Twice-Yearly Depemokimab in Severe Asthma with an Eosinophilic Phenotype.

BACKGROUND: Depemokimab is an ultra-long-acting biologic therapy with enhanced binding affinity for interleukin-5 that may enable effective 6-month dosing intervals. METHODS: In these phase 3A, randomized, placebo-controlled replicate trials, we evaluated the efficacy and safety of depemokimab in patients with severe asthma and an eosinophilic phenotype characterized by a high eosinophil count (≥300 cells per microliter in the previous 12 months or ≥150 cells per microliter at screening) and a history of exacerbations despite the receipt of medium- or high-dose inhaled glucocorticoids. Patients were randomly assigned in a 2:1 ratio to receive either depemokimab (at a dose of 100 mg subcutaneously) or placebo at weeks 0 and 26, plus standard care. The primary end point was the annualized rate of exacerbations at 52 weeks. Secondary end points, which were analyzed in a hierarchical manner to adjust for multiplicity, included the change from baseline in the score on the St. George's Respiratory Questionnaire (SGRQ), the forced expiratory volume in 1 second, and asthma symptom reports at 52 weeks. RESULTS: Across the two trials, 792 patients underwent randomization and 762 were included in the full analysis; 502 were assigned to receive depemokimab and 260 to receive placebo. The annualized rate of exacerbations was 0.46 (95% confidence interval [CI]), 0.36 to 0.58) with depemokimab and 1.11 (95% CI, 0.86 to 1.43) with placebo (rate ratio, 0.42; 95% CI, 0.30 to 0.59; P<0.001) in SWIFT-1 and 0.56 (95% CI, 0.44 to 0.70) with depemokimab and 1.08 (95% CI, 0.83 to 1.41) with placebo (rate ratio, 0.52; 95% CI, 0.36 to 0.73; P<0.001) in SWIFT-2. No significant between-group difference in the change from baseline in the SGRQ score was observed in either trial, so no statistical inference was drawn on subsequent secondary end points. The proportion of patients with any adverse event was similar in the two groups in both trials. CONCLUSIONS: Depemokimab reduced the annualized rate of exacerbations among patients with severe asthma with an eosinophilic phenotype. (Funded by GSK; SWIFT-1 and SWIFT-2 ClinicalTrials.gov numbers, NCT04719832 and NCT04718103.).

Inactivation of ERK1/2 Signaling in Dopaminergic Neurons by Map Kinase Phosphatase MKP3 Regulates Dopamine Signaling and Motivation for Cocaine.

The mesolimbic dopamine system is a crucial component of reward and reinforcement processing, including the psychotropic effects of drugs of abuse such as cocaine. Drugs of abuse can activate intracellular signaling cascades that engender long-term molecular changes to brain reward circuitry, which can promote further drug use. However, gaps remain about how the activity of these signaling pathways, such as ERK1/2 signaling, can affect cocaine-induced neurochemical plasticity and cocaine-associated behaviors specifically within dopaminergic cells. To enable specific modulation of ERK1/2 signaling in dopaminergic neurons of the ventral tegmental area, we utilize a viral construct that Cre dependently expresses Map kinase phosphatase 3 (MKP3) to reduce the activity of ERK1/2, in combination with transgenic rats that express Cre in tyrosine hydroxylase (TH)-positive cells. Following viral transfection, we found an increase in the surface expression of the dopamine transporter (DAT), a protein associated with the regulation of dopamine signaling, dopamine transmission, and cocaine-associated behavior. We found that inactivation of ERK1/2 reduced post-translational phosphorylation of the DAT, attenuated the ability of cocaine to inhibit the DAT, and decreased motivation for cocaine without affecting associative learning as tested by conditioned place preference. Together, these results indicate that ERK1/2 signaling plays a critical role in shaping the dopamine response to cocaine and may provide additional insights into the function of dopaminergic neurons. Further, these findings lay important groundwork toward the assessment of how signaling pathways and their downstream effectors influence dopamine transmission and could ultimately provide therapeutic targets for treating cocaine use disorders.

Epigenetic and transcriptional dysregulation in CD4+ T cells in patients with atopic dermatitis.

Atopic dermatitis (AD) is one of the most common skin disorders among children. Disease etiology involves genetic and environmental factors, with 29 independent AD risk loci enriched for risk allele-dependent gene expression in the skin and CD4+ T cell compartments. We investigated the potential epigenetic mechanisms responsible for the genetic susceptibility of CD4+ T cells. To understand the differences in gene regulatory activity in peripheral blood T cells in AD, we measured chromatin accessibility (an assay based on transposase-accessible chromatin sequencing, ATAC-seq), nuclear factor kappa B subunit 1 (NFKB1) binding (chromatin immunoprecipitation with sequencing, ChIP-seq), and gene expression levels (RNA-seq) in stimulated CD4+ T cells from subjects with active moderate-to-severe AD, as well as in age-matched non-allergic controls. Open chromatin regions in stimulated CD4+ T cells were highly enriched for AD genetic risk variants, with almost half of the AD risk loci overlapping AD-dependent ATAC-seq peaks. AD-specific open chromatin regions were strongly enriched for NF-κB DNA-binding motifs. ChIP-seq identified hundreds of NFKB1-occupied genomic loci that were AD- or control-specific. As expected, the AD-specific ChIP-seq peaks were strongly enriched for NF-κB DNA-binding motifs. Surprisingly, control-specific NFKB1 ChIP-seq peaks were not enriched for NFKB1 motifs, but instead contained motifs for other classes of human transcription factors, suggesting a mechanism involving altered indirect NFKB1 binding. Using DNA sequencing data, we identified 63 instances of altered genotype-dependent chromatin accessibility at 36 AD risk variant loci (30% of AD risk loci) that might lead to genotype-dependent gene expression. Based on these findings, we propose that CD4+ T cells respond to stimulation in an AD-specific manner, resulting in disease- and genotype-dependent chromatin accessibility alterations involving NFKB1 binding.

Safety and Immunogenicity of a Delayed Heterologous Avian Influenza A(H7N9) Vaccine Boost Following Different Priming Regimens: A Randomized Clinical Trial.

BACKGROUND: Influenza A (H7N9) has caused multiple disease waves with evidence of strain diversification. Optimal influenza A (H7N9) prime-boost vaccine strategies are unknown. METHODS: We recruited participants who had received monovalent inactivated A/Shanghai/2/2013 (H7N9) vaccine (MIV) approximately 5 years earlier, as follows: MIV with MF59 (MF59 × 2 group), MIV with AS03 (AS03 × 2 group), unadjuvanted MIV (No Adj group), MIV with MF59 or AS03 followed by unadjuvanted MIV (Adjx1 group), and A/H7-naive (unprimed group). Participants were randomized to receive 1 dose of AS03-adjuvanted or unadjuvanted A/Hong Kong/125/2017 (H7N9) MIV and were followed for safety and immunogenicity using hemagglutination inhibition (HAI) and neutralizing antibody assays. RESULTS: We enrolled 304 participants: 153 received the adjuvanted boost and 151 received the unadjuvanted boost. At 21 days postvaccination, the proportion of participants with HAI antibody titers against the boosting vaccine strain of ≥40 in the adjuvanted and unadjuvanted arms, respectively, were 88% and 49% in MF59 × 2 group, 89% and 75% in AS03 × 2 group, 59% and 20% in No Adj group, 94% and 55% in Adjx1group, and 9% and 11% in unprimed group. CONCLUSIONS: Serologic responses to a heterologous A(H7N9) MIV boost were highest in participants primed and boosted with adjuvant-containing regimens. CLINICAL TRIALS REGISTRATION: NCT03738241.

Human Cytomegalovirus mRNA-1647 Vaccine Candidate Elicits Potent and Broad Neutralization and Higher Antibody-Dependent Cellular Cytotoxicity Responses Than the gB/MF59 Vaccine.

BACKGROUND: MF59-adjuvanted gB subunit (gB/MF59) vaccine demonstrated approximately 50% efficacy against human cytomegalovirus (HCMV) acquisition in multiple clinical trials, suggesting that efforts to improve this vaccine design might yield a vaccine suitable for licensure. METHODS: A messenger RNA (mRNA)-based vaccine candidate encoding HCMV gB and pentameric complex (PC), mRNA-1647, is currently in late-stage efficacy trials. However, its immunogenicity has not been compared to the partially effective gB/MF59 vaccine. We assessed neutralizing and Fc-mediated immunoglobulin G (IgG) effector antibody responses induced by mRNA-1647 in both HCMV-seropositive and -seronegative vaccinees from a first-in-human clinical trial through 1 year following third vaccination using a systems serology approach. Furthermore, we compared peak anti-gB antibody responses in seronegative mRNA-1647 vaccinees to that of seronegative gB/MF59 vaccine recipients. RESULTS: mRNA-1647 vaccination elicited and boosted HCMV-specific IgG responses in seronegative and seropositive vaccinees, respectively, including neutralizing and Fc-mediated effector antibody responses. gB-specific IgG responses were lower than PC-specific IgG responses. gB-specific IgG and antibody-dependent cellular phagocytosis responses were lower than those elicited by gB/MF59. However, mRNA-1647 elicited higher neutralization and antibody-dependent cellular cytotoxicity (ADCC) responses. CONCLUSIONS: Overall, mRNA-1647 vaccination induced polyfunctional and durable HCMV-specific antibody responses, with lower gB-specific IgG responses but higher neutralization and ADCC responses compared to the gB/MF59 vaccine. CLINICAL TRIALS REGISTRATION: NCT03382405 (mRNA-1647) and NCT00133497 (gB/MF59).

Evaluating E. coli genome-scale metabolic model accuracy with high-throughput mutant fitness data.

The Escherichia coli genome-scale metabolic model (GEM) is an exemplar systems biology model for the simulation of cellular metabolism. Experimental validation of model predictions is essential to pinpoint uncertainty and ensure continued development of accurate models. Here, we quantified the accuracy of four subsequent E. coli GEMs using published mutant fitness data across thousands of genes and 25 different carbon sources. This evaluation demonstrated the utility of the area under a precision-recall curve relative to alternative accuracy metrics. An analysis of errors in the latest (iML1515) model identified several vitamins/cofactors that are likely available to mutants despite being absent from the experimental growth medium and highlighted isoenzyme gene-protein-reaction mapping as a key source of inaccurate predictions. A machine learning approach further identified metabolic fluxes through hydrogen ion exchange and specific central metabolism branch points as important determinants of model accuracy. This work outlines improved practices for the assessment of GEM accuracy with high-throughput mutant fitness data and highlights promising areas for future model refinement in E. coli and beyond.

Are Commonly Used Geographically Based Social Determinant of Health Indices in Orthopaedic Surgery Research Correlated With Each Other and With PROMIS Global-10 Physical and Mental Health Scores?

