The molecular determinants of classical pathway complement inhibition by OspEF-related proteins of Borrelia burgdorferi.

The complement system serves as the first line of defense against invading pathogens by promoting opsonophagocytosis and bacteriolysis. Antibody-dependent activation of complement occurs through the classical pathway and relies on the activity of initiating complement proteases of the C1 complex, C1r and C1s. The causative agent of Lyme disease, Borrelia burgdorferi, expresses two paralogous outer surface lipoproteins of the OspEF-related protein family, ElpB and ElpQ, that act as specific inhibitors of classical pathway activation. We have previously shown that ElpB and ElpQ bind directly to C1r and C1s with high affinity and specifically inhibit C2 and C4 cleavage by C1s. To further understand how these novel protease inhibitors function, we carried out a series of hydrogen-deuterium exchange mass spectrometry (HDX-MS) experiments using ElpQ and full-length activated C1s as a model of Elp-protease interaction. Comparison of HDX-MS profiles between unbound ElpQ and the ElpQ/C1s complex revealed a putative C1s-binding site on ElpQ. HDX-MS-guided, site-directed ElpQ mutants were generated and tested for direct binding to C1r and C1s using surface plasmon resonance. Several residues within the C-terminal region of ElpQ were identified as important for protease binding, including a single conserved tyrosine residue that was required for ElpQ- and ElpB-mediated complement inhibition. Collectively, our study identifies key molecular determinants for classical pathway protease recognition by Elp proteins. This investigation improves our understanding of the unique complement inhibitory mechanism employed by Elp proteins which serve as part of a sophisticated complement evasion system present in Lyme disease spirochetes.

Antibodies to coagulase of Staphylococcus aureus crossreact to Efb and reveal different binding of shared fibrinogen binding repeats.

Staphylococcus aureus pathology is caused by a plethora of virulence factors able to combat multiple host defence mechanisms. Fibrinogen (Fg), a critical component in the host coagulation cascade, plays an important role in the pathogenesis of this bacterium, as it is the target of numerous staphylococcal virulence proteins. Amongst its secreted virulence factors, coagulase (Coa) and Extracellular fibrinogen-binding protein (Efb) share common Fg binding motives and have been described to form a Fg shield around staphylococcal cells, thereby allowing efficient bacterial spreading, phagocytosis escape and evasion of host immune system responses. Targeting these proteins with monoclonal antibodies thus represents a new therapeutic option against S. aureus. To this end, here we report the selection and characterization of fully human, sequence-defined, monoclonal antibodies selected against the C-terminal of coagulase. Given the functional homology between Coa and Efb, we also investigated if the generated antibodies bound the two virulence factors. Thirteen unique antibodies were isolated from naïve antibodies gene libraries by antibody phage display. As anticipated, most of the selected antibodies showed cross-recognition of these two proteins and among them, four were able to block the interaction between Coa/Efb and Fg. Furthermore, our monoclonal antibodies could interact with the two main Fg binding repeats present at the C-terminal of Coa and distinguish them, suggesting the presence of two functionally different Fg-binding epitopes.

Birth plans: definitions, content, effects, and best practices.

The first written guide for birth plans was introduced in 1980 as a means for birthing people to document their choices in the child birthing experience. The birth plan offers an opportunity for the patient and the provider to discuss the birthing process and determine how to safely accommodate patient preferences. Patient satisfaction with birthing plans is variable and may depend on how many requests they have, how many of their plans are accomplished, route of delivery, and whether complications arise during or after delivery. Unmet expectations may lead to posttraumatic stress disorder, but following a birth plan may also be protective against it. Birthing people who use a birth plan may be less likely to use epidural anesthesia, have early amniotomy, or use oxytocin. The first stage of labor may be longer when a birth plan is used; however, there does not seem to be a decrease in the length of the second stage of labor among patients with a birth plan. Some providers believe that a disadvantage of birth plans is disappointment when birth plans are not able to be followed, and others consider that birth plans interfere with professional autonomy.

Clinical trial transparency in gastrointestinal endoscopy research.

