Process Development of a Macrocyclic Peptide Inhibitor of PD-L1.

This article outlines the process development leading to the manufacture of 800 g of BMS-986189, a macrocyclic peptide active pharmaceutical ingredient. Multiple N-methylated unnatural amino acids posed challenges to manufacturing due to the lability of the peptide to cleavage during global side chain deprotection and precipitation steps. These issues were exacerbated upon scale-up, resulting in severe yield loss and necessitating careful impurity identification, understanding the root cause of impurity formation, and process optimization to deliver a scalable synthesis. A systematic study of macrocyclization with its dependence on concentration and pH is presented. In addition, a side chain protected peptide synthesis is discussed where the macrocyclic protected peptide is extremely labile to hydrolysis. A computational study explains the root cause of the increased lability of macrocyclic peptide over linear peptide to hydrolysis. A process solution involving the use of labile protecting groups is discussed. Overall, the article highlights the advancements achieved to enable scalable synthesis of an unusually labile macrocyclic peptide by solid-phase peptide synthesis. The sustainability metric indicates the final preparative chromatography drives a significant fraction of a high process mass intensity (PMI).

An Opportunity in Cancer Prevention: Human Papillomavirus Vaccine Delivery in the Hospital.

OBJECTIVE: Pediatric hospitalizations are a missed opportunity for delivery of the human papilloma virus (HPV) vaccination. In this study, the authors' aim was to increase HPV vaccination rates among adolescents cared for by the pediatric hospital medicine (PHM) service at our academic children's hospital. METHODS: This quality improvement (QI) study included adolescents ≥13 years who were discharged from PHM. Interventions included: modification of discharge order sets to include vaccination status and provider training seminars regarding the delivery of the HPV vaccine. Follow-up materials were distributed to providers by e-mail. The primary outcome measure was adolescent HPV vaccination rates. Secondary outcome measures were adolescent meningococcal vaccination rates and accuracy of immunization status documentation. The balancing measure was length of stay (LOS). Data were collected via chart review. Statistical process control charts were used to analyze for special cause variation. RESULTS: From May 2019 through February 2020, 440 patients were included in this analysis. Throughout the study, HPV and meningococcal vaccination rates increased from a baseline median of 4.6% to 21.2% and 8.3% to 26.6%, respectively. HPV vaccination was not significantly associated with sex, HPV dose due, or admitting service. Accuracy of immunization status documentation and LOS remained unchanged. CONCLUSIONS: Using QI methodology we were successful in increasing HPV and meningococcal vaccination rates among hospitalized adolescents. Considering the relationship of these 2 vaccines is a potential topic of future work. Discerning the correct immunization status at time of admission may be a potential opportunity for improvement in future work.

Comparison of Symptoms and Antibody Response Following Administration of Moderna or Pfizer SARS-CoV-2 Vaccines.

CONTEXT.­: Moderna (mRNA-1272) and Pfizer (BNT162b2) SARS-CoV-2 vaccines demonstrate favorable safety and efficacy profiles, but direct comparison data are lacking. OBJECTIVE.­: To determine the vaccines' side effect profiles and expected antibody responses. These data may help personalize vaccine selection and identify individuals with a suboptimal vaccine response. DESIGN.­: One hundred forty-nine healthy, largely seronegative adults were assigned Moderna (n = 79) or Pfizer (n = 70). Following the second dose, participants completed a survey documenting their side effects. Serum was collected 0 to 4 days prior to dose 2, and 14 ± 4 days, 30 ± 4 days, 90 ± 10 days, and 180 ± 20 days after dose 2. Convalescent serum specimens were collected 32 to 54 days from donors after a polymerase chain reaction-confirmed SARS-CoV-2 infection (n = 20). Anti-spike antibodies were measured using the Roche Diagnostics Elecys Anti-SARS-CoV-2 S assay on a Roche cobas e801 instrument. RESULTS.­: Participants receiving the Moderna vaccine experienced side effects with greater frequency and severity. Both vaccines elicited a robust antibody response, but median signal was higher in Moderna recipients. Symptom severity decreased with age. Antibody response in Pfizer recipients negatively correlated with age. Antibody response decreased after 6 months (84% reduction in Moderna, 79% Pfizer), but values remained greater than for convalescent donors. Antibody response did not correlate with gender or symptom severity. CONCLUSIONS.­: Moderna may be preferred in individuals in need of greater immune stimulation (eg, older individuals), whereas Pfizer may be preferred in those concerned about vaccine reactions. Anti-spike antibody signal varies by vaccine, so specific reference intervals will be needed to identify individuals with a suboptimal response.