BACKGROUND: Geographically based social determinants of health (SDoH) measures are useful in research and policy aimed at addressing health disparities. In the United States, the Area Deprivation Index (ADI), Neighborhood Stress Score (NSS), and Social Vulnerability Index (SVI) are frequently used, but often without a clear reason as to why one is chosen over another. There is limited evidence about how strongly correlated these geographically based SDoH measures are with one another. Further, there is a paucity of research examining their relationship with patient-reported outcome measures (PROMs) in orthopaedic patients. Such insights are important in order to determine whether comparisons of policies and care programs using different geographically based SDoH indices to address health disparities in orthopaedic surgery are appropriate. QUESTIONS/PURPOSES: Among new patients seeking care at an orthopaedic surgery clinic, (1) what is the correlation of the NSS, ADI, and SVI with one another? (2) What is the correlation of Patient-Reported Outcomes Measurement Information System (PROMIS) Global-10 physical and mental health scores and the NSS, ADI, and SVI? (3) Which geographically based SDoH index or indices are associated with presenting PROMIS Global-10 physical and mental health scores when accounting for common patient-level sociodemographic factors? METHODS: New adult orthopaedic patient encounters at clinic sites affiliated with a tertiary referral academic medical center between 2016 and 2021 were identified, and the ADI, NSS, and SVI were determined. Patients also completed the PROMIS Global-10 questionnaire as part of routine care. Overall, a total of 75,335 new patient visits were noted. Of these, 62% (46,966 of 75,335) of new patient visits were excluded because of missing PROMIS Global-10 physical and mental health scores. An additional 2.2% of patients (1685 of 75,335) were excluded because they were missing at least one SDoH index at the time of their visit (for example, if a patient only had a Post Office box listed, the SDoH index could not be determined). This left 35% of the eligible new patient visits (26,684 of 75,335) in our final sample. Though only 35% of possible new patient visits were included, the diversity of these individuals across numerous characteristics and the wide range of sociodemographic status-as measured by the SDoH indices-among included patients supports the generalizability of our sample. The mean age of patients in our sample was 55 ± 18 years and a slight majority were women (54% [14,366 of 26,684]). Among the sample, 16% (4381of 26,684) of patients were of non-White race. The mean PROMIS Global-10 physical and mental health scores were 43.4 ± 9.4 and 49.7 ± 10.1, respectively. Spearman correlation coefficients were calculated among the three SDoH indices and between each SDoH index and PROMIS Global-10 physical and mental health scores. In addition, regression analysis was used to assess the association of each SDoH index with presenting functional and mental health, accounting for key patient characteristics. The strength of the association between each SDoH index and PROMIS Global-10 physical and mental health scores was determined using partial r-squared values. Significance was set at p < 0.05. RESULTS: There was a poor correlation between the ADI and the NSS (ρ = 0.34; p < 0.001). There were good correlations between the ADI and SVI (ρ = 0.43; p < 0.001) and between the NSS and SVI (ρ = 0.59; p < 0.001). There was a poor correlation between the PROMIS Global-10 physical health and NSS (ρ = -0.14; p < 0.001), ADI (ρ = -0.24; p < 0.001), and SVI (ρ = -0.17; p < 0.001). There was a poor correlation between PROMIS Global-10 mental health and NSS (ρ = -0.13; p < 0.001), ADI (ρ = -0.22; p < 0.001), and SVI (ρ = -0.17; p < 0.001). When accounting for key sociodemographic factors, the ADI demonstrated the largest association with presenting physical health (regression coefficient: -0.13 [95% CI -0.14 to -0.12]; p < 0.001) and mental health (regression coefficient: -0.13 [95% CI -0.14 to -0.12]; p < 0.001), as confirmed by the partial r-squared values for each SDoH index (physical health: ADI 0.04 versus SVI 0.02 versus NSS 0.01; mental health: ADI 0.04 versus SVI 0.02 versus NSS 0.01). This finding means that as social deprivation increases, physical and mental health scores decrease, representing poorer health. For further context, an increase in ADI score by approximately 36 and 39 suggests a clinically meaningful (determined using distribution-based minimum clinically important difference estimates of one-half SD of each PROMIS score) worsening of physical and mental health, respectively. CONCLUSION: Orthopaedic surgeons, policy makers, and other stakeholders looking to address SDoH factors to help alleviate disparities in musculoskeletal care should try to avoid interchanging the ADI, SVI, and NSS. Because the ADI has the largest association between any of the geographically based SDoH indices and presenting physical and mental health, it may allow for easier clinical and policy application. CLINICAL RELEVANCE: We suggest using the ADI as the geographically based SDoH index in orthopaedic surgery in the United States. Further, we caution against comparing findings in one study that use one geographically based SDoH index to another study's findings that incorporates another geographically based SDoH index. Although the general findings may be the same, the strength of association and clinical relevance could differ and have policy ramifications that are not otherwise appreciated; however, the degree to which this may be true is an area for future inquiry.

Sublingual immunotherapy tablets in monosensitized and polysensitized adults with allergic rhinoconjunctivitis.