BACKGROUND: Under-reporting of clinical trial results can lead to negative consequences that include inhibiting propagation of knowledge, limiting the understanding of how devices work, affecting conclusions of meta-analyses, and failing to acknowledge patient participation. Therefore clinical trial transparency, through publication of trial results on ClinicalTrials.gov or in manuscript form, is important. We aimed to examine clinical trial transparency in endoscopic clinical trials. METHODS: The ClinicalTrials.gov database was searched for endoscopy trials up to October 2019. Adherence to the reporting of results to the database or in publication form was recorded for each trial. RESULTS: The final analysis included 923 trials, of which 801 were completed and 122 were either terminated or suspended. Results were available either on ClinicalTrials.gov or in publication for 751/923 trials (81.4 %). Other fields have reported a publication rate of 40 %-63 %. Results were available on ClinicalTrials.gov for 168 trials (18.2 %) and in the form of a publication for 720 trails (78.0 %). CONCLUSIONS: Compared with other fields in medicine, endoscopy clinical trials have a high rate of clinical trial transparency. However, there is room for improvements as close to one-fifth of trials fail to report results and 81.8 % do not report results to ClinicalTrials.gov.

Outer surface lipoproteins from the Lyme disease spirochete exploit the molecular switch mechanism of the complement protease C1s.

Proteolytic cascades comprise several important physiological systems, including a primary arm of innate immunity called the complement cascade. To safeguard against complement-mediated attack, the etiologic agent of Lyme disease, Borreliella burgdorferi, produces numerous outer surface-localized lipoproteins that contribute to successful complement evasion. Recently, we discovered a pair of B. burgdorferi surface lipoproteins of the OspEF-related protein family-termed ElpB and ElpQ-that inhibit antibody-mediated complement activation. In this study, we investigate the molecular mechanism of ElpB and ElpQ complement inhibition using an array of biochemical and biophysical approaches. In vitro assays of complement activation show that an independently folded homologous C-terminal domain of each Elp protein maintains full complement inhibitory activity and selectively inhibits the classical pathway. Using binding assays and complement component C1s enzyme assays, we show that binding of Elp proteins to activated C1s blocks complement component C4 cleavage by competing with C1s-C4 binding without occluding the active site. C1s-mediated C4 cleavage is dependent on activation-induced binding sites, termed exosites. To test whether these exosites are involved in Elp-C1s binding, we performed site-directed mutagenesis, which showed that ElpB and ElpQ binding require C1s residues in the anion-binding exosite located on the serine protease domain of C1s. Based on these results, we propose a model whereby ElpB and ElpQ exploit activation-induced conformational changes that are normally important for C1s-mediated C4 cleavage. Our study expands the known complement evasion mechanisms of microbial pathogens and reveals a novel molecular mechanism for selective C1s inhibition by Lyme disease spirochetes.

Adaptation and Testing of a Military Version of the Measure of Moral Distress for Healthcare Professionals.

BACKGROUND: Moral distress is well-documented among civilian critical care nurses and adversely affects patient outcomes, care delivery, and retention of health care providers. Despite its recognized significance, few studies have addressed moral distress in military critical care nurses. OBJECTIVES: To refine and validate an instrument to assess moral distress in military critical care nurses. METHODS: This study examined moral distress in military critical care nurses (N = 245) using a new instrument, the Measure of Moral Distress for Healthcare Professionals-Military (MMD-HP-M). The psychometric properties of the refined scale were assessed by use of descriptive statistics, tests of reliability and validity, exploratory factor analysis, correlations, and qualitative analysis of open-ended responses. RESULTS: Initial testing showed promising evidence of instrument performance. The Cronbach α (0.94) suggested good internal consistency of the instrument for the overall sample. Scores for the MMD-HP items and the MMD-HP-M items showed a strong, significant correlation (α= 0.78, P < .001). Unique attributes of military nursing that contribute to moral distress included resource access, futile care, and austere conditions. Exploratory factor analysis established a new military-centric factor for question items associated with inadequate training for patient care, providing care in resource-limited settings, and personal exhaustion. CONCLUSIONS: These results will help guide specific, targeted interventions to reduce the negative effects of moral distress on our military health care providers, especially in terms of readiness for the next global pandemic and retention of these invaluable personnel.

