Evaluation of valganciclovir's neutropenia risk in pediatric solid organ transplant recipients utilizing two dosing regimens.

BACKGROUND: Valganciclovir is approved for cytomegalovirus prophylaxis in pediatrics using the Pescovitz algorithm. There are reports of valganciclovir overdoses in children with low body surface area and overestimated creatinine clearance utilizing this algorithm. This study compared the incidence of neutropenia and cytomegalovirus infection between the Pescovitz and weight-based dosing algorithms. METHODS: A single-center retrospective chart review from January 2010 to September 2018 was performed on pediatric heart, liver, and kidney transplant recipients, who received valganciclovir. Data were collected from the initiation of valganciclovir prophylaxis to 30 days after discontinuation. The primary objective was the incidence of neutropenia in patients receiving valganciclovir dosed by the Pescovitz versus weight-based dosing algorithms. RESULTS: This study included 187 pediatric transplant recipients who received valganciclovir dosed via the Pescovitz (62 recipients) or weight-based dosing algorithms (125 recipients). The incidence of neutropenia was higher in the Pescovitz (69.4%) compared to the weight-based dosing group (53.6%; p = .04) including moderate and severe neutropenia. Cytomegalovirus viremia was not significantly different between the two groups and occurred in 4.8% of the Pescovitz group compared to 2.4% of the weight-based group (p = .4). CONCLUSIONS: The incidence of neutropenia was greater in recipients receiving valganciclovir dosed via the Pescovitz algorithm compared to the weight-based dosing. There were no significant differences in regard to cytomegalovirus viremia or disease between the two groups.

'We want it all': ART preferences assessed by Desirability of Outcome Ranking.

OBJECTIVES: Understanding how people living with HIV (PLWH) view antiretroviral therapy (ART) prescribing choices is fundamental to patient-centred care. We used the Desirability of Outcome Ranking (DOOR) approach to explore patient ART preferences. METHODS: Seventy-four PLWH entered the study, 20 into the 'pilot study', and 54 in the 'comparative study'. Participants ranked five different hypothetical patient stories by desirability. Each story comprised five narrative lines, each line addressing one treatment characteristic drawn from one of five pre-selected domains (treatment failure, treatment difficulty, adverse effects, long-term complications, life events). Narrative lines could be favourable or adverse. In the pilot study the number of adverse domains varied from one to five. Comparative study stories were fixed at two adverse versus three favourable domains, to test the relative ranking of different domains. RESULTS: The pilot study identified a relationship between the number of adverse domains and rank (R2  = 0.54; p < 0.0001, Friedman test), however pairwise differences in ranking were not significant beyond three adverse domains. In the comparative study, all domains were ranked equally across the cohort (p = 0.88; Friedman test). In pre-defined demographic subgroup analyses, women ranked the 'treatment failure' domain significantly less desirable than men (p = 0.0014, Mann-Whitney test). CONCLUSIONS: People living with HIV appear to care equally about all aspects of ART. The observation that male and female PLWH have different treatment priorities merits further investigation in larger studies. Interindividual differences highlight the importance of individualized shared decision-making and treatment personalization. DOOR may have a role as a pre-treatment assessment tool as well as a research technique.

Estimation of Gingival Crevicular Blood as Noninvasive Method to Determine the Blood Glucose Level: A Comparative Study.