Background: Most patients with allergic rhinitis/conjunctivitis (AR/C) are sensitized to more than one allergen. An ongoing question is the efficacy of single-allergen immunotherapy in patients who are polysensitized. Objective: To evaluate the efficacy and safety of grass, ragweed, tree, and house-dust mite (HDM) sublingual immunotherapy (SLIT) tablets in adults with AR/C who are mono- or polysensitized. Methods: Data from adults (ages ≥ 18 years) with AR/C who participated in phase III double-blind, placebo controlled field trials (four grass, two ragweed, two HDM, one tree) were included in the post hoc analyses. Efficacy was assessed by the total combined score (TCS) (sum of AR/C daily symptom and medication scores) during the entire pollen season for grass and tree trials, and peak pollen season for ragweed trials versus placebo. Efficacy for the HDM SLIT-tablet was assessed by the total combined rhinitis score (TCRS) (sum of rhinitis daily symptom and medication scores) during the last 8 weeks of treatment versus placebo. Results: For the grass SLIT-tablet, TCS improved by 20% (mean difference 1.33 [95% confidence interval {CI}, 0.44-2.22]) in the subjects who were monosensitized (n = 442) and 20% (mean difference 1.28 [95% CI, 0.90-1.67]) in the subjects who were polysensitized (n = 1857). For the ragweed SLIT-tablet, TCS improved by 19% (mean difference 1.72 [95% CI, -0.20 to 3.63]) in the subjects who were monosensitized (n = 115) and 27% (mean difference 2.27 [95% CI, 1.28-3.27]) in the subjects who were polysensitized (n = 528). For the tree SLIT-tablet, TCS improved by 54% (mean difference 4.65 [95% CI, 2.48-6.82]) in the subjects who were monosensitized (n = 138) and 34% (mean difference 2.51 [95% CI, 1.34-3.69]) in the subjects who were polysensitized (n = 437). For the HDM SLIT-tablet, TCRS improved by 20% (mean difference 1.24 [95% CI, 0.48-1.99]) in the subjects who were monosensitized (n = 468) and 17% (mean difference 0.85 [95% CI, 0.43-1.28]) in the subjects who were polysensitized (n = 1294). The overall safety profile was not qualitatively different between the subjects who were monosensitized and the subjects who were polysensitized. Conclusion: Grass, ragweed, tree, or HDM SLIT-tablet treatment is effective for the specific allergen in question in adults with AR/C and who are monosensitized or polysensitized. Targeting one relevant allergen with SLIT-tablets induces a clinical effect for that allergen in patients who were polysensitized.

Consistent efficacy and safety of sublingual immunotherapy tablets across allergens and geographic regions.

Background: The clinical development program of the SQ grass, ragweed, tree, and house dust mite (HDM) sublingual immunotherapy (SLIT)-tablets for allergic rhinitis/conjunctivitis (AR/C) included clinical trials conducted in North America, Europe, and Japan. Objective: Data from these trials were analyzed to assess efficacy, immunologic mechanisms, and safety outcomes across allergens and geographic regions. Methods: Thirteen phase III, double-blind, placebo controlled trials in the subjects with AR/C were conducted in North America, Europe (including Russia), and Japan (N = 7763 analyzed). Trials were generally similar with respect to medical practice, target population, eligibility criteria, and efficacy and safety monitoring. Data were analyzed for the approved doses in North America and Europe. Four statistical models were used to enhance comparison of the efficacy end points among the trials. Results: The SLIT-tablets demonstrated consistent efficacy across allergens and regions, regardless of the statistical analysis used. Relative improvement in the primary efficacy end point compared with placebo by using the predefined protocol analysis ranged from 17.9% to 32.8%, 17.5% to 19.3%, 20.6% to 38.3%, and 39.6% with the grass, HDM, ragweed, and tree SLIT-tablets, respectively. The kinetics of specific immunoglobulin E (IgE) and IgG4 responses were similar among the allergens and regions. Local application-site reactions were the most common adverse events for all allergens and in all regions. Most treatment-related adverse events for all allergens and in all regions were mild in severity. The rate of systemic allergic reactions was similar across regions (0%-0.54%). Conclusion: Confirmatory phase III trials for SLIT-tablets in the treatment of AR/C showed consistent efficacy, immunologic, and safety outcomes across allergens and geographic regions.

A Multicenter, Controlled Human Infection Study of Influenza A(H1N1)pdm09 in Healthy Adults.

BACKGROUND: We evaluated the associations between baseline influenza virus-specific hemagglutination inhibition (HAI) and microneutralization (MN) titers and subsequent symptomatic influenza virus infection in a controlled human infection study. METHODS: We inoculated unvaccinated healthy adults aged 18-49 years with an influenza A/California/04/2009/H1N1pdm-like virus (NCT04044352). We collected serial safety labs, serum for HAI and MN, and nasopharyngeal swabs for reverse-transcription polymerase chain reaction (RT-PCR) testing. Analyses used the putative seroprotective titer of ≥40 for HAI and MN. The primary clinical outcome was mild-to-moderate influenza disease (MMID), defined as ≥1 postchallenge positive qualitative RT-PCR test with a qualifying symptom/clinical finding. RESULTS: Of 76 participants given influenza virus challenge, 54 (71.1%) experienced MMID. Clinical illness was generally very mild. MMID attack rates among participants with baseline titers ≥40 by HAI and MN were 64.9% and 67.9%, respectively, while MMID attack rates among participants with baseline titers <40 by HAI and MN were 76.9% and 78.3%, respectively. The estimated odds of developing MMID decreased by 19% (odds ratio, 0.81 [95% confidence interval, .62-1.06]; P = .126) for every 2-fold increase in baseline HAI. There were no significant adverse events. CONCLUSIONS: We achieved a 71.1% attack rate of MMID. High baseline HAI and MN were associated with protection from illness. Clinical Trials Registration. NCT04044352.

Safety and Immunogenicity of a monovalent inactivated influenza A/H5N8 virus vaccine given with and without AS03 or MF59 adjuvants in healthy adults.