Factors Related to Biologic Adherence and Outcomes Among Moderate-to-Severe Asthma Patients.

BACKGROUND: Adherence barriers to asthma biologics may not be uniform across administration settings for patients with moderate-to-severe asthma. OBJECTIVE: To examine differences in asthma biologic adherence and associated factors, as well as association with a 1-year all-cause emergency department (ED) visit, across administration settings. METHODS: A retrospective study of biologic naïve moderate-to-severe asthma patients with initial biologic therapy between January 1, 2016, and April 30, 2020, in the Optum Clinformatics Data Mart was performed. Three administration settings were identified: Clinic-only (outpatient office/infusion center), Home (self-administration), and Hybrid setting (mixture of clinic and self-administration). Asthma biologic adherence was the proportion of observed over expected biologic dose administrations received within 6 months from initial therapy. Factors associated with adherence were identified by administration setting, using Poisson regression analyses. A relationship between a 1-year all-cause ED visit and adherence was assessed for each administration setting using Cox regression analyses. RESULTS: The study cohort was 3932 patients. Biologics adherence was 0.75 [0.5, 1] in Clinic setting, the most common administration setting, and 0.83 [0.5, 1] in both Home and Hybrid settings. Specialist access was consistently associated with better biologic adherence, whereas Black race, Hispanic ethnicity, lower education, Medicare only insurance, and higher patient out-of-pocket cost were associated with worse biologic adherence in some settings. In the Hybrid setting, hazard for a 1-year all-cause ED visit decreased with biologic adherence. CONCLUSIONS: Asthma biologic adherence varied by administration setting. Efforts to improve asthma biologic adherence should consider promoting self-administration when beneficial, improving prior specialist access, and targeting patients with higher risk of suboptimal adherence particularly Black and Hispanic patients.

Gastroenterology Clinical Trials Transparency: An Analysis of Publication Rates From the ClinicalTrials.gov Database.

INTRODUCTION: There is limited information on the transparency of gastroenterology clinical trials. METHODS: The ClinicalTrials.gov database was searched for trials focused on most common gastrointestinal diseases up to August 2018. Adherence to reporting of results to the database or in publication form was recorded for each trial along with trial characteristics. RESULTS: Of the 2,429 trials included in the final analysis, 1824 (75%, 95% confidence interval: 73.4%-76.8%) had results on ClinicalTrials.gov or in the form of a publication. However, only 534 (29%) had results posted on ClinicalTrials.gov. DISCUSSION: Improvement of clinical trial transparency is needed in gastroenterology.

vhp Is a Fibrinogen-Binding Protein Related to vWbp in Staphylococcus aureus.

Staphylococcus aureus can target a variety of tissues, causing life-threatening infections. The basis for this diversity stems from the microorganism's ability to spread in the vascular system throughout the body. To survive in blood, S. aureus coats itself with a fibrinogen (Fg)/fibrin shield. The protective shield is assembled by the coordinated actions of a number of Fg-binding bacterial proteins that manipulate the host's blood coagulation system. Several of the Fg binders appear redundant, sharing similar functional motifs. This observation led us to screen for the presence of novel proteins with significant amino acid identities to von Willebrand factor-binding protein (vWbp), a key component in the shield assembly machinery. One identified protein showed significant sequence identity with the C-terminal region of vWbp, and we consequently named it vWbp homologous protein (vhp). The vhp gene lies within a cluster of genes that encode other virulence factors in S. aureus. Although each isolate only contains one copy of the vhp gene, S. aureus has at least three distinct alleles, vhpA, B, and C, that are present in the core genome. All three vhp isoforms bind Fg with high affinity, targeting a site located in the D fragment of Fg. We further identified an ∼79 amino acid-long, conserved segment within the C-terminal region of vWbp that shares high sequence identities (54 to 67%) with the vhps and binds soluble Fg with high affinity. Further analysis of this conserved motif and the intact vhps revealed intriguing differences in the Fg binding behavior, perhaps suggesting that these proteins have similar but discrete functions in the shield assembly. IMPORTANCE The life-threatening diseases caused by multidrug-resistant Staphylococcus aureus strains are a worldwide medical problem due to treatment limitations and the lack of an effective vaccine. The ability of S. aureus to coat itself with a protective fibrinogen (Fg)/fibrin shield allows the organism to survive in blood and to disseminate and cause invasive diseases. This process represents a promising target for novel antistaphylococcal treatment strategies but is incompletely understood. S. aureus expresses a number of Fg-binding proteins. Some of these proteins have apparently redundant functions. Proteins with similar functions often share a structural or functional motif with each other. In this study, we identified a protein homologous to the C-terminal of von Willebrand factor-binding protein (vWbp), a key contributor in the Fg shield assembly that also binds Fg. Further analysis allowed us to identify a common Fg-binding motif.