Using Quality Improvement Methodology to Increase Communication of Discharge Criteria on Rounds.

OBJECTIVE: Clear communication about discharge criteria with families and the interprofessional team is essential for efficient transitions of care. Our aim was to increase the percentage of pediatric hospital medicine patient- and family-centered rounds (PFCR) that included discharge criteria discussion from a baseline mean of 32% to 75% over 1 year. METHODS: We used the Model for Improvement to conduct a quality improvement initiative at a tertiary pediatric academic medical center. Interventions tested included (1) rationale sharing, (2) PFCR checklist modification, (3) electronic discharge SmartForms, (4) data audit and feedback and (5) discharge criteria standardization. The outcome measure was the percentage of observed PFCR with discharge criteria discussed. Process measure was the percentage of PHM patients with criteria documented. Balancing measures were rounds length, length of stay, and readmission rates. Statistical process control charts assessed the impact of interventions. RESULTS: We observed 700 PFCR (68 baseline PFCR from July to August 2019 and 632 intervention period PFCR from November 2019 to June 2021). At baseline, discharge was discussed during 32% of PFCR. After rationale sharing, checklist modification, and criteria standardization, this increased to 90%, indicating special cause variation. The improvement has been sustained for 10 months.At baseline, there was no centralized location to document discharge criteria. After development of the SmartForm, 21% of patients had criteria documented. After criteria standardization for common diagnoses, this increased to 71%. Rounds length, length of stay, and readmission rates remained unchanged. CONCLUSION: Using quality improvement methodology, we successfully increased verbal discussions of discharge criteria during PFCR without prolonging rounds length.

Cardiac Physical Exam Skills and Auscultation Session for Pediatric Interns.

Introduction: Physicians need adequate physical exam skills. Unfortunately, interns have variable physical exam skills, and teaching is often limited to rounds, an inconsistent setting. Physical exam skills, particularly those involving auscultation, require practice. Our goal was to create a cardiac physical exam workshop for pediatric interns that would improve their performance on an interactive assessment of their ability and understanding in physical exam and murmur interpretation. Methods: We completed a targeted needs assessment and then developed a 2-hour workshop on the pediatric cardiac physical exam targeted to pediatrics residents. The workshop included didactics, group discussion, and practice interpreting common pediatric murmurs. Pediatrics residents completed the assessment as a pretest and then participated in the workshop. At the end of the workshop, the assessment was administered as a posttest, followed by a reassessment 3 months later. Nonparametric statistical analysis was conducted. Pre- and posttest scores were compared using the Wilcoxon signed rank test. Results: Twenty-five residents completed the workshop, including 22 pediatrics residents, one pediatrics/anesthesia combined resident, one pediatric neurology resident, and one resident completing a preliminary year in pediatrics prior to dermatology residency. There was a significant increase in the mean score on the assessment from pre- to posttest (pretest M = 54%, posttest M = 71%, p < .001). This increase was sustained at the 3-month reassessment (M = 67%). Discussion: This cardiac physical exam workshop demonstrated improvement in physical exam knowledge and interpretation ability as measured by an online pre-/posttest.