BACKGROUND: Avian influenza A/H5N8 virus infections have been circulating widely in wild and domestic bird populations with transmission to a few human poultry workers. This phase 1, randomized, blinded trial evaluated the safety and immunogenicity of a monovalent inactivated influenza A/H5N8 virus vaccine (H5N8 IIV) given with and without AS03 or MF59 adjuvants. METHODS: 275 healthy adults, ages 19-64 years, were randomized to one of five groups to receive two doses of 15 µg unadjuvanted influenza A/gyrfalcon/Washington/41088-6/2014(H5N8) (clade 2.3.4.4c) virus vaccine or two doses of 7.5 or 15 µg of vaccine adjuvanted with AS03 or MF59. Immunogenicity was assessed through 21 days following the second dose of vaccine using hemagglutination inhibition (HAI) and microneutralization (MN) assays for the homologous influenza A/H5N8 and three heterologous influenza A/H5 viruses. Safety was assessed through 1 year. RESULTS: The vaccines were well tolerated. Only modest immune responses were seen following receipt of a single dose of vaccine. Seroprotection (HAI titers ≥40) was more common in groups that received AS03 plus 7.5 or 15 µg of vaccine (89% and 93%, respectively) compared to the MF59-adjuvanted groups (56% and 73%), while unadjuvanted vaccine showed a poor response (27%). Higher antigen content resulted in modestly improved immune responses. HAI and MN GMTs and seroconversion rates were low across all study groups for all three heterologous strains of influenza A/H5 virus. CONCLUSIONS: AS03 or MF59-adjuvanted H5N8 IIV generated strong immunogenic responses following two doses. There was poor cross-reactivity for the three antigenically drifted H5N1 strains tested.

Schema therapy for violent PD offenders: a randomized clinical trial.

BACKGROUND: Violent criminal offenders with personality disorders (PD's) can cause immense harm, but are often deemed untreatable. This study aimed to conduct a randomized clinical trial to test the effectiveness of long-term psychotherapy for rehabilitating offenders with PDs. METHODS: We compared schema therapy (ST), an evidence-based psychotherapy for PDs, to treatment-as-usual (TAU) at eight high-security forensic hospitals in the Netherlands. Patients in both conditions received multiple treatment modalities and differed only in the individual, study-specific therapy they received. One-hundred-three male offenders with antisocial, narcissistic, borderline, or paranoid PDs, or Cluster B PD-not-otherwise-specified, were assigned to 3 years of ST or TAU and assessed every 6 months. Primary outcomes were rehabilitation, involving gradual reintegration into the community, and PD symptoms. RESULTS: Patients in both conditions showed moderate to large improvements in outcomes. ST was superior to TAU on both primary outcomes - rehabilitation (i.e. attaining supervised and unsupervised leave) and PD symptoms - and six of nine secondary outcomes, with small to moderate advantages over TAU. ST patients moved more rapidly through rehabilitation (supervised leave, treatment*time: F(5308) = 9.40, p < 0.001; unsupervised leave, treatment*time: F(5472) = 3.45, p = 0.004), and showed faster improvements on PD scales (treatment*time: t(1387) = -2.85, p = 0.005). CONCLUSIONS: These findings contradict pessimistic views on the treatability of violent offenders with PDs, and support the effectiveness of long-term psychotherapy for rehabilitating these patients, facilitating their re-entry into the community.

Impaired reciprocal regulation between SIRT6 and TGF-ß signaling in fatty liver.

Dysregulated transforming growth factor-beta (TGF-ß) signaling contributes to fibrotic liver disease and hepatocellular cancer (HCC), both of which are associated with fatty liver disease. SIRT6 limits fibrosis by inhibiting TGF-ß signaling through deacetylating SMAD2 and SMAD3 and limits lipogenesis by inhibiting SREBP1 and SREBP2 activity. Here, we showed that, compared to wild-type mice, high-fat diet-induced fatty liver is worse in TGF-ß signaling-deficient mice (SPTBN1+/- ) and the mutant mice had reduced SIRT6 abundance in the liver. Therefore, we hypothesized that altered reciprocal regulation between TGF-ß signaling and SIRT6 contributes to these liver pathologies. We found that deficiency in SMAD3 or SPTBN1 reduced SIRT6 mRNA and protein abundance and impaired TGF-ß induction of SIRT6 transcripts, and that SMAD3 bound to the SIRT6 promoter, suggesting that an SMAD3-SPTBN1 pathway mediated the induction of SIRT6 in response to TGF-ß. Overexpression of SIRT6 in HCC cells reduced the expression of TGF-ß-induced genes, consistent with the suppressive role of SIRT6 on TGF-ß signaling. Manipulation of SIRT6 abundance in HCC cells altered sterol regulatory element-binding protein (SREBP) activity and overexpression of SIRT6 reduced the amount of acetylated SPTBN1 and the abundance of both SMAD3 and SPTBN1. Furthermore, induction of SREBP target genes in response to SIRT6 overexpression was impaired in SPTBN1 heterozygous cells. Thus, we identified a regulatory loop between SIRT6 and SPTBN1 that represents a potential mechanism for susceptibility to fatty liver in the presence of dysfunctional TGF-ß signaling.

NPP-669, a Novel Broad-Spectrum Antiviral Therapeutic with Excellent Cellular Uptake, Antiviral Potency, Oral Bioavailability, Preclinical Efficacy, and a Promising Safety Margin.