Therapeutic Inertia in Prescribing Biologics for Patients with Moderate-to-Severe Asthma: Workshop Summary.

Moderate-to-severe asthma represents about a quarter of the nearly 10% of Americans diagnosed with asthma. Many patients with moderate-to-severe asthma have uncontrolled symptoms that lead to exacerbations requiring oral corticosteroids. There are many factors contributing to poor asthma control, including poor adherence to prescribed therapies, the under-prescribing of biologics and therapeutic inertia. We convened an eight-member panel from fields of primary care, pulmonology, immunology, health services and clinical research, behavioral science and pharmaceutical medical affairs, with the goal of identifying contributing factors and solutions to therapeutic inertia with asthma biologics. We used the Capability, Opportunity, and Motivation (COM-B) model to classify patient and provider behavior towards therapeutic inertia. The model incorporates existing behavior theories and is driven by the interaction of capability, opportunity, and motivation. We used a Delphi method to identify and develop six primary solutions: 1) integration of patient-centered outcomes into asthma management practice; 2) provider education about asthma treatment; 3) moderate-to-severe asthma care delivery redesign; 4) harmonized, evidence-based protocol for the management of moderate-to-severe asthma; 5) designated coordinator approach for optimal asthma management; and 6) a case coordination digital support tool. Integration of patient-centered outcomes into asthma management practice and provider education were identified as having the highest potential to impact therapeutic and clinical inertia. The COM-B model is effective in identifying improvement within therapeutic inertia targeting the capabilities, opportunities, and motivations of patients, providers, and payer systems.

Spatial distribution of dysplasia in Barrett's esophagus segments before and after endoscopic ablation therapy: a meta-analysis.

BACKGROUND: Dysplasia in Barrett's esophagus (BE) is focal and difficult to locate. The aim of this meta-analysis was to understand the spatial distribution of dysplasia in BE before and after endoscopic ablation therapy. METHODS: A systematic search was performed of multiple databases to July 2019. The location of dysplasia prior to ablation was determined using a clock-face orientation (right or left half of the esophagus). The location of the dysplasia post-ablation was classified as within the tubular esophagus or at the top of the gastric folds (TGF). RESULTS: 13 studies with 2234 patients were analyzed. Pooled analysis from six studies (819 lesions in 802 patients) showed that before ablation, dysplasia was more commonly located in the right half versus the left half (odds ratio [OR] 4.3; 95 % confidence interval [CI] 2.33 - 7.93; P < 0.001). Pooled analysis from seven studies showed that dysplasia after ablation recurred in 101 /1432 patients (7.05 %; 95 %CI 5.7 % - 8.4 %). Recurrence of dysplasia was located more commonly at the TGF (n = 68) than in the tubular esophagus (n = 34; OR 5.33; 95 %CI 1.75 - 16.21; P = 0.003). Of the esophageal lesions, 90 % (27 /30) were visible, whereas only 46 % (23 /50) of the recurrent dysplastic lesions at the TGF were visible (P < 0.001). CONCLUSION: Before ablation, dysplasia in BE is found more frequently in the right half of the esophagus versus the left. Post-ablation recurrence is more commonly found in the TGF and is non-visible, compared with the tubular esophagus, which is mainly visible.

