, and high forced vital capacity:DLCO ratio at baseline also appeared to be risk factors for mortality.
High parenchymal lung disease burden and the presence of more emphysema than fibrosis might have predisposed patients with pulmonary hypertension associated with idiopathic interstitial pneumonia to poor outcomes in RISE-IIP. Future studies of therapy for group 3 pulmonary hypertension should include centrally adjudicated imaging for morphologic phenotyping and disease burden evaluation during screening.
Aims
To compare glycaemic control, maternal and neonatal outcomes in pregnancies with Type 1 diabetes, managed either by continuous subcutaneous insulin infusion, multiple daily insulin injection or ...switch from multiple daily insulin injection (MDI) to continuous subcutaneous insulin infusion (CSII) in early pregnancy.
Research design and methods
Data from 339 singleton pregnancies were retrospectively reviewed. HbA1c values were measured preconception and in each trimester. In a secondary analysis, use of CSII pre‐pregnancy was compared with initiation of CSII during pregnancy.
Results
MDI was used in 140 pregnancies (41.3%) and CSII was used in 199 (58.7%), including 34 pregnancies (10.0%) during which the women switched to CSII. In pregnancies during which CSII was used duration of diabetes median (interquartile range) 16.0 (8.0–23.0) years vs 11.0 (5.5–17.5) years; P<0.001 was longer, and the Institute of Medicine recommendations for appropriate weight gain were exceeded more often (64.8% vs. 50.8%; P=0.01). CSII use and pre‐pregnancy BMI were independent predictors of excess weight gain. There was no difference in glucose control, but CSII was associated with higher birth weight median (interquartile range) 3720 (3365–4100) g vs 3360 (3365–4100) g; P<0.001 and higher large‐for‐gestational‐age (LGA) rate (44.7% vs. 33.6%; P=0.04) than MDI. HbA1c concentration in the third trimester and excess weight gain were predictive of LGA infants odds ratio 2.33 (95% CI 1.54–3.51); P<0.001 and 1.89 (95% CI 1.02–3.51); P=0.04. In pregnancies where CSII therapy was initiated in the first trimester and in those with pre‐pregnancy use, similar glucose control and outcome was achieved.
Conclusions
There was no advantage of CSII with respect to glycaemic control and neonatal outcomes. The rate of LGA neonates was higher in the CSII group, possibly mediated by excess maternal weight gain, which was more frequent than in women treated with MDI.
What's new?
The use of continuous subcutaneous insulin infusion (CSII) in pregnancies complicated by Type 1 diabetes is increasing but the benefits remain controversial.
Our study of 339 pregnancies demonstrated no advantage of CSII with regard to achievement of good glucose control and neonatal outcomes. Rates of large‐for‐gestational‐age neonates were higher with CSII use, potentially mediated by excess weight gain.
The high rates of excess weight gain in women using insulin pumps in pregnancy highlight the importance of intensified weight gain counselling.
When planning pregnancy, data do not support a switch to CSII in women who have adequate control with multiple daily insulin injections.
The cumulative burden of chronic health conditions as childhood cancer survivors transition to adult health care and insurance systems is unknown. We estimated the cumulative burden (N = 4612 ...survivors, 625 controls) in the St. Jude Lifetime Cohort. At 18 and 26 years old, survivors experienced (per 100 individuals) an average of 22.3 (95% confidence interval CI: 17.2–27.4) and 40.3 (95% CI: 34.8–45.8) disabling conditions versus 3.5 (95% CI: 2.0–5.0) and 5.7 (95% CI: 3.7–7.7) in controls, and 128.7 (95% CI: 119.5–137.8) and 240.5 (95% CI: 229.9–251.0) lower severity conditions versus 12.4 (95% CI: 8.9–16.0) and 51.3 (95% CI: 43.1–59.4) in controls. Survivors experience a high cumulative burden at key health care transition ages, underscoring the need to optimize access to care.