DNA viruses are responsible for many diseases in humans. Current treatments are often limited by toxicity, as in the case of cidofovir (CDV, Vistide), a compound used against cytomegalovirus (CMV) and adenovirus (AdV) infections. CDV is a polar molecule with poor bioavailability, and its overall clinical utility is limited by the high occurrence of acute nephrotoxicity. To circumvent these disadvantages, we designed nine CDV prodrug analogues. The prodrugs modulate the polarity of CDV with a long sulfonyl alkyl chain attached to one of the phosphono oxygens. We added capping groups to the end of the alkyl chain to minimize ß-oxidation and focus the metabolism on the phosphoester hydrolysis, thereby tuning the rate of this reaction by altering the alkyl chain length. With these modifications, the prodrugs have excellent aqueous solubility, optimized metabolic stability, increased cellular permeability, and rapid intracellular conversion to the pharmacologically active diphosphate form (CDV-PP). The prodrugs exhibited significantly enhanced antiviral potency against a wide range of DNA viruses in infected human foreskin fibroblasts. Single-dose intravenous and oral pharmacokinetic experiments showed that the compounds maintained plasma and target tissue levels of CDV well above the EC50 for 24 h. These experiments identified a novel lead candidate, NPP-669. NPP-669 demonstrated efficacy against CMV infections in mice and AdV infections in hamsters following oral (p.o.) dosing at a dose of 1 mg/kg BID and 0.1 mg/kg QD, respectively. We further showed that NPP-669 at 30 mg/kg QD did not exhibit histological signs of toxicity in mice or hamsters. These data suggest that NPP-669 is a promising lead candidate for a broad-spectrum antiviral compound.

House dust mite sublingual immunotherapy tablet safety in adolescents with allergic rhinoconjunctivitis: Worldwide clinical trial results.

BACKGROUND: The house dust mite (HDM) sublingual immunotherapy (SLIT)-tablet is a treatment option for allergic rhinitis with/without conjunctivitis (AR/C) approved in adults worldwide and in adolescents in some countries. OBJECTIVE: To supplement existing adolescent HDM SLIT-tablet safety data by conducting the MT-18 trial in adolescents. METHODS: MT-18 (EudraCT:2020-000446-34) was a phase 3, open-label, single-arm, 28-day safety trial of daily HDM SLIT-tablet (12 SQ-HDM dose) in European adolescents (12-17 years) with HDM AR/C, with or without asthma. The primary end point was at least 1 treatment-emergent adverse event (TEAE). MT-18 results were compared with 12 SQ-HDM adolescent subpopulation data from previously described 1-year phase 3 trials conducted in North America (P001; clinicaltrials.gov:NCT01700192) or Japan (TO-203-3-2; JapicCTI:121848). RESULTS: No treatment-related anaphylaxis, epinephrine administrations, severe local swellings, severe mouth or throat edema, or eosinophilic esophagitis occurred in the trials. For MT-18 (N = 253), P001 (N adolescents = 189), and TO-203-3-2 (N adolescents = 206), the percentage of adolescents treated with 12 SQ-HDM reporting any TEAE was 88%, 95%, and 93%, respectively, and the percentage reporting any treatment-related AE (TRAE) was 86%, 93%, and 66%, respectively. The most common TRAEs were local application site reactions. Most TRAEs were mild in intensity and were typically experienced the first 1 to 2 days of treatment. There were no asthma-related TEAEs with the HDM SLIT-tablet. The safety profile appears similar between adolescents with or without asthma at baseline. CONCLUSION: The HDM SLIT-tablet was well tolerated in European, North American, and Japanese adolescents with HDM AR/C, indicating safety of the HDM SLIT-tablet is insensitive to age or geographic region. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: (P001: NCT01700192); EudraCT: (MT-18; 2020-000446-34); JapicCTI: (TO-203-3-2; 121848).

Non-asbestiform elongate mineral particles and mesothelioma risk: Human and experimental evidence.

The presentations in this session of the Monticello II conference were aimed at summarizing what is known about asbestiform and non-asbestiform elongate mineral particles (EMPs) and mesothelioma risks based on evidence from experimental and epidemiology studies. Dr. Case discussed case reports of mesothelioma over the last several decades. Dr. Taioli indicated that the epidemiology evidence concerning non-asbestiform EMPs is weak or lacking, and that progress would be limited unless mesothelioma registries are established. One exception discussed is that of taconite miners, who are exposed to grunerite. Drs. Mandel and Odo noted that studies of taconite miners in Minnesota have revealed an excess rate of mesothelioma, but the role of non-asbestiform EMPs in this excess incidence of mesothelioma is unclear. Dr. Becich discussed the National Mesothelioma Virtual Bank (NMVB), a virtual mesothelioma patient registry that includes mesothelioma patients' lifetime work histories, exposure histories, biospecimens, proteogenomic information, and imaging data that can be used in epidemiology research on mesothelioma. Dr. Bernstein indicated that there is a strong consensus that long, highly durable respirable asbestiform EMPs have the potential to cause mesothelioma, but there is continued debate concerning the biodurability required, and the dimensions (both length and diameter), the shape, and the dose associated with mesothelioma risk. Finally, Dr. Nel discussed how experimental studies of High Aspect Ratio Engineered Nanomaterials have clarified dimensional and durability features that impact disease risk, the impact of inflammation and oxidative stress on the epigenetic regulation of tumor suppressor genes, and the generation of immune suppressive effects in the mesothelioma tumor microenvironment. The session ended with a discussion of future research needs.

Are Detailed, Patient-level Social Determinant of Health Factors Associated With Physical Function and Mental Health at Presentation Among New Patients With Orthopaedic Conditions?