AIM: The current study's aim was to assess gingival crevicular blood as a noninvasive method to measure blood glucose levels. MATERIALS AND METHODS: The current study comprised a total of 50 patients who had been diagnosed with chronic periodontitis and age was ≥30 years old. The study's procedures were carried out after receiving informed consent. For finger capillary blood collection method, a sterile lancet was used to prick the finger and a drop of blood was taken, for gingival crevicular blood collection method, blood was taken from the gingival margin of the chosen site, and for venous blood collection method with the aid of a disposable syringe, a venous blood sample was taken from the patient's antecubital fossa for determining blood glucose levels. One-way analysis of variance (ANOVA) was used to examine the differences between the three methodologies' significance, and Karl Pearson's correlation (r) was used to determine their correlation. RESULTS: The maximum glucose level was found in venous blood (187.78 ± 18.23), followed by finger capillary blood (181.88 ± 21.67) and gingival crevicular blood (169.04 ± 11.24). And there was no significant difference between the different blood collection methods (p > 0.05). The positive significant correlation was found between gingival crevicular blood and finger capillary blood (r = 0.912, p < 0.001). Correlation with gingival crevicular blood and venous blood showed a positive correlation (r = 0.898, p < 0.001). Correlation between venous blood and finger capillary blood also showed a strong positive correlation (r = 0.988, p < 0.001). CONCLUSION: In conclusion, the findings of the current study suggest that blood drawn from the gingival crevicular during a clinical examination may be a great source for glucometric analysis. The gingival crevicular blood may show to be a promising technique for routine dental office screening for diabetes mellitus in periodontal patients, even if capillary/venous blood samples used for diabetes mellitus screening are the gold standard. CLINICAL SIGNIFICANCE: Oral health is crucial for the early detection of many systemic disorders. As a result, dentists are crucial in the screening for systemic disorders. One of the prevalent chronic disorders is diabetes. Any systemic disease that is detected early enough can avoid long-term problems.

Adoption of Opioid-Sparing and Non-Opioid Regimens After Breast Surgery in a Large, Integrated Health Care Delivery System.

BACKGROUND: Postoperative prescriptions have contributed to the opioid epidemic. In response, a large, integrated health care delivery system implemented initiatives to reduce outpatient opioid prescriptions. We evaluated the impact of these interventions on opioid-prescribing practices after breast surgery. METHODS: We examined postoperative prescribing practices before and after the 2016-2018 intervention period. Primary endpoints were the use of non-opioid regimens (NORs) and morphine milligram equivalents (MMEs) prescribed for postoperative pain management, while secondary endpoints were emergency department (ED) visits and readmissions within 7 days of surgery. RESULTS: In a survey of breast surgeons, 23% reported using NORs in 2017 versus 79% in 2019 (p < 0.001). Comparing 1917 breast operations from 2016 with 2166 operations from 2019, NORs increased from 9% in 2016 to 39% in 2019 (p < 0.001). Average discharge MMEs per operation decreased from 190 in 2016 to 106 in 2019 (p < 0.001). NOR failure (defined as an additional opioid prescription within 2 weeks of surgery) was < 1%. Significantly fewer postoperative ED visits occurred in the NOR group (1.9% NOR vs. 3.4% opioid regimen [OR]; p < 0.001). The 7-day readmission rates for NOR and OR patients were similar (0.49% NOR vs. 0.32% OR; p = 0.45). CONCLUSION: Between 2016 and 2019, breast surgeons in a large, integrated health care delivery system adopted NORs for nearly 40% of breast operations, and prescribed significantly fewer MMEs, with no increases in ED visits or readmissions for NOR patients. This suggests that initiatives to decrease opioid prescribing were successful and that a NOR for pain management after breast surgery is feasible.

MetaRNAseq analysis of surti buffalo rumen content reveals that transcriptionally active microorganisms need not be abundant.

The present study describes rumen microbiota composition and their functional profiles in Indian Surti buffaloes by metagenomic (MG) and metatranscriptomic (MT) approaches. The study compares samples from buffaloes fed three different proportion of roughages; green and dry type of roughage; and different rumen liquor fractions. Irrespective of sample, Bacteroidetes and Firmicutes were the most predominant bacterial phyla, followed by Proteobacteria, Fibrobacteres and Actinobacteria while, Prevotella, Bacteroides, Ruminococcus and Clostridium were the most abundant genera. Different proportions of taxa were observed in both MG and MT approaches indicating the differences in organisms present and organisms active in the rumen. Higher proportions of fungal taxa were observed in MT while important organisms like Fibrobacter and Butyrivibrio and abundant organisms like Bacteroides and Prevotella were underrepresented in MT data. Functionally, higher proportions of genes involved in Carbohydrate metabolism, Amino acid metabolism and Translation were observed in both data. Genes involved in Metabolism were observed to be underrepresented in MT data while, those involved in Genetic information processing were overrepresented in MT data. Further, genes involved in Carbohydrate metabolism were overexpressed compared to genes involved in Amino acid metabolism in MT data compared to MG data which had higher proportion of genes involved in Amino acid metabolism than Carbohydrate metabolism. In all significant differences were observed between both approaches, different fractions of rumen liquor (liquid and solid) and different proportions of roughage in diet.