P(III) vs P(V): A P(V) Reagent for Thiophosphoramidate Linkages and Application to an Asymmetric Synthesis of a Cyclic Dinucleotide STING Agonist.

A highly stereoselective synthesis of a cyclic dinucleotide (CDN) STING agonist containing two chiral thiophosphoramidate linkages is described. These rare yet key functional groups were, for the first time, installed efficiently and with high diastereoselectivity using a specially designed P(V) reagent. By utilizing this strategy, the CDN was prepared in greater than 16-fold higher yield than the prior P(III) approach, with fewer hazardous reagents and chromatographic purifications.

Stereoselective and Divergent Aza-Adenosine and Aza-Guanosine Syntheses from Xylofuranose, the Key Fragments of a STING Cyclic Dinucleotide Agonist.

The stereoselective and divergent synthesis of two aza-nucleosides is reported. Starting from xylofuranose 9, aza-adenosine 2 was prepared in 13 steps and 7% overall yield, and aza-guanosine 3 was prepared in 13 steps and 7.8% overall yield. Compared to the original syntheses, some advantages of these new routes are significant yield improvement, overall step-count reduction, an optimized protecting group strategy, the development of a versatile platform for nitrogenous base incorporation, and the elimination of hazardous reagents (e.g., benzyl isocyanate, Et3N·HF).

Meet the Team: A Quality Improvement Initiative to Improve Family Knowledge of Their Care Team.

OBJECTIVES: Hospitalized families often have poor knowledge of care team members, which can negatively impact communication. Local baseline data revealed that few families had knowledge of team members. Our primary aim was to increase the percentage of families able to identify a member of their team to 75% over 1 year and sustain use of our improvement tools over 6 months. METHODS: We conducted a quality improvement initiative at a tertiary pediatric academic center. Plan-do-study-act cycles were used to implement and test 3 main interventions: (1) a "Meet the Team" form (MTTF), a visual handout outlining care team members; (2) verbal introductions at the start of patient- and family-centered rounds (PFCR); and (3) data sharing regarding family feedback about tool use. The outcome measure was the percentage of families successfully identifying team members. Process measures were the percentage of families who received the MTTF and the percentage of PFCR that included verbal introductions. Balancing measures included rounds length. RESULTS: We conducted structured interviews of 141 families and observed 11 597 PFCR events. There was an increase in the percentage of families who could identify a team member from 10% to 84%. The percentage of PFCR events that included verbal introductions revealed special cause variation, increasing from 40% to 80%. Rounds length held steady at ∼11 minutes per patient. CONCLUSIONS: Implementing paired interventions of MTTF distribution and verbal team introductions was associated with increased family knowledge of team members and no change in rounds length.

Pausing During the Pandemic: Addressing Cognitive Biases in Providers' Medical Decision-Making During the COVID-19 Era.

INTRODUCTION: The COVID-19 pandemic has not only exacerbated traditional cognitive biases but also created new cognitive biases specific to the pandemic that contribute to diagnostic errors. Cases of suspected multisystem inflammatory syndrome in children (MIS-C)-one of the more clinically significant manifestations of COVID-19 in children-need to be reported and reviewed by clinicians as they have varied presentations and lack definitive confirmatory testing, presenting challenges to effective diagnosis. CASE PRESENTATION: We present 3 cases of pediatric patients initially diagnosed with COVID-19/MIS-C who were ultimately found to have alternative diagnoses. DISCUSSION: For each case, we describe conventional and COVID-19-related cognitive biases to enhance awareness of their role in diagnostics and promote strategies to support diagnostic accuracy and timeliness. CONCLUSION: With rapidly changing knowledge about COVID-19 and MIS-C, providers must remain diligent to counteract heuristic thinking and provide timely and accurate diagnostic evaluations.

Taking the Pulse on Pediatric Simulation: A National Survey of Pediatric Residency Programs' Simulation Practices and Challenges.