BACKGROUND: It is well documented that routinely collected patient sociodemographic characteristics (such as race and insurance type) and geography-based social determinants of health (SDoH) measures (for example, the Area Deprivation Index) are associated with health disparities, including symptom severity at presentation. However, the association of patient-level SDoH factors (such as housing status) on musculoskeletal health disparities is not as well documented. Such insight might help with the development of more-targeted interventions to help address health disparities in orthopaedic surgery. QUESTIONS/PURPOSES: (1) What percentage of patients presenting for new patient visits in an orthopaedic surgery clinic who were unemployed but seeking work reported transportation issues that could limit their ability to attend a medical appointment or acquire medications, reported trouble paying for medications, and/or had no current housing? (2) Accounting for traditional sociodemographic factors and patient-level SDoH measures, what factors are associated with poorer patient-reported outcome physical health scores at presentation? (3) Accounting for traditional sociodemographic factor patient-level SDoH measures, what factors are associated with poorer patient-reported outcome mental health scores at presentation? METHODS: New patient encounters at one Level 1 trauma center clinic visit from March 2018 to December 2020 were identified. Included patients had to meet two criteria: they had completed the Patient-Reported Outcome Measure Information System (PROMIS) Global-10 at their new orthopaedic surgery clinic encounter as part of routine clinical care, and they had visited their primary care physician and completed a series of specific SDoH questions. The SDoH questionnaire was developed in our institution to improve data that drive interventions to address health disparities as part of our accountable care organization work. Over the study period, the SDoH questionnaire was only distributed at primary care provider visits. The SDoH questions focused on transportation, housing, employment, and ability to pay for medications. Because we do not have a way to determine how many patients had both primary care provider office visits and new orthopaedic surgery clinic visits over the study period, we were unable to determine how many patients could have been included; however, 9057 patients were evaluated in this cross-sectional study. The mean age was 61 ± 15 years, and most patients self-reported being of White race (83% [7561 of 9057]). Approximately half the patient sample had commercial insurance (46% [4167 of 9057]). To get a better sense of how this study cohort compared with the overall patient population seen at the participating center during the time in question, we reviewed all new patient clinic encounters (n = 135,223). The demographic information between the full patient sample and our study subgroup appeared similar. Using our study cohort, two multivariable linear regression models were created to determine which traditional metrics (for example, self-reported race or insurance type) and patient-specific SDoH factors (for example, lack of reliable transportation) were associated with worse physical and mental health symptoms (that is, lower PROMIS scores) at new patient encounters. The variance inflation factor was used to assess for multicollinearity. For all analyses, p values < 0.05 designated statistical significance. The concept of minimum clinically important difference (MCID) was used to assess clinical importance. Regression coefficients represent the projected change in PROMIS physical or mental health symptom scores (that is, the dependent variable in our regression analyses) accounting for the other included variables. Thus, a regression coefficient for a given variable at or above a known MCID value suggests a clinical difference between those patients with and without the presence of that given characteristic. In this manuscript, regression coefficients at or above 4.2 (or at and below -4.2) for PROMIS Global Physical Health and at or above 5.1 (or at and below -5.1) for PROMIS Global Mental Health were considered clinically relevant. RESULTS: Among the included patients, 8% (685 of 9057) were unemployed but seeking work, 4% (399 of 9057) reported transportation issues that could limit their ability to attend a medical appointment or acquire medications, 4% (328 of 9057) reported trouble paying for medications, and 2% (181 of 9057) had no current housing. Lack of reliable transportation to attend doctor visits or pick up medications (ß = -4.52 [95% CI -5.45 to -3.59]; p < 0.001), trouble paying for medications (ß = -4.55 [95% CI -5.55 to -3.54]; p < 0.001), Medicaid insurance (ß = -5.81 [95% CI -6.41 to -5.20]; p < 0.001), and workers compensation insurance (ß = -5.99 [95% CI -7.65 to -4.34]; p < 0.001) were associated with clinically worse function at presentation. Trouble paying for medications (ß = -6.01 [95% CI -7.10 to -4.92]; p < 0.001), Medicaid insurance (ß = -5.35 [95% CI -6.00 to -4.69]; p < 0.001), and workers compensation (ß = -6.07 [95% CI -7.86 to -4.28]; p < 0.001) were associated with clinically worse mental health at presentation. CONCLUSION: Although transportation issues and financial hardship were found to be associated with worse presenting physical function and mental health, Medicaid and workers compensation insurance remained associated with worse presenting physical function and mental health as well even after controlling for these more detailed, patient-level SDoH factors. Because of that, interventions to decrease health disparities should focus on not only sociodemographic variables (for example, insurance type) but also tangible patient-specific SDoH characteristics. For example, this may include giving patients taxi vouchers or ride-sharing credits to attend clinic visits for patients demonstrating such a need, initiating financial assistance programs for necessary medications, and/or identifying and connecting certain patient groups with social support services early on in the care cycle. LEVEL OF EVIDENCE: Level III, prognostic study.

Self-Reported Physical Function and Grit Are Not Correlated in Patients Who Undergo Open Reduction Internal Fixation for Distal Radius Fractures.