Isolation and characterization of novel multifunctional recombinant family 26 glycoside hydrolase from Mehsani buffalo rumen metagenome.

Rumen microbiota harbor a diverse set of carbohydrate-active enzymes (CAZymes), which play a crucial role in the degradation of a complex plant polysaccharide thereby providing metabolic energy to the host animals. Earlier, we reported CAZYme analysis from the buffalo rumen metagenome by high throughput shotgun sequencing. Among the various CAZymes, glycoside hydrolase family 26 (GH26) enzymes have a number of industrial applications including in paper, oil, biofuel, food, feed, pharmaceutical, coffee, and detergent industries. Here, we report isolation and characterization of GH26 enzyme from the buffalo rumen metagenome. A novel GH26 gene composed of 1,119 base pairs was successfully amplified using the gene-specific primers inferred based on the contig generated from metagenome sequence assembly and cloned in a pET32a (+) expression vector as an N-terminal histidine tag fusion protein. A novel GH26 protein from an unknown rumen microorganism shared a maximum of 68% identity with the Prevotella ruminicola 23 encoded carbohydrate esterase family 7 and 46% with Bacteroides sp. 2_1_33B encoded mannan endo-1, 4-ß-mannosidase. The recombinant GH26-histidine tag fusion protein was expressed in Escherichia coli and purified using Ni-NTA affinity chromatography. The purified enzyme displayed multifunctional activities against various carbohydrate substrates including locust bean gum, beechwood xylan, pectin, and carboxymethyl cellulose suggesting mannanase, xylanase, pectin esterase, and endoglucanase activities, respectively.

Co-opting the E3 ligase KLHDC2 for targeted protein degradation by small molecules.

Targeted protein degradation (TPD) by PROTAC (proteolysis-targeting chimera) and molecular glue small molecules is an emerging therapeutic strategy. To expand the roster of E3 ligases that can be utilized for TPD, we describe the discovery and biochemical characterization of small-molecule ligands targeting the E3 ligase KLHDC2. Furthermore, we functionalize these KLHDC2-targeting ligands into KLHDC2-based BET-family and AR PROTAC degraders and demonstrate KLHDC2-dependent target-protein degradation. Additionally, we offer insight into the assembly of the KLHDC2 E3 ligase complex. Using biochemical binding studies, X-ray crystallography and cryo-EM, we show that the KLHDC2 E3 ligase assembles into a dynamic tetramer held together via its own C terminus, and that this assembly can be modulated by substrate and ligand engagement.

Chronic exposure to nanocellulose altered depression-related behaviors in mice on a western diet: The role of immune modulation and the gut microbiome.

AIMS: To determine if cellulose nanofibrils (CNF) have potential applications as food additives. MATERIALS AND METHODS: Male C57BL/6 mice on a Western diet were exposed to CNF for one month at a dose of 30 mg/kg by gavage. Male NOD mice, a model for type 1 diabetes (T1D), were used in a six-month study. KEY FINDINGS: Sequencing analysis of 16S rRNA genes suggested significant changes in gut microbiome of male C57BL/6 mice exposed to CNF. Analysis of functional metagenomics indicated that many of the functional contents that might be altered following CNF ingestion were associated with lipid and carbohydrate processing. Further studies in NOD mice suggested that there were some decreases in the blood glucose levels during the insulin tolerance test and glucose tolerance test following CNF treatment. However, these small decreases were not considered biologically meaningful as there were no significant changes in either the area under the curve or the first-order rate constant for glucose disappearance. Moreover, serum concentrations of cytokines/chemokines including IL-3, IL-12(p70) and the keratinocyte chemoattractant were increased following chronic exposure to CNF. In addition, behavioral studies suggested that the percentage of immobility time during the tail-suspension test was significantly increased following six months of exposure to CNF in NOD mice, signifying an increase in depression-related behavior. SIGNIFICANCE: Collectively, long-term CNF consumption was associated with changes in the ecology of the gut microbiome, immune homeostasis, and possibly energy metabolism and mental health in male NOD mice on a Western diet.