Patient-Centric Structural Determinants of Adherence Rates Among Asthma Populations: Exploring the Potential of Patient Activation and Encouragement Tool TRUSTR to Improve Adherence.

BACKGROUND: Lack of adherence with prescribed medications among the asthma populations exacerbates health outcomes and increases social and economic costs. OBJECTIVES: The proposed study aims to model patient-centric structural determinants of adherence rates among asthma patients and explore the potential of mobile health apps such as the TRUSTR platform to improve adherence using its power of monetary and non-monetary chatbotting and non-non-monetary nudges. Following specific hypotheses are tested: (1) Patient attributes, such as their age and monetary medical condition, have significant effect on their adherence with the prescribed treatment plans. (2) Behavioral nudging with rewards and engagement via mobile health apps will increase adherence rates. METHODS: The patient population (N = 37 359) consists of commercially insured patients with asthma who have been identified from administrative claims in the HealthCore Integrated Research Database (HIRD) between April 1, 2018 and March 31, 2019. Two Structural Equation Models (SEMs) are estimated to quantify direct, indirect, and total effect sizes of age and medical condition on proportion of days covered (PDC) and medical possession ratio (MPR), mediated by patient medical and pharmacy visits. Fourteen additional SEMs were estimated to lateralize TRUSTR findings and conduct sensitivity analysis. RESULTS: HIRD data reveal mean adherence rate of 59% (standard deviation (SD) 29%) for PDC and 58% for MPR (SD 36%). Key structural findings from SEMs derived from the HIRD dataset indicate that each additional year in the age of the patient has a positive total effect on the adherence rate. Patients with poor medical condition are likely to have lower adherence rate, but this direct effect is countered by mediating variables. Further, each additional reward and higher engagement with a mobile app is likely to have a positive total effect on increasing the adherence rate. CONCLUSIONS: HIRD data reveal mean adherence rate of 59% (SD 29%), providing the evidence for the opportunity to increase adherence rate by around 40%. Statistical modeling results reveal structural determinants, such as the opportunity to nudge, are higher among younger patients, as they have higher probability of being non-adherent. Methodologically, lateralization approach demonstrates the potential to capture real-world evidence beyond clinical data and merge it with clinical data.

Statin Therapy and Risk of Incident Diabetes Mellitus in Adults With Cardiovascular Risk Factors.

The association between statins and diabetes mellitus (DM) remains controversial. The Kaiser Permanente CHAMP Study identified adults without DM who had cardiovascular (CV) risk factors and no previous lipid lowering therapy (LLT) between 2008 and 2010. The CV risk factors included known atherosclerotic CV disease (ASCVD), elevated low-density lipoprotein cholesterol ≥190 mg/dl, or a low-density lipoprotein cholesterol between 70 and 189 mg/dl and an estimated 10-year ASCVD risk ≥7.5%. Incident DM was defined as ≥2 abnormal tests (i.e., A1C ≥6.5% or a fasting blood glucose ≥126 mg/dl) or ≥1 abnormal test result plus a new diagnostic code or medication for DM. Among 213,289 eligible adults, 28,149 patients initiating statins were carefully matched to an equal number of patients who remained off LLT during follow-up. Compared with matched patients not receiving statins, those initiating statin therapy had the same mean age (67.9 ± 9.4 years) and gender (42.8% women). The crude rate (per 100 person-years) of incident DM was low (0.55, 95% confidence interval [CI] 0.52 to 0.59) but was marginally higher in patients who were treated with a statin (0.69, 95% CI 0.64 to 0.74) versus no LLT (0.42, 95% CI 0.38 to 0.46). After additional adjustment, statin therapy was associated with a modestly increased risk of incident DM (adjusted hazard ratio 1.17, 95% CI 1.02 to 1.34). In conclusion, in adults without DM at increased ASCVD risk, initiation of statin therapy was independently associated with a modestly higher risk of incident DM.

Medical School Home Page Library Links: What Has Changed Since 2010.

The purpose of this study was to compare the visibility and placement of links to the library on home pages of 165 American Association of Medical Colleges member medical schools with the results from a study performed in 2010. Visibility on the home page declined from 50.7% to 41.2%, and one-click pathways declined from 61% to 44.8%. On 14 medical school websites, no discoverable navigation to the library could be found, including use of the search function. During the same time period, librarian partnerships with health care professionals and biomedical researchers have increased and expanded.

Impact of Tai Chi Exercise on Balance Disorders: A Systematic Review.

Purpose Tai chi is receiving increasing research attention with its benefit of improving flexibility and balance. The objective of this review was to examine the evidence concerning the impact of tai chi as a practical therapy for vestibular rehabilitation on individuals with balance and vestibular disorders. Method A systematic review using 4 electronic databases was conducted. Randomized clinical trials and quasi-experimental studies were included. Results Four studies met the inclusion criteria and were included for data analysis. Results indicate positive effect of tai chi practice on dynamic postural stability in balance of its practitioners. Conclusion Tai chi may be a useful therapy as for vestibular rehabilitation as it improves dynamic balance control and flexibility of individuals with balance and vestibular disorders.

The Complex Fibrinogen Interactions of the Staphylococcus aureus Coagulases.

The two coagulases, von Willebrand factor binding protein (vWbp) and Coagulase (Coa), are critical virulence factors in several animal models of invasive Staphylococcus aureus (S. aureus) infections. These proteins are part of an intricate system of proteins that S. aureus uses to assemble a fibrinogen (Fg)/fibrin protective shield surrounding itself. This shield allows the microorganism to evade clearance by the host phagocytic cells. The coagulases can non-proteolytically activate the zymogen prothrombin to convert Fg to fibrin and promote the Fg/fibrin shield formation. The coagulases also bind directly to Fg and the interaction between Coa and Fg has been previously characterized in some detail. However, the mechanism(s) by which vWbp interacts with Fg remains unclear. Here, we show that vWbp and Coa have distinct interactions with Fg, despite being structurally similar. Coa binds with a significantly higher affinity to soluble Fg than to Fg coated on a plastic surface, whereas vWbp demonstrates no preference between the two forms of Fg. The two coagulases appear to target different sites on Fg, as they do not compete with each other in binding to Fg. Similar to Coa, both the N- and C-terminal halves of vWbp (vWbp-N, vWbp-C, respectively) harbor Fg-binding activities. The higher affinity Fg-binding activity resides in vWbp-N; whereas, the C-terminal region of Coa encompasses the major Fg-binding activity. Peptides constituting the previously identified Coa/Efb1 Fg-binding motif fail to inhibit vWbp-C from binding to Fg, indicating that vWbp-C lacks a functional homolog to this motif. Interestingly, the N-terminal prothrombin-binding domains of both coagulases recognize the Fg ß-chain, but they appear to interact with different sequence motifs in the host protein. Collectively, our data provide insight into the complex interactions between Fg and the S. aureus coagulases.

Delays in anti-hyperglycaemic therapy initiation and intensification are associated with cardiovascular events, hospitalizations for heart failure and all-cause mortality.

AIMS: The aims of this study were to assess the impact of delays in treatment intensification (TI) on cardiovascular events, heart failure, and all-cause mortality at typical stages of anti-hyperglycaemic therapy. MATERIALS AND METHODS: Using electronic health record data, we created three TI cohorts of diabetes patients who: 1) initiated metformin (MET) as their first anti-hyperglycaemic therapy; 2) added a sulfonylurea (SU) to MET; and 3) initiated insulin (INS) while using MET or SU, alone or in combination. Primary exposure variables were haemoglobin A1C value preceding cohort therapy (pre-TI A1C) and time to intensification, that is, the time between pre-TI A1C >7% and cohort index date. Cox regression models were used to analyse the associated risk of cardiovascular events, hospitalizations for heart failure and all-cause mortality. RESULTS: In the MET cohort, each additional percentage point of pre-TI A1C was associated with a 10% increased risk of a CV event (HR, 1.10; 95% CI, 1.03-1.07; P = 0.004), a 7% increased risk of HF hospitalization (HR, 1.07; 95% CI, 1.01-1.14; P = 0.034) and a 7% increased risk of all-cause mortality (HR, 1.07; 95% CI, 1.01-1.14; P = 0.032). Pre-TI A1C was associated with a 9% increased risk of a CV event in the INS cohort (HR,1.09; 95% CI, 1.04-1.13; P < 0.001). Each month of delay in TI was significantly associated with a 6% increased risk of hospitalization for HF (HR, 1.06; 95% CI, 1.00-1.13; P = 0.040) and all-cause mortality (HR, 1.06; 95% CI, 1.00-1.13; P = 0.050) in the MET cohort. CONCLUSIONS: Delays in TI were associated with poor outcomes over a mean follow-up period of nearly five years. Earlier initiation and more rapid intensification of pharmacotherapy could reduce the risk of poor outcomes.

