Diagnostic Re-Evaluation and Potential Predictor Factors of Transient and Permanent Congenital Hypothyroidism in Eutopic Thyroid Gland

Background: The incidence of congenital hypothyroidism (CH) has increased over the years, and many predictors for detecting newborns with transient forms (TCH) as early as possible have been considered. Methods: All newborns diagnosed with primary CH and eutopic gland in the Piedmont region of Italy in the period of January 2014–June 2019 were enrolled and re-evaluated at the age of 2 years. Results: 105 newborns were diagnosed with CH during the study period. Dyshormonogenesis was observed in 55/105. At re-evaluation, we found that 52.7% had permanent CH (PCH), while 47.3% had TCH. Male/female rate, TSH levels at diagnosis, levothyroxine requirement at withdrawal and extra-thyroid congenital malformations rate were higher in the PCH group (p = 0.02, p = 0.009, p = 0.02 and p = 0.01), while fT4 levels at diagnosis were lower (p = 0.03). Sensitivity of 72.4% and specificity of 80.7% for serum TSH above 60 mcUI/mL, sensitivity of 73% and specificity of 72.4% for serum fT4 level below 7.2 pg/mL and sensitivity of 66% and specificity of 68% for drug requirement above 2.25 mcg/kg/day were observed in PCH. Conclusions: Demographic, clinical and hormonal data at diagnosis and levothyroxine requirement during the first two years should be adequately monitored to identify infants who are most likely to discontinue therapy after the age of 24 months.

Experience of long-term use of denosumab in women with osteoporosis and various concomitant diseases

Background: Possible differences in the results of planned RCTs and real clinical practice were the reason for the analysis of long-term therapy with denosumab in patients with osteoporosis (OP) of various origins on an outpatient basis.Aim: To assess the effectiveness of long-term administration of denosumab in terms of the effect on BMD and markers of bone metabolism, tolerance and consequences of drug withdrawal in patients with OP of various etiologies.Materials And Methods: A retrospective analysis of the outpatient records of women with OP of various etiology, who were observed at the FSBI «NMRC TPM» from 1 to 10 years and regularly received denosumab 60 mg once every 6 months subcutaneously (at least 2 injections), was carried out. All completed examination and anthropometric research; DXA of the lumbar spine and proximal femur (PF); laboratory tests: marker of bone resorption CTx (β-crosslaps) in blood serum; survey on the presence of adverse events.Results: The study included 148 patients who were divided into 2 groups: 1 (N=98) - did not take anti-osteoporotic therapy (AT), 2 (N=50) - who took AT before the appointment of denosumab. Long-term therapy with denosumab was associated with a steady and reliable increase in BMD in the spine and PF, as well as a decrease in the concentration of CTx of both those who didn’t take and who previously took AT. In 54% of patients BMD in the spine reached values of osteopenia, in 43.4% of women target BMD values in the femoral neck were determined. During the first year of therapy, there was a decrease in the concentration of CTx by 67% in those who didn’t take AT and by 58% in those who had previously taken AT. Discontinuation of denosumab therapy without subsequent administration of AT was associated with a significant decrease in BMD in the spine (by 4.4-8.2%) during the first year after discontinuation of the drug.Conclusion: Denosumab therapy effectively increases BMD in the spine and PF and decreases CTx levels both in untreated patients and in those who previously received AT. It is necessary to discontinue therapy, further management of the patient should be discussed to prevent «withdrawal syndrome».

45. Significantly Decreased Broad Spectrum Antimicrobial Use (Carbapenems And Fluoroquinolones) with Implementation of Antibiotic Stewardship Program (ASP) and Pharmacist Interventions