The Clot Thickens: COVID-19-Related ST-Elevation Myocardial Infarction in the Setting of Recent Boosters.

The coronavirus disease of 2019 (COVID-19) has an array of pathological effects that continue to be discovered. Vaccines against COVID-19 have quickly emerged as our main tool. However, the thrombotic risk of both the virus and the vaccine is yet to be established, let alone together. In this case report, we present a case involving a recently diagnosed COVID-19 patient who developed an ST-elevated myocardial infarction (STEMI) after receiving his booster shot. Our aim is to highlight the standard of treatment outcomes in COVID-19-associated clots, familiarize ourselves with the complexity of the clot burden in a COVID-19-associated STEMI, and illustrate the potential role of the cumulative pro-thrombotic effects of a recent COVID-19 booster with a concomitant symptomatic COVID-19 infection.

Evidence-Based Approach of Biologic Therapy in Bronchial Asthma.

The emergence of biologic agents in the treatment of bronchial asthma has a wide impact on improving quality of life, reducing morbidity, and overall health care utilization. These therapies usually work by targeting specific inflammatory pathways involving type 2 inflammation and are particularly effective in severe eosinophilic asthma. Various randomized controlled trials have shown their effectiveness by reducing exacerbation rates and decreasing required glucocorticoid dosages. One of the relatively newer agents, tezepelumab, targets thymic stromal lymphoprotein and has proven its efficacy in patients independent of asthma phenotype and serum biomarker levels. This article reviews the pathophysiologic mechanism behind biologic therapy and offers an evidence-based discussion related to the indication, benefits, and adverse effects of such therapies.

Effectiveness of an algorithm-based care pathway for patients with non-valvular atrial fibrillation presenting to the emergency department.

OBJECTIVE: Atrial fibrillation (AF) carries substantial morbidity and mortality. Evidence-based guidelines have been synthesized into emergency department (ED) AF care pathways, but the effectiveness and scalability of such approaches are not well established. We thus evaluated the impacts of an algorithmic care pathway for ED management of non-valvular AF (EDAFMP) on hospital use and care process measures. METHODS: We deployed a voluntary-use EDAFMP in 4 EDs (1 tertiary hospital, 1 cardiac hospital, 2 community hospitals) of an integrated delivery organization using a multifaceted implementation approach. We compared outcomes between patients with AF treated using the EDAFMP and historical and contemporaneous "usual care" controls, using a propensity-score adjusted generalized estimating equation. Patients with an index ED encounter for a primary visit reason of non-valvular AF (and no excluding concurrent diagnoses) were eligible for inclusion. RESULTS: Preimplementation (January 1, 2016-December 31, 2016), 628 AF patients were eligible; postimplementation (September 1, 2017-June 30, 2019), 1296, including 271 (20.9%) treated with the EDAFMP, were eligible. EDAFMP patients were less likely to be admitted than both historical (adjusted odds ratio [aOR], 95% confidence interval [CI]: 0.45, 0.29-0.71) and contemporaneous controls (aOR, 95%CI: 0.63, 0.46-0.86). ED visits and hospital readmissions over 90 days subsequent to index ED encounters were similar between postimplementation EDAFMP and usual care groups. EDAFMP patients were more likely to be prescribed anticoagulation (38% v. 5%, P < 0.001) and be referred to a cardiologist (93% vs 29%, P < 0.001) versus the comparator group. CONCLUSION: EDAFMP use is associated with decreased hospital admission during an index ED encounter for non-valvular AF, and improved delivery of AF care processes.