OBJECTIVES: There is abundant literature on simulation use in individual pediatric residency programs but limited overall data on simulation in US pediatric residency programs. This study sought to determine how US pediatric residency programs use simulation for teaching and assessment and the challenges programs face in their use of simulation. METHODS: The Association of Pediatric Program Director's Healthcare Simulation in Pediatrics Learning Community members developed a 15-multipart question survey on the use of simulation in US pediatric residency programs using best practices in survey design. The survey was distributed electronically to US pediatric residency program directors. Qualitative questions were analyzed by content analysis and quantitative questions using descriptive statistics. RESULTS: The survey response rate was 21%; respondents were disproportionately from large academic medical centers. Qualitative analysis found that respondents use simulation to teach pediatric residents in the areas of urgent/emergent situations, procedures, and communication, and common challenges to simulation implementation are time, physical resources, expertise, competing priorities, logistics, and buy-in. Quantitative analysis demonstrated that, although respondents are largely confident that their simulation programs improve resident preparedness and competence, few objectively evaluate their simulation programs. CONCLUSIONS: Pediatric residency programs use simulation for similar purposes and face similar challenges. By collaborating, the resources of the national pediatric simulation community can be leveraged to collect evidence for best practices for simulation use in pediatric residency training.

A novel faculty development tool for writing a letter of recommendation.

OBJECTIVE: Based on a national survey of program directors we developed a letter of recommendation (LOR) scoring rubric (SR) to assess LORs submitted to a pediatric residency program. The objective was to use the SR to analyze: the consistency of LOR ratings across raters and LOR components that contributed to impression of the LOR and candidate. METHODS: We graded 30 LORs submitted to a pediatric residency program that were evenly distributed based on final rank by our program. The SR contained 3 sections (letter features, phrases, and applicant abilities) and 2 questions about the quality of the LOR (LORQ) and impression of the candidate (IC) after reading the LOR on a 5-point Likert scale. Inter-rater reliability was calculated with intraclass correlation coefficients (ICC(2,1)). Pearson (r) correlations and stepwise multivariate linear regression modeling predicted LORQ and IC. Mean scores of phrases, features, and applicant abilities were analyzed with ANOVA and Bonferroni correction. RESULTS: Phrases (ICC(2,1) = 0.82, p<0.001)) and features (ICC(2,1) = 0.60, p<0.001)) were rated consistently, while applicant abilities were not (ICC(2,1) = 0.28, p<0.001)). For features, LORQ (R2 = 0.75, p<0.001) and IC (R2 = 0.58, p<0.001) were best predicated by: writing about candidates' abilities, strength of recommendation, and depth of interaction with the applicant. For abilities, LORQ (R2 = 0.47, p<0.001) and IC (R2 = 0.51, p<0.001) were best predicted by: clinical reasoning, leadership, and communication skills (0.2). There were significant differences for phrases and features (p<0.05). CONCLUSIONS: The SR was consistent across raters and correlates with impression of LORQ and IC. This rubric has potential as a faculty development tool for writing LORS.

Pulse oral corticosteroids in pediatric chronic inflammatory demyelinating polyneuropathy.

Childhood onset chronic inflammatory demyelinating polyneuropathy (CIDP) often requires long-term immunomodulatory therapy. We report a comprehensive review of our treatment of pediatric CIDP with a focus on high-dose weekly corticosteroids ("pulse oral corticosteroids"), a treatment method that is not commonly reported. We retrospectively reviewed medical records of pediatric patients with CIDP treated at our center between 2000 and 2018 for whom we had at least 12 mo follow-up. Here, we describe the demographics, disease course, treatment regimens, and long-term outcomes of these patients. Twenty-five patients were identified for analysis. Pulse oral corticosteroid monotherapy was the predominant maintenance treatment in 56% of patients. Patients were followed for a median of 4 y. Side effects were seen in a minority of patients. The probability of a normal exam or being off treatment at last follow-up was similar regardless of predominant maintenance therapy. Pulse oral corticosteroid therapy is a safe and effective long-term treatment option in children with CIDP.