Background According to the WHO, carbapenems and fluoroquinolones (FQ) should be key targets for stewardship programs. Methods A multifaceted antimicrobial stewardship program (ASP) was implemented in July 2018 at a 160-bed tertiary care center serving the tristate area of Iowa, South Dakota and Nebraska. Carbapenem and FQ use during pre-ASP intervention period (P1: 12/01/2016-6/30/2018) was compared with ASP-intervention period (P2: 07/01/2018-1/31/2020). ASP interventions included: stewardship educational pearls in monthly physician newsletters; educational posters in provider areas; suppression of carbapenem results on microbiology susceptibility reports; provider counseling for appropriate ordering; creating carbapenem alternative alert in order-entry software; removing FQ and carbapenems from order-sets where appropriate; default antibiotic stop dates changed to 7 days in EMR (Epic); adverse effects warning fired as an alert when ordering FQ. Pharmacist interventions: procalcitonin protocol allowing pharmacists to reorder follow-up procalcitonin and make recommendations to discontinue therapy where appropriate. Results FQ use declined significantly from a mean of 133 days of therapy (DOT) per 1000 days to 46 DOT per 1000 patient days during P2 (p< 0.0001). Carbapenem use declined significantly from a mean of 65 DOT per 1000 patient days during P1 to 9 DOT per 1000 patient days in P2 (p< 0.001). All hospital units showed a significant decrease in use, with intensive care units (ICUs) noting 56% reduction (p< 0.00001) during P2 compared to P1. During P2, 55% of orders for carbapenems and FQ during P2 were found to be appropriate compared to 39% in P1 (p< 0.0001). Sensitivity profile for Pseudomonas aeruginosa improved from 86% carbapenem sensitivity during P1 to 89% in P2 and no Carbapenem-Resistant Enterobacteriaceae isolates were identified during the study period; FQ sensitivity remained stable at 81%. Cost savings of &757 per 1000 patient days were recognized in P2 as a result of reduced use. Conclusion With ASP and pharmacist interventions, a significant decline in total utilization of carbapenem and FQ, considerable cost savings and an increase in proportion of appropriate use were observed. Disclosures All Authors: No reported disclosures

Novel Multidisciplinary Approach for Outpatient Antimicrobial Stewardship Using an Emergency Department Follow-Up Program

Purpose: Outpatient antimicrobial stewardship programs (ASPs) are becoming increasingly prevalent in healthcare. Many programs have demonstrated the effectiveness of pharmacist-driven outpatient consultations or follow-up programs to ensure appropriate antimicrobial prescribing. However, there is a paucity of literature describing multidisciplinary approaches in large healthcare systems for patients discharged from the emergency department (ED). The objective of this study was to describe the feasibility and impact of a combined effort between ASP pharmacotherapy specialists and nurse practitioners (NPs) in managing an ED follow-up center. Methods: A retrospective analysis was conducted for patients discharged from the ED between January 2018 and June 2019. Patients were identified for inclusion based on documentation by ASP pharmacotherapy specialists in the electronic health record for patient-specific inquiries from ED follow-up center NPs. The primary outcome of this study was to describe the number and types of interventions made by ASP pharmacotherapy specialists. Results: A total of 1088 patients were included in the study, for 1114 documented ASP calls. The urinary tract was the most common source of positive culture (79%), and third-generation cephalosporins were the most frequent antibiotic associated with calls (20%). Out of total calls, 60% lead to ASP interventions. Among total calls, the most frequent interventions were to correct drug-bug mismatches (20%), initiate new therapy (10%), and discontinue therapy (7%). Conclusion: This report describes a novel initiative that combines the efforts of ED NPs and ASP pharmacotherapy specialists in managing an ED follow-up center at a large healthcare system.

EFFECTS OF TRASTUZUMAB ON MYOCARDIAL FUNCTION ON BREAST CANCER PATIENTS

Objective: To investigate the effect of Trastuzumab on myocardial function on breast cancer patients at Thong Nhat hospital. Subjects and methods: a retrospective study on 48 patients with breast cancer treated with Trastuzumab at Thong Nhat hospital. Results: Percentage of patients with heart failure according to the Frammingham diagnostic criteria was 4.17%. The proportion of patients with no symptoms of heart failure according to Frammingham diagnostic criteria was 95.83%. According to the degree of EF change, the proportion of patients with decreased EF > 10% after treatment was 43.75%. With 9 patients with EF < 53%, accounting for 18.75%. The proportion of patients who had to discontinue therapy due to cardiotoxicity during treatment with Trastuzumab was 12.5%, with 6.25% stopping completely and 6.25% of patients stopping temporarily. Conclusion: the rate of patients with heart failure was little, the proportion of EF <53% was low. The proportion of patients who had to discontinue therapy due to cardiotoxicity during treatment with Trastuzumab was low.