PURPOSE: "Grit" is defined as the perseverance and passion for long-term goals. Thus, grittier patients may have a better function after common hand procedures; however, this is not well-documented in the literature. Our purpose was to assess the correlation between grit and self-reported physical function among patients undergoing open reduction internal fixation (ORIF) for distal radius fractures (DRFs). METHODS: Between 2017 and 2020, patients undergoing ORIF for DRFs were identified. They were asked to complete the Quick Disabilities of the Arm, Shoulder, and Hand (QuickDASH) questionnaire before surgery and at 6 weeks, 3 months, and 1 year after surgery. The first 100 patients with at least 1-year follow-up also completed the 8-question GRIT Scale, a validated measure of passion and perseverance for long-term goals measured on a scale of 0 (least grit) to 5 (most grit). The correlation between the QuickDASH and GRIT Scale scores was calculated using Spearman rho (ρ). RESULTS: The average GRIT Scale score was 4.0 (SD, 0.7), with a median of 4.1 (range, 1.6-5.0). The median QuickDASH scores at the preoperative, 6-week postoperative, 6-month postoperative, and 1-year postoperative time points were 80 (range, 7-100), 43 (range, 2-100), 20 (range, 0-100), and 5 (range, 0-89), respectively. No significant correlation was found between the GRIT Scale and QuickDASH scores at any time. CONCLUSIONS: We found no correlation between self-reported physical function and GRIT levels in patients undergoing ORIF for DRFs, suggesting no correlation between grit and patient-reported outcomes in this context. Future studies are needed to investigate the influence of individual differences in character traits other than grit on patient outcomes, which may help better align resources where needed and further the ability to deliver individualized, quality health care. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic IV.

Surgeon idiosyncrasy is a key driver of cost in arthroscopic rotator cuff repair: a time-driven activity-based costing analysis.

BACKGROUND: Delivering high-value orthopedic care requires optimizing value, defined as health outcomes achieved per dollar spent. Published literature is stippled with inaccurate proxies for cost, including negotiated reimbursement rates, fees paid, or listed prices. Time-driven activity-based costing (TDABC) offers a more robust and accurate approach to calculating cost, including shoulder care. In the present study, we sought to determine the drivers of total cost in arthroscopic rotator cuff repair (aRCR) using TDABC. METHODS: Consecutive patients undergoing aRCR at multiple sites associated with a large urban health care system between January 2019 and September 2021 were identified. Total cost was determined using TDABC methodology. The episode of care was defined by 3 phases: preoperative, intraoperative, and postoperative care. Patient, procedure, rotator cuff tear morphology, and surgeon characteristics were collected. Bivariate analysis was performed across all characteristics between high-cost (top decile) and all other aRCRs. Multivariable linear regression was used to identify the key cost drivers. RESULTS: In total, 625 aRCRs performed by 24 orthopedic surgeons and 572 aRCRs performed by 13 orthopedic surgeons were included in the bivariate and multivariable linear regression analyses, respectively. By TDABC analysis, total aRCR cost varied 6-fold (5.9×) from least to most costly. Intraoperative costs accounted for 91% of average total cost, followed by preoperative costs and postoperative costs (6% and 3%, respectively). Biologic adjuncts (regression coefficient [RC] 0.54, 95% confidence interval [CI] 0.49-0.58, P < .001) and surgeon idiosyncrasy (RC of highest-cost surgeon 0.50, 95% CI 0.26-0.73, P < .001) were the major cost drivers in aRCR. Patient age, comorbidities, number of rotator cuff tendons torn, and revision surgery were not significantly associated with total cost. The amount of tendon retraction (RC 0.0012, 95% CI 0.000020-0.0024, P = .046), average Goutallier grade (RC 0.029, 95% CI 0.0086-0.049, P = .005), and the number of anchors used (RC 0.039, 95% CI 0.032-0.046, P < .001) were also significantly associated with cost, but with far smaller effect sizes. DISCUSSION AND CONCLUSION: Episode of care costs vary nearly 6-fold in aRCR and are almost exclusively dictated by the intraoperative phase. Tear morphology and repair technique contribute to cost, although the largest cost drivers of aRCR are the use of biologic adjuncts and surgeon idiosyncrasy, defined as something a surgeon does or does not do that impacts total cost and is not controlled for in the current analysis. Future work should seek to better delineate what these surgeon idiosyncrasies may represent.

Patient-Reported Outcomes Measurement Information System Physical Function and Global Physical Health Subscale Strongly Correlate and Perform Similarly to the Knee Injury and Osteoarthritis Outcome Score-Physical Function Short Form.

BACKGROUND: Arthroplasty surgeons use a variety of patient-reported outcome measures (PROMs) to assess functional well-being, including the Knee Injury and Osteoarthritis Outcome Score (KOOS) Physical Function short form (KOOS-PS), Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function Short Form 10a (PROMIS PF SF 10a), and PROMIS Global-10 Physical Health subscale. However, there is a paucity of literature assessing their concurrent validity and performance. METHODS: Between June 2016 and December 2020, patient visits at an arthroplasty clinic for knee concerns were identified. Patients who completed KOOS-PS, PROMIS PF SF 10a, and PROMIS Global-10, including its physical and mental health subscales, at the same visit were identified. Spearman rho (ρ) correlations were calculated and ceiling and floor effects identified. Overall, 5,303 patient encounters were included. RESULTS: Among physical function domains, strong correlation existed between the KOOS-PS and PROMIS PF SF 10a (ρ = 0.76, P < .001), KOOS-PS and PROMIS Global Physical Health (ρ = 0.71, P < .001), and PROMIS PF SF 10a and PROMIS Global Physical Health (ρ = 0.78, P < .001). No physical function-focused PROM had an appreciable floor effect (ie, at or more than 1%). The KOOS-PS had a small but measurable ceiling effect (n = 105 [2.0%]). CONCLUSIONS: All of the examined PROMs are acceptable to measure the functional status of patients with knee pathology, with the PROMIS Global-10 also being able to capture elements of mental health too. The PROMIS Global-10 may be of most value of the PROMs assessed, as the United States Centers for Medicare and Medicaid Services already incorporate the mental health component into new alternative payment models.