Not Throwing Away My Shot: Leveraging a Peer Vaccination Workshop to Increase Residents' Immunization Skills.

OBJECTIVE: The Accreditation Council for Graduate Medical Education (ACGME) requires that pediatric residents demonstrate competence administering immunizations. Despite mandatory simulation training, less than half our residents reported immunization competence. All residents need to receive their influenza vaccination, but schedule restrictions present logistical challenges. We implemented a peer influenza immunization workshop and assessed the impact on resident immunization competence compared to simulation-only training. METHODS: Prospective cohort study at a pediatric residency program in a tertiary academic center. We implemented an annual influenza immunization workshop including immunization education, simulated practice, and peer influenza immunization. We compared workshop participation to simulation-only training on resident confidence immunizing, number of immunizations logged, and ACGME survey results for immunization skills. RESULTS: In 2019, 80% (N = 59) of residents participated in the workshop. Participants were more likely to report confidence in immunization skills than nonparticipants (P = .001). Resident-administered immunizations increased from 1 in the 3 years preceding workshop implementation to 74 during the 2019 to 2020 academic year. Significantly, more ACGME survey respondents reported preparedness to immunize after workshop implementation (P = .02). CONCLUSIONS: Implementation of an influenza immunization workshop provides an innovative opportunity to increase resident preparedness performing an ACGME-required procedure while also helping ensure programs remain compliant with influenza requirements.

Clinical Guideline Highlights for the Hospitalist: Clostridium difficile Infections in Children.

GUIDELINE TITLE: Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). RELEASE DATE: February 15, 2018 PRIOR VERSIONS: Cohen SH, Gerding DN, Johnson S, et al; Society for Healthcare Epidemiology of America; Infectious Diseases Society of America. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol. 2010; 31:431-55.Gerding DN, Johnson S, Peterson LR, et al. Clostridium difficile-associated diarrhea and colitis. Infect Control Hosp Epidemiol 1995;16:459-477. DEVELOPER: IDSA and SHEA. FUNDING SOURCE: Support for this guideline was provided by the IDSA and SHEA. TARGET POPULATION: Children and adults with Clostridium difficile infections.

Using Quality Improvement to Change Testing Practices for Community-acquired Pneumonia.

BACKGROUND: National guidelines for pediatric community-acquired pneumonia (CAP) contain recommendations regarding diagnostic testing including chest radiographs (CXRs), complete blood counts (CBCs), and blood cultures. Local data indicated that our institution was not delivering care at standards outlined by these guidelines. This project aimed to decrease CXRs for children with CAP discharged from the emergency department (ED) by 10% and decrease CBCs and blood cultures for patients hospitalized with uncomplicated CAP by 20% within 1 year. METHODS: This single-site quality improvement initiative targeted otherwise healthy children 3 months to 18 years who presented to the ED with uncomplicated CAP at a free-standing academic children's hospital. A quality improvement team performed a series of interventions including guideline implementation, data sharing, and annual education. Process measures included CXR, CBC, and blood culture rates. Balancing measures included the number of patients diagnosed with CAP, the frequency of antibiotic use, length of stay, and ED and hospital return rates. The team used statistical process control charts to plot measures. RESULTS: There was special cause improvement with a desirable downward shift in testing that correlated with the project's interventions. The percentage of CXRs for discharged patients decreased from 79% to 57%. CBCs and blood cultures for hospitalized patients decreased from 30% to 19% and 24% to 14%, respectively. Balancing measures remained unchanged. CONCLUSIONS: We used elements of quality improvement methodology to reduce testing for uncomplicated CAP without impacting the number of patients diagnosed with CAP, the frequency of antibiotic use, length of stay, and reutilization rates.

De novo KCNA1 variants in the PVP motif cause infantile epileptic encephalopathy and cognitive impairment similar to recurrent KCNA2 variants.