Longitudinal changes in glycated haemoglobin following treatment intensification after inadequate response to two oral antidiabetic agents in patients with type 2 diabetes.

AIMS: To identify change in glycated haemoglobin (HbA1c) for 1 year after treatment intensification in patients with HbA1c >53 mmol/mol (7.0%) while on two classes of oral antidiabetic drugs (OADs). MATERIAL AND METHODS: A retrospective cohort study was conducted using a regional health plan claims database for the period January 1, 2010 to March 31, 2017. Patients with type 2 diabetes (T2DM) whose treatment was intensified with insulin, a glucagon-like peptide-1 receptor agonist or a third OAD within 365 days of having HbA1c ≥53 mmol/mol (7.0%) on two OADs were included. The HbA1c trajectory for 1 year after intensification was estimated using a mixed-effects regression model. RESULTS: The analysis included 1226 patients with a mean ± SD HbA1c at treatment intensification of 74.2 ± 18.7 mmol/mol (8.93 ± 1.7%). HbA1c was higher in the insulin group (74.2 mmol/mol) than in the non-insulin group (70.6 mmol/mol), as was the HbA1c decrease (P < 0.01) over the 1-year follow-up, particularly in patients with baseline HbA1c >9%. After intensification, insulin- and non-insulin-treated patients achieved an average change by month in HbA1c of -4.7 mmol/mol and -2.6 mmol/mol points, respectively. The analysis predicted HbA1c to be the lowest at 6 to 10 months post intensification, depending on intensification treatment and HbA1c at intensification; however, on average, HbA1c remained above 64.0 mmol/mol (8.0%). CONCLUSION: In patients with T2DM, intensification following an HbA1c value ≥53 mmol/mol (7.0%) while on two OADs was associated with a significant improvement in glycaemic control. Patients intensified with insulin had a higher baseline HbA1c but greater HbA1c reduction than those intensified with a non-insulin agent. However, HbA1c remained above 64 mmol/mol (8.0%) overall. Additional opportunity exists to further intensify therapy to improve glycaemic control.

Influence of Treatment Intensification on A1c in Patients with Suboptimally Controlled Type 2 Diabetes After 2 Oral Antidiabetic Agents.