Efficacy of venetoclax plus rituximab for relapsed CLL: Five-year follow-up of continuous or limited-duration therapy

We report long-term follow-up of the phase 1b study of venetoclax and rituximab (VenR) in patients with relapsed chronic lymphocytic leukemia (CLL), including outcomes with continuous or limited-duration therapy. Patients received venetoclax daily (200-600 mg) and rituximab over 6 months, then venetoclax monotherapy. Patients achieving complete response (CR), CR with incomplete marrow recovery (CRi), or undetectable minimal residual disease (uMRD) assessed by flow cytometry (&lt;10-4 cutoff) were allowed, but not required, to discontinue therapy, while remaining on study and could be re-treated with VenR upon progression. Median follow-up for all patients (N=49) was 5.3 years. Five-year rates for overall survival, progression-free survival, and duration of response were 86% (95% CI, 72-94), 56% (40-70), and 58% (40-73), respectively. Of the 33 deep responders (CR/CRi or uMRD), 14 remained on venetoclax monotherapy (continuous therapy), and 19 stopped venetoclax therapy (limited-duration therapy) after a median of 1.4 years. Five-year estimates of ongoing response were similar between continuous (71% [95% CI, 39-88]) or limited-duration therapy (79% [49-93]). Six of 19 patients in the latter group had subsequent disease progression, all &gt;2 years off venetoclax (range, 2.1-6.4). Four patients were re-treated with VenR, with partial responses observed in the 3 evaluable to date. VenR induced deep responses that were highly durable with either continuous or limited-duration therapy. Retreatment with VenR induced responses in patients with CLL progression after discontinuing therapy. Continuous exposure to venetoclax in deep responders does not appear to provide incremental benefit. ClinicalTrials.gov ID: NCT01682616

SLCO1B1 Phenotype and CYP3A5 Polymorphism Significantly Affect Atorvastatin Bioavailability

Atorvastatin, prescribed for the treatment of hypercholesterolemia, demonstrated overwhelming benefits in reducing cardiovascular morbidity and mortality. However, many patients discontinue therapy due to adverse reactions, especially myopathy. The Dutch Pharmacogenetics Working Group (DPWG) recommends an alternative agent to atorvastatin and simvastatin or a dose adjustment depending on other risk factors for statin-induced myopathy in SLCO1B1 rs4149056 CC or TC carriers. In contrast, the Clinical Pharmacogenetics Implementation Consortium (CPIC) published their guideline on simvastatin, but not on atorvastatin. In this work, we aimed to demonstrate the effect of SLCO1B1 phenotype and other variants (e.g., in CYP3A4/5, UGT enzymes or SLC transporters) on atorvastatin pharmacokinetics. For this purpose, a candidate-gene pharmacogenetic study was proposed. The study population comprised 156 healthy volunteers enrolled in atorvastatin bioequivalence clinical trials. The genotyping strategy comprised a total of 60 variants in 15 genes. Women showed higher exposure to atorvastatin compared to men (p = 0.001), however this difference disappeared after dose/weight (DW) correction. The most relevant pharmacogenetic differences were the following: AUC/DW and Cmax /DW based on (a) SLCO1B1 phenotype (p < 0.001 for both) and (b) CYP3A5*3 (p = 0.004 and 0.018, respectively). As secondary findings: SLC22A1 *2/*2 genotype was related to higher Cmax/DW (ANOVA p = 0.030) and SLC22A1 *1/*5 genotype was associated with higher Vd/F (ANOVA p = 0.032) compared to SLC22A1 *1/*1, respectively. Finally, UGT2B7 rs7439366 *1/*1 genotype was associated with higher tmax as compared with the *1/*3 genotype (ANOVA p = 0.024). Based on our results, we suggest that SLCO1B1 is the best predictor for atorvastatin pharmacokinetic variability and that prescription should be adjusted based on it. We suggest that the CPIC should include atorvastatin in their statin-SLCO1B1 guidelines. Interesting and novel results were observed based on CYP3A5 genotype, which should be confirmed with further studies.

Adherence to Single-Pill Versus Free-Equivalent Combination Therapy in Hypertension

Poor adherence to antihypertensive therapy is a major cause of poor blood pressure (BP) control in patients with hypertension. Regimen simplification may improve adherence and BP control. This systematic review assessed whether single-pill combination (SPC) therapy led to improved adherence, persistence, and better BP control compared with free-equivalent combination (FEC) therapy in patients with hypertension. PubMed, Medline, Embase, and the Cochrane Library were searched until July 2020, in addition to manual searching of relevant congress abstracts from 2014 to 2020 for studies including adults with hypertension aged ≥18 years receiving SPC or FEC antihypertensive therapy measuring any of the following: adherence, persistence, and reductions in systolic BP and/or diastolic BP. Adherence and persistence were summarized in a narrative analysis; direct pair-wise meta-analysis was conducted to compare BP reductions with SPC therapy versus FEC therapy using fixed-effect and random-effects models. Following screening, 44 studies were included. The majority (18 of 23) of studies measuring adherence showed adherence was significantly improved in patients receiving SPCs versus FECs. Overall, 16 studies measured persistence, of which 14 showed that patients receiving SPCs had significantly improved persistence or were significantly less likely to discontinue therapy than patients receiving FECs. Systolic BP (mean difference, −3.99 [95% CI, −7.92 to −0.07]; P =0.05) and diastolic BP (−1.54 [95% CI, −2.67 to −0.41]; P =0.0076) were both significantly reduced with SPC therapy compared with FEC therapy at week 12. SPC therapy leads to improved adherence and persistence compared with FEC therapy and may lead to better BP control in patients with hypertension.

Thioguanine Therapy in Inflammatory Bowel Diseases. A Practical Guide

Thiopurine-derivates azathioprine and mercaptopurine are frequently used to maintain remission in inflammatory bowel diseases (IBD). Despite their efficacy, more than 50% of patients discontinue therapy, mainly due to the development of adverse events. Thioguanine is an alternative thiopurine and has been conditionally licensed in The Netherlands as IBD treatment for patients after conventional thiopurine therapy failure. In this review we will provide practical information on initiating and maintaining thioguanine therapy in IBD and provide information concerning safety issues and future perspectives. The thioguanine toxicity profile is relatively mild and the reported incidence of nodular regenerative hyperplasia related to thioguanine use seems comparable to conventional thiopurines and the background incidence in IBD patients. Routine monitoring of laboratory parameters and adverse events is recommended, comparable to the monitoring of patients on conventional thiopurine therapy.

The effect of angiotensin-converting enzyme levels on Covid-19 susceptibility and severity: a Mendelian randomization study

Background There has been uncertainty about the safety or benefit of angiotensin-converting enzyme (ACE) inhibitors during the Covid-19 pandemic. We used Mendelian randomization using genetic determinants of serum-ACE levels to test whether decreased ACE levels increase susceptibility to SARS-CoV-2 infection or Covid-19 severity, while reducing potential bias from confounding and reverse causation in observational studies. Methods Genetic variants strongly associated with ACE levels, which were nearby the ACE gene, were identified from the ORIGIN trial and a separate genome-wide association study (GWAS) of ACE levels from the AGES cohort. The ORIGIN trial included 4147 individuals of European and Latino ancestries. Sensitivity analyses were performed using a study of 3200 Icelanders. Cohorts from the COVID-19 Host Genetics Initiative GWAS of up to 960 186 individuals of European ancestry were used for Covid-19 susceptibility, hospitalization and severe-disease outcome. Results Genetic variants were identified that explain between 18% and 37% of variance in ACE levels. Using genetic variants from the ORIGIN trial, a standard-deviation decrease in ACE levels was not associated with an increase in Covid-19 susceptibility [odds ratio (OR): 1.02, 95% confidence interval (CI): 0.90, 1.15], hospitalization (OR: 0.86, 95% CI: 0.68, 1.08) or severe disease (OR: 0.74, 95% CI: 0.51, 1.06). Using genetic variants from the AGES cohort, the result was similar for susceptibility (OR: 0.98, 95% CI: 0.89, 1.09), hospitalization (OR: 0.86, 95% CI: 0.66, 1.11) and severity (OR: 0.75, 95% CI: 0.50, 1.14). Multiple-sensitivity analyses led to similar results. Conclusion Genetically decreased serum ACE levels were not associated with susceptibility to, or severity of, Covid-19 disease. These data suggest that individuals taking ACE inhibitors should not discontinue therapy during the Covid-19 pandemic.