Derangements in voltage-gated potassium channel function are responsible for a range of paroxysmal neurologic disorders. Pathogenic variants in the KCNA1 gene, which encodes the voltage-gated potassium channel Kv1.1, are responsible for Episodic Ataxia Type 1 (EA1). Patients with EA1 have an increased incidence of epilepsy, but KCNA1 variants have not been described in epileptic encephalopathy. Here, we describe four patients with infantile-onset epilepsy and cognitive impairment who harbor de novo KCNA1 variants located within the Kv-specific Pro-Val-Pro (PVP) motif which is essential for channel gating. The first two patients have KCNA1 variants resulting in (p.Pro405Ser) and (p.Pro405Leu), respectively, and a set of identical twins has a variant affecting a nearby residue (p.Pro403Ser). Notably, recurrent de novo variants in the paralogous PVP motif of KCNA2 have previously been shown to abolish channel function and also cause early-onset epileptic encephalopathy. Importantly, this report extends the range of phenotypes associated with KCNA1 variants to include epileptic encephalopathy when the PVP motif is involved.

Greening in sunflower butter cookies as a function of egg replacers and baking temperature.

Chlorogenic acid (CGA) binding to proteins in alkaline conditions results in the production of green trihydroxy benzacradine (TBA) derivatives. The formation of TBA derivatives could decrease product quality due to the potential losses in soluble protein and antioxidants and the production of an undesirable green color. To determine how cookie formulation affected the formation of TBA derivatives in sunflower butter cookies, two egg replacers (chia and banana) and two baking temperatures (162.8 and 190.6 °C) were used. Moisture, greening intensity, CGA content and antioxidant capacity were measured. Cookies made with egg and baked at 162.8 °C had the highest moisture, internal greening intensity, and TBA derivative formation, in addition to lower CGA content and antioxidant capacity. Cookies made with banana baked at 190.6 °C produced the opposite outcome with 35, 4, and 23% less internal greening, moisture, and TBA derivatives, respectively, and 90 and 76% higher CGA and antioxidant capacity. Internal greening was positively correlated with moisture and adduct concentration, and negatively correlated with spread factor and CGA content. Moisture had a significant impact on greening, which indicates that baking temperature and cookie dough formulation can be modified to produce a less green cookie with more unreacted antioxidants and protein.

Project IMPACT Pilot Report: Feasibility of Implementing a Hospital-to-Home Transition Bundle.

BACKGROUND AND OBJECTIVES: To improve hospital to home transitions, a 4-element pediatric patient-centered transition bundle was developed, including: a transition readiness checklist; predischarge teach-back education; timely and complete written handoff to the primary care provider; and a postdischarge phone call. The objective of this study was to demonstrate the feasibility of bundle implementation and report initial outcomes at 4 pilot sites. Outcome measures included postdischarge caregiver ability to teach-back key home management information and 30-day reuse rates. METHODS: A multisite, observational time series using multiple planned sequential interventions to implement bundle components with non-technology-supported and technology-supported patients. Data were collected via electronic health record reviews and during postdischarge phone calls. Statistical process control charts were used to assess outcomes. RESULTS: Four pilot sites implemented the bundle between January 2014 and May 2015 for 2601 patients, of whom 1394 had postdischarge telephone encounters. Improvement was noted in the implementation of all bundle elements with the transitions readiness checklist posing the greatest feasibility challenge. Phone contact connection rates were 69%. Caregiver ability to teach-back essential home management information postdischarge improved from 18% to 82%. No improvement was noted in reuse rates, which differed dramatically between technology-supported and non-technology-supported patients. CONCLUSIONS: A pediatric care transition bundle was successfully tested and implemented, as demonstrated by improvement in all process measures, as well as caregiver home management skills. Important considerations for successful implementation and evaluation of the discharge bundle include the role of local context, electronic health record integration, and subgroup analysis for technology-supported patients.