BACKGROUND: In the United States, more than 50% of patients with type 2 diabetes mellitus (T2DM) have hemoglobin A1c (A1c) levels that fail to achieve the recommended target of < 7.0%. Of these, 30%-45% have an A1c > 9.0%, the threshold for poorly controlled T2DM per National Committee for Quality Assurance (NCQA) measures. Treatment inertia is a known challenge. However, recent treatment intensification patterns and outcomes after treatment fails 2 classes of oral antidiabetic agents (OADs) are not well understood. OBJECTIVE: To characterize treatment intensification patterns and glycemic control outcomes in patients with A1c ≥ 7.0% on 2 OADs. METHODS: A retrospective cohort study was conducted in patients with T2DM from a regional health plan claims dataset augmented with A1c results between January 1, 2010, and March 31, 2017. Patients were identified with an A1c ≥ 7.0% (baseline), while on 2 OADs, and whose treatment was intensified with basal/biphasic insulin (insulin), glucagon-like peptide-1 receptor antagonist (GLP-1RA), or a third OAD within 365 days after the baseline A1c ≥ 7.0%. Patients had at least 1 A1c value 60-365 days (follow-up period) after treatment intensification. The proportion of patients with an A1c < 7.0% and < 9.0% at follow-up were identified by therapeutic intensification strategy. Odds ratios for achieving A1c < 7.0% and < 9.0% were calculated. RESULTS: 1,226 patients were included in the analysis, and 33.5% of the patients had a baseline A1c ≥ 9.0%. 24% of patients received insulin; 16% received GLP-1RA; and 60% received a third OAD for the treatment intensification. Overall, 26.0% achieved A1c < 7.0% and 76.1% of patients achieved < 9.0%, with a median follow-up of 119 days. The proportion of patients intensified with insulin who had an A1c ≥ 9.0% at follow-up was 34.6% versus 53.2% at baseline (P < 0.01). The corresponding percentages for those intensified with a GLP-1RA and OAD were 21.6% versus 27.1% (P = 0.24) and 20.1% versus 27.3% (P < 0.01). After controlling for baseline characteristics, the odds ratio (95% CI) of achieving A1c < 7.0% and < 9.0% was 2.05 (1.45-2.90) for GLP-1RA and 0.92 (0.61-1.40) for OAD. The association between goal attainment and GLP-1RA versus OAD intensification was influenced by the time to the A1c follow-up and baseline A1c. CONCLUSIONS: Treatment intensification was associated with improved glycemic control in patients after therapy failed 2 OADs. Patients with higher A1c at baseline were likely to initiate insulin, which was associated with a greater drop in A1c. GLP-1RA was associated with a higher likelihood of achieving NCQA-suggested glycemic control compared with a third OAD. However, the association varied by the follow-up period. These findings are important to health plans seeking to improve patient outcomes as reflected in high performance on NCQA diabetes quality measures by promoting effective and timely treatment intensification. DISCLOSURES: Research funding was provided by Sanofi to the Pharmacotherapy Outcomes Research Center at the University of Utah and SelectHealth to conduct this study. Thomas, Sterling, and Johnstone are employees and stock/shareholders of Sanofi. Kim, Unni, McAdam-Marx, and Brixner are employees of the Department of Pharmacotherapy at the University of Utah. Brixner also has served as an advisory board member and presenter for Sanofi. McAdam-Marx also reports grants to the Department of Pharmacotherapy, University of Utah, from AstraZeneca and Janssen, outside of the submitted work. Olsen is employed by SelectHealth. Part of the results of this study was presented at the Academy of Managed Care & Specialty Pharmacy Annual Meeting 2018 in Boston, MA, during April 23-26, 2018.

Clinically Relevant Herb-Micronutrient Interactions: When Botanicals, Minerals, and Vitamins Collide.

The ability of certain foods to impair or augment the absorption of various vitamins and minerals has been recognized for many years. However, the contribution of botanical dietary supplements (BDSs) to altered micronutrient disposition has received little attention. Almost half of the US population uses some type of dietary supplement on a regular basis, with vitamin and mineral supplements constituting the majority of these products. BDS usage has also risen considerably over the last 2 decades, and a number of clinically relevant herb-drug interactions have been identified during this time. BDSs are formulated as concentrated plant extracts containing a plethora of unique phytochemicals not commonly found in the normal diet. Many of these uncommon phytochemicals can modulate various xenobiotic enzymes and transporters present in both the intestine and liver. Therefore, it is likely that the mechanisms underlying many herb-drug interactions can also affect micronutrient absorption, distribution, metabolism, and excretion. To date, very few prospective studies have attempted to characterize the prevalence and clinical relevance of herb-micronutrient interactions. Current research indicates that certain BDSs can reduce iron, folate, and ascorbate absorption, and others contribute to heavy metal intoxication. Researchers in the field of nutrition may not appreciate many of the idiosyncrasies of BDSs regarding product quality and dosage form performance. Failure to account for these eccentricities can adversely affect the outcome and interpretation of any prospective herb-micronutrient interaction study. This review highlights several clinically relevant herb-micronutrient interactions and describes several common pitfalls that often beset clinical research with BDSs.