The impact of caregiver anxiety/depression symptoms and family functioning on child quality of life during pediatric cancer treatment: From diagnosis to 6 months.

A pediatric cancer diagnosis can have a significant impact on the quality of life (QOL) of the child. Diagnosis and treatment impact caregiver anxiety/depression symptoms and family functioning, and these in turn may influence child QOL. However, there has been limited longitudinal examination of the impact of both caregiver anxiety/depression symptoms and family functioning on youth QOL at specific points during the early diagnosis and treatment period.Ninety-six caregivers of youth (diagnosed with leukemia/lymphoma or a solid tumor) reported on their own anxiety/depression symptoms, family functioning, demographic and medical factors, and on their child's generic and cancer-specific QOL shortly after diagnosis (T1) and 6 months later (T2).Caregiver anxiety/depression symptoms were associated with poorer cancer-specific and generic child QOL within and across time points. Family conflict was associated with youth cancer-related QOL at T1.Attendance to caregiver anxiety/depression symptoms and family functioning, beginning early in the cancer trajectory, is an important aspect of family-centered care. Routine psychosocial screening and triage may help identify and intervene to support both caregiver and child psychosocial well-being.

Healthcare provider utility ratings of a psychosocial screening summary: from diagnosis to 6 months.

BACKGROUND: Psychosocial screening has been proposed as a core standard of care in pediatric oncology. However, there has been limited application of this standard thus far. Understanding healthcare provider (HCP) attitudes towards psychosocial screening is an important element towards furthering implementation initiatives of standard screening practices in pediatric oncology. OBJECTIVE: To compare HCP perceptions of the utility of a psychosocial risk summary by discipline (oncologist, nurse, social worker), risk level (Universal, Targeted, Clinical) derived from the Psychosocial Assessment Tool (PAT), and time (shortly after a child's diagnosis [T1] and 6 months later [T2]). METHOD: All participating HCPs (oncologists, nurses, social workers) were asked to rate how useful they found the psychosocial risk summary using a visual analogue scale (VAS). RESULTS: The psychosocial risk summary was perceived as equally useful across providers (oncologists, nurses, social workers) and PAT risk levels at T1. At T2, the psychosocial risk summary was perceived as more useful by oncologists and nurses than social workers, and summaries indicating elevated risk were perceived as more useful than those indicating low risk. Overall, healthcare providers reported greater utility of psychosocial risk summary near diagnosis compared with 6 months later, largely driven by lower utility ratings reported by social workers at T2. CONCLUSION: Understanding perceived utility and factors affecting perceived utility is a key component to designing effective implementation strategies for systematic psychosocial screening. Active engagement of HCPs in the screening process is critical in improving implementation of psychosocial screening throughout pediatric cancer treatment.

Quality of life in pediatric oncology patients, caregivers and siblings after psychosocial screening: a randomized controlled trial.

OBJECTIVE: We evaluated whether conducting psychosocial screening using a validated measure (the Psychosocial Assessment Tool, PAT) and providing a summary of PAT results to the patient's treating team improves quality of life (QOL) in newly diagnosed patients with cancer, their caregivers and siblings, in general, and in relation to the initial family psychosocial risk. METHODS: Families were randomly allocated to an intervention (IG, treating team received PAT summary describing low, medium, or high psychosocial risk) or control group (CG, no summary provided to treating team) in two Canadian pediatric cancer centers. Caregivers (N = 122) of children newly diagnosed with cancer, patients (n = 36), and siblings (n = 25) completed QOL assessments at 2-4 weeks (T1) and 6 months post-diagnosis (T2). Caregivers also completed PAT and proxy QOL for patient and sibling. RESULTS: In general, patient-proxy total QOL improved in IG compared to CG over time but only for high psychosocial risk patients (p < .05). Patient proxy cancer-related QOL improved over time regardless of group allocation; caregiver QOL also improved over time (ps < .05). CONCLUSION: This study demonstrated the benefits of psychosocial screening results only on proxy patient QOL outcomes with high psychosocial risk near diagnosis. Evaluating QOL benefits in pediatric oncology patients is critical for establishing the clinical value of psychosocial screening. CLINICAL TRIAL REGISTRATION NUMBER: NCT02788604 (REGISTERED WITH HTTPS://CLINICALTRIALS.GOV/CT2/SHOW/NCT02788604 ).

Outpatient High-dose Methotrexate for Osteosarcoma: It's Safe and Feasible, If You Want It.

BACKGROUND: High-dose methotrexate (HD MTX) is usually administered as an inpatient to those with osteosarcoma. We prospectively tested the safety and feasibility of administering HD MTX in the ambulatory setting. MATERIALS AND METHODS: In this single arm prospective observational study, eligible patients had previously completed 2 courses of HD MTX as an inpatient. On study, patients received MTX in hospital, discharged home and returned for daily assessment. Criteria to determine safety and feasibility included: (1) parent compliance with home instructions, (2) pump functioning/failure, and/or (3) admission for toxicity/noncompliance. Outpatient therapy was deemed feasible if <25% courses resulted in study event. Patient satisfaction was assessed. RESULTS: Six patients (median age, 13.5 y) with extremity osteosarcoma completed 35 courses of MTX. There were no study events-no hospitalizations or pump failures and all parents were compliant. The Data and Safety Committee concluded that with zero events in 35 courses, it was unlikely for outpatient MTX to be infeasible; study was thus terminated early. Participants reported value to stay out of hospital, permitted life to feel "more normal"; however, burden of daily commute to hospital was cited. CONCLUSIONS: The delivery of HD MTX is safe and feasible in patients with osteosarcoma.

Perceived benefits of and barriers to psychosocial risk screening in pediatric oncology by health care providers.

BACKGROUND: Although systematic psychosocial screening has been established as a standard of psychosocial care in pediatric oncology, this is not yet widely implemented in clinical practice. Limited information is available regarding the reasons behind this. In this study, we investigated perceptions of psychosocial screening by health care providers (HCPs) involved in pediatric cancer care. METHODS: Using purposeful sampling, 26 HCPs (11 oncologists, 8 nurses, and 7 social workers) from a large North American pediatric cancer center participated in semistructured interviews. Interviews were recorded and transcribed verbatim. Themes were then derived using content analysis. RESULTS: The themes were organized into perceived benefits of and barriers to psychosocial risk screening, and practical issues regarding implementation. Perceived benefits of screening included obtaining concise documentation of family psychosocial risk, identifying psychosocial factors important to medical treatment, starting a conