Citations

Abstract Background Upadacitinib (UPA), an oral, reversible JAK inhibitor engineered for increased selectivity for JAK1 over JAK2, JAK3, or tyrosine kinase 2 (TYK2), demonstrated significantly greater efficacy compared with placebo (PBO) for induction of remission in patients with moderately to severely active ulcerative colitis (UC) in two phase 3 trials, U-ACHIEVE Induction (NCT02819635) and U-ACCOMPLISH (NCT03653026). This analysis evaluated the efficacy of UPA on early symptomatic improvement for the first 14 days, using pooled data from U-ACHIEVE Induction and U-ACCOMPLISH. Methods U-ACHIEVE and U-ACCOMPLISH were multicentre, double-blind, PBO-controlled trials that enrolled patients who have had moderately to severely UC with an Adapted Mayo Score of 5 to 9 points and centrally reviewed endoscopy subscore of 2 to 3. A total of 998 patients were randomized to receive UPA 45mg once daily (QD) (n=658) or PBO (n=328) for 8 weeks (wks) in a 2:1 ratio. First dose of study drug was administered on Day 0. Improvement in symptoms including stool frequency subscore (SFS), rectal bleeding subscore (RBS), abdominal pain, and bowel urgency were analysed from daily symptom diary data. Multivariate regression analysis was used to determine if early changes in UC symptoms could be used to evaluate a potential correlation with patients’ likelihood of achieving clinical response or clinical remission per Adapted Mayo score at the end of induction. Results Baseline characteristics were similar between both treatment groups. Patients treated with UPA 45 mg QD experienced significant improvement in daily symptoms, with significantly more subjects achieving SFS≤1 (p<0.001), RBS of 0 (p<0.05), and SFS of 0 (p<0.05) as early as day 1 and maintained through day 14 (Figure 1). A significantly higher percentage of patients who received UPA 45 mg QD compared to PBO, achieved abdominal pain=0 and the absence of bowel urgency within 3 days of beginning treatment through day 14 (p<0.05). Multivariate analysis revealed that patients who achieved day 7 SFS≤1 (OR 2.42, 95% CI, 1.53–3.82) were more likely to attain clinical response (Table). Patients who attained day 7 SFS≤1 (OR 2.53, 95% CI 1.59–4.00) or day 7 bowel urgency absent (OR 2.40, 95% CI 1.52–3.79) were more likely to achieve clinical remission at week 8. Conclusion UPA 45 mg QD significantly improved UC symptoms as early as day 1, providing patients with rapid symptom relief. Patients who achieved early symptom improvement were more likely to attain clinical remission or clinical response at week 8. [Clinicaltrials.gov, U-ACHIEVE Induction (NCT02819635) and U-ACCOMPLISH (NCT03653026)]

Abstract Background Genetics play an important role in late-onset Alzheimer’s Disease (AD) etiology and dozens of genetic variants have been implicated in AD risk through large-scale GWAS meta-analyses. However, the precise mechanistic effects of most of these variants have yet to be determined. Deeply phenotyped cohort data can reveal physiological changes associated with genetic risk for AD across an age spectrum that may provide clues to the biology of the disease. Methods We utilized over 2000 high-quality quantitative measurements obtained from blood of 2831 cognitively normal adult clients of a consumer-based scientific wellness company, each with CLIA-certified whole-genome sequencing data. Measurements included: clinical laboratory blood tests, targeted chip-based proteomics, and metabolomics. We performed a phenome-wide association study utilizing this diverse blood marker data and 25 known AD genetic variants, adjusting for sex, age, vendor (for clinical labs), and the first four genetic principal components; sex-SNP interactions were also assessed. Results We observed statistically significant SNP-analyte associations for five genetic variants after correction for multiple testing (for SNPs in or near NYAP1, ABCA7, INPP5D, and APOE), with effects detectable from early adulthood. The ABCA7 SNP and the APOE2 and APOE4 encoding alleles were associated with lipid variability, as seen in previous studies; in addition, six novel proteins were associated with the e2 allele. The most statistically significant finding was between the NYAP1 variant and PILRA and PILRB protein levels, supporting previous functional genomic studies in the identification of a putative causal variant within the PILRA gene. Sex modified the effects of four genetic variants, with multiple interrelated immune-modulating effects associated with the PICALM variant. In post-hoc analysis, sex-stratified GWAS results from an independent AD case-control meta-analysis supported sex-specific disease effects of the PICALM variant, highlighting the importance of sex as a biological variable. Conclusions Known AD genetic variation influenced lipid metabolism and immune response systems in a population of non-AD individuals, with associations observed from early adulthood onward. Further research is needed to determine whether and how these effects are implicated in early-stage biological pathways to AD. These analyses aim to complement ongoing work on the functional interpretation of AD-associated genetic variants.

AbstractBackgroundMalnutrition is underrecognized and underdiagnosed, despite high prevalence rates and associated poor clinical outcomes. The involvement of clinical nutrition experts, especially physicians, in the care of high‐risk patients with malnutrition remains low despite evidence demonstrating lower complication rates with nutrition support team (NST) management. To facilitate solutions, a survey was designed to elucidate the nature of NSTs and physician involvement and identify needs for novel nutrition support care models.MethodsThis survey assessed demographics of NSTs, factors contributing to the success of NSTs, elements of nutrition education, and other barriers to professional growth.ResultsOf 255 respondents, 235 complete surveys were analyzed. The geographic distribution of respondents correlated with population concentrations of the United States (r = 90.8%, p < .0001). Most responding physicians (46/57; 80.7%) reported being a member of NSTs, compared with 56.5% (88/156) of dietitians. Of those not practicing in NSTs (N = 81/235, 34.4%), 12.3% (10/81) reported an NST was previously present at their institution but had been disbanded. Regarding NSTs, financial concerns were common (115/235; 48.9%), followed by leadership (72/235; 30.6%), and healthcare professional (HCP) interest (55/235; 23.4%). A majority (173/235; 73.6%) of all respondents wanted additional training in nutrition but reported insufficient protected time, ability to travel, or support from administrators or other HCPs.ConclusionCore actions resulting from this survey focused on formalizing physician roles, increasing interdisciplinary nutrition support expertise, utilizing cost‐effective screening for malnutrition, and implementing intervention protocols. Additional actions included increasing funding for clinical practice, education, and research, all within an expanded portfolio of pragmatic nutrition support care models.

Particles of many paramyxoviruses include small amounts of proteins with a molecular weight of about 20 kDa. These proteins, termed “C”, are basic, have low amino acid homology and some secondary structure conservation. C proteins are encoded in alternative reading frames of the phosphoprotein gene. Some viruses express nested sets of C proteins that exert their functions in different locations: In the nucleus, they interfere with cellular transcription factors that elicit innate immune responses; in the cytoplasm, they associate with viral ribonucleocapsids and control polymerase processivity and orderly replication, thereby minimizing the activation of innate immunity. In addition, certain C proteins can directly bind to, and interfere with the function of, several cytoplasmic proteins required for interferon induction, interferon signaling and inflammation. Some C proteins are also required for efficient virus particle assembly and budding. C-deficient viruses can be grown in certain transformed cell lines but are not pathogenic in natural hosts. C proteins affect the same host functions as other phosphoprotein gene-encoded proteins named V but use different strategies for this purpose. Multiple independent systems to counteract host defenses may ensure efficient immune evasion and facilitate virus adaptation to new hosts and tissue environments.

ABSTRACT Background Critically ill patients with severe acute kidney injury (AKI) requiring kidney replacement therapy (KRT) have a grim prognosis. Recently, multiple studies focused on the impact of KRT initiation time [i.e., accelerated versus watchful waiting KRT initiation (WWS-KRT)] on patient outcomes. We aim to review the results of all related clinical trials. Methods In this systematic review, we searched all relevant randomized clinical trials from January 2000 to April 2021. We assessed the impacts of accelerated versus WWS-KRT on KRT dependence, KRT-free days, mortality and adverse events, including hypotension, infection, arrhythmia and bleeding. We rated the certainty of evidence according to Cochrane methods and the GRADE approach. Results A total of 4932 critically ill patients with AKI from 10 randomized clinical trials were included in this analysis. The overall 28-day mortality rate was 38.5%. The 28-day KRT-dependence rate was 13.0%. The overall incident of KRT in the accelerated group was 97.4% and 62.8% in the WWS-KRT group. KRT in the accelerated group started 36.7 h earlier than the WWS-KRT group. The two groups had similar risks of 28-day [pooled log odds ratio (OR) 1.001, P = 0.982] and 90-day (OR 0.999, P = 0.991) mortality rates. The accelerated group had a significantly higher risk of 90-day KRT dependence (OR 1.589, P = 0.007), hypotension (OR 1.687, P &lt; 0.001) and infection (OR 1.38, P = 0.04) compared with the WWS-KRT group. Conclusions This meta-analysis revealed that accelerated KRT leads to a higher probability of 90-day KRT dependence and dialysis-related complications without any impact on mortality rate when compared with WWS-KRT. Therefore, we suggest the WWS-KRT strategy for critically ill patients.