Introduction: Basal insulin is the first choice for geriatric persons with type 2 diabetes (T2D) who require insulin therapy. A digital workflow and decision support system (GlucoTab@MobileCare) with ...an integrated basal or basal-plus insulin algorithm has demonstrated to be an effective and safe treatment in geriatric persons with T2D receiving home health care during a three months study period. The aim of this study was to investigate the long-term effect on diabetes management following treatment by GlucoTab@MobileCare.
Methods: Diabetes related aspects (glycemic control, acute hospital admissions, general practitioner (GP) consultations under routine conditions) were assessed in nine patients (5 female, age 77±10 years, BMI 27.7±4.7 kg/m2, HbA1c 60±13 mmol/mol start of intervention vs. 57±12 mmol/mol end of intervention) during the three months study intervention, six months before (n=9) and six months after (n=8, due to the death of one patient) study intervention. Data from electronic health records and diabetes documentation were analyzed.
Results: Mean fasting blood glucose (BG) was 212±72 mg/dL before, 156±33 mg/dL during and 162±42 mg/dL after intervention. During the study, no acute hospital admissions due to BG derailments were observed. Eight derailments before and four derailments after intervention occurred. Causes for diabetes-related emergency department (ED) admissions were hyperglycemia (n=10), hypoglycemia (n=1) and undefined (n=1). Nine of the twelve admissions resulted in hospitalizations. GPs were consulted for diabetes management 19-times before and 16-times after GlucoTab@MobileCare treatment. Reasons for consultations were routine check-up (n=12), therapy adjustment (n=22) and HbA1c measurement (n=1).
Conclusion: A sustained effect on glycemic control with reduced requirements for hospital admissions was observed six months after GlucoTab@MobileCare treatment, whereas GP consultations were not affected.
Disclosure
J. Kopanz: None. T. Pieber: Advisory Panel; Self; ADOCIA, Arecor, AstraZeneca, Eli Lilly and Company, Novo Nordisk A/S, Sanofi, Research Support; Self; AstraZeneca, Novo Nordisk A/S. J. K. Mader: Advisory Panel; Self; Becton, Dickinson and Company, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic, Roche Diabetes Care, Speaker’s Bureau; Self; Abbott Diabetes, Novo Nordisk A/S, Roche Diabetes Care, Sanofi, Stock/Shareholder; Self; decide Clinical Software GmbH. L. K. Scholle: None. K. M. Lichtenegger: None. G. Ambrosch: None. A. Libiseller: None. F. Aberer: None. M. Pandis: None. K. Donsa: Stock/Shareholder; Self; decide Clinical Software GmbH. T. Truskaller: None.
•During visual naming, high-gamma modulation occurs in a posteroanterior sequential pattern with overlapping temporal profiles.•Cortical activations during visual naming represent cognitive ...sub-components with different relative contributions from the left and right cerebral hemispheres.•Post-surgical neuropsychological deficits correlated with the location of resected parcels within the visual naming network.
Cerebral spatiotemporal dynamics of visual naming were investigated in epilepsy patients undergoing stereo-electroencephalography (SEEG) monitoring.
Brain networks were defined by Parcel-Activation-Resection-Symptom matching (PARS) approach by matching high-gamma (50–150 Hz) modulations (HGM) in neuroanatomic parcels during visual naming, with neuropsychological outcomes after resection/ablation of those parcels. Brain parcels with >50% electrode contacts simultaneously showing significant HGM were aligned, to delineate spatiotemporal course of naming-related HGM.
In 41 epilepsy patients, neuroanatomic parcels showed sequential yet temporally overlapping HGM course during visual naming. From bilateral occipital lobes, HGM became increasingly left lateralized, coursing through limbic system. Bilateral superior temporal HGM was noted around response time, and right frontal HGM thereafter. Correlations between resected/ablated parcels, and post-surgical neuropsychological outcomes showed specific regional groupings.
Convergence of data from spatiotemporal course of HGM during visual naming, and functional role of specific parcels inferred from neuropsychological deficits after resection/ablation of those parcels, support a model with six cognitive subcomponents of visual naming having overlapping temporal profiles.
Cerebral substrates supporting visual naming are bilaterally distributed with relative hemispheric contribution dependent on cognitive demands at a specific time. PARS approach can be extended to study other cognitive and functional brain networks.
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