The Utility of Patient Engagement in Drug Research and Development.

Drug development of transformative medicine has compounding complexity as researchers seek to address the varying needs of patients, providers, payers, and policymakers. Patient engagement frameworks and guidance are under development with health authorities that will further guide patient engagement in drug research. Patient insights have been captured in registries, online health networks, and other forums to inform evidence on disease progression and identify gaps in care. Patient representation and disease awareness have improved in partnership with patient advocacy groups that have led to patient-informed drug development. One effort to incorporate the patient voice into early research and development (R&D) is the Patient Insights Database (PID). Currently comprising 102 indications, the PID was developed to uncover trends in mixed methods research data, including direct patient interviews and evidence-based medicine. The database is used to understand patient symptomology, diagnosis, treatment, health-related quality of life (HR-QoL), economic burden, and hope for new therapies, based on patient interviews, patient testimonials, real-world evidence studies, and HR-QoL research. A deep understanding of the patient experience informs internal R&D decisions to bring forth healthcare solutions that address patient needs.

A case of Methicillin-sensitive Staphylococcus aureus infective endocarditis that rapidly changed prognosis in a patient with cirrhosis: An atypical case with literature review.

Bacterial infections represent a major cause of mortality and morbidity in patients with cirrhosis that can alter the clinical course of compensated cirrhosis. The most common infections are spontaneous bacterial peritonitis by gram-negative organisms, urinary-tract infection, and pneumonia. In this case report, we raise the question of considering infections in the prognosis scoring in this patient group.

A Phase 1 Study to Investigate the Effects of Cortexolone 17α-Propionate, Also Known as Clascoterone, on the QT Interval Using the Meal Effect to Demonstrate ECG Assay Sensitivity.

Cortexolone 17α-propionate, also known as clascoterone, is a potent androgen receptor inhibitor intended for the topical treatment of skin diseases associated with androgenic pathway alterations. In nonclinical studies, cortexolone 17α-propionate was found to have a weak inhibitory effect on human Ether-à-go-go-Related Gene (hERG) potassium channels, which are vital for normal electrical activity in the heart. When used in a cream formulation, little cortexolone 17α-propionate is absorbed. However, the solution formulation developed for the treatment of androgenetic alopecia leads to a measurable systemic concentration and accumulation of the antiandrogen. This phase 1 study assessed the effect of cortexolone 17α-propionate on the QTc interval using concentration-effect analysis and the effect of a meal on QTc to confirm assay sensitivity. Thirty-two volunteers were randomly assigned to receive the active drug or a matching vehicle as placebo. Participants were dosed twice daily on days 1 to 3 (225 mg applied topically as a 7.5% solution 12 hours apart) and once on day 4. Pharmacokinetic and electrocardiogram assessments were performed after supratherapeutic doses. Assay sensitivity was successfully confirmed by using the food effect on the QTc interval. The results of this concentration-QTc analysis demonstrate that cortexolone 17α-propionate and its metabolite/degradation product had no effect on the QTc interval in the concentration range tested.

Protein interactions and subcellular localization in S-RNase-based self-incompatibility.

The recent identification of several proteins playing key roles in S-RNase-based gametophytic self-incompatibility has led both to a greater understanding of the molecular biology of this response, as well as to questions regarding the precise mechanism by which compatible pollen tubes are recognized and accepted. A proposed variant SCF(SLF) (where SCF is SSK1/cullin/F-box and SLF is S-locus F-box) ubiquitin ligase complex is thought to play a central role in recognizing and inhibiting non-self S-RNases, but the exact role of ubiquitination remains unclear. How the possible sequestration of non-self S-RNases in a pollen vacuolar compartment can be reconciled with the need for protein interaction between S-RNase and the SCF(SLF) complex needs to be determined. Current work to answer these questions focuses on more precisely defining quantitative protein interactions and subcellular localization of proteins involved in S-RNase-based gametophytic self-incompatibility.