PURPOSE The PALLAS study investigated whether the addition of palbociclib, an oral CDK4/6 inhibitor, to adjuvant endocrine therapy (ET) improves invasive disease-free survival (iDFS) in early hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) breast cancer. In this analysis, we evaluated palbociclib exposure and discontinuation in PALLAS. METHODS Patients with stage II-III HR+, HER2– disease were randomly assigned to 2 years of palbociclib with adjuvant ET versus ET alone. The primary objective was to compare iDFS between arms. Continuous monitoring of toxicity, dose modifications, and early discontinuation was performed. Association of baseline covariates with time to palbociclib reduction and discontinuation was analyzed with multivariable competing risk models. Landmark and inverse probability weighted per-protocol analyses were performed to assess the impact of drug persistence and exposure on iDFS. RESULTS Of the 5,743 patient analysis population (2,840 initiating palbociclib), 1,199 (42.2%) stopped palbociclib before 2 years, the majority (772, 27.2%) for adverse effects, most commonly neutropenia and fatigue. Discontinuation of ET did not differ between arms. Discontinuations for non–protocol-defined reasons were greater in the first 3 months of palbociclib, and in the first calendar year of accrual, and declined over time. No significant relationship was seen between longer palbociclib duration or ≥ 70% exposure intensity and improved iDFS. In the weighted per-protocol analysis, no improvement in iDFS was observed in patients receiving palbociclib versus not (hazard ratio 0.89; 95% CI, 0.72 to 1.11). CONCLUSION Despite observed rates of discontinuation in PALLAS, analyses suggest that the lack of significant iDFS difference between arms was not directly related to inadequate palbociclib exposure. However, the discontinuation rate illustrates the challenge of introducing novel adjuvant treatments, and the need for interventions to improve persistence with oral cancer therapies.

AstraZeneca coronavirus disease 2019 (COVID-19) vaccinations have recently been implicated in thromboembolism formations. Our aim was to investigate the outcomes of patients with thromboembolic events following the AstraZeneca vaccine (ChAdOx1 nCoV-19, AZD1222). A literature search was performed from December 2019 to September 2021. Eligible studies must report participants older than 18 years vaccinated with AstraZeneca and outcomes of thromboembolic events. Pooled mean or proportion were analyzed using a random-effects model. A total of 45 unique studies (number of patients = 144, 64.6% women, mean age 21–68 years) were included. The most common presenting adverse events were headache (12.1%), intracerebral hemorrhage (7.5%), and hemiparesis (7%). The most common thromboembolic adverse events were cerebral venous sinus thrombosis (38.5%) and deep vein thrombosis/pulmonary embolism (21.1%). The most common radiologic finding were intracerebral hemorrhage and cerebral venous thrombosis. Laboratory findings included thrombocytopenia (75%) and hypofibrinogenemia (41%). On admission, 64 patients tested positive for PF4-Heparin ELISA assay (80%). Seventy-four patients were hospitalized with 22 being admitted to the ICU. A total of 78 patients recovered while 39 patients died. This meta-analysis presents evidence to suggest vaccine-induced immune thrombotic thrombocytopenia (VITT) following AstraZeneca vaccine. Clinical practice must, therefore, account for the possibility of VITT and subsequent embolic events in certain individuals’ postvaccination with adenovirus-based COVID-19 vaccines. Serum anti-PF4 suggests diagnostic value for VITT and could subsequently inform treatment choices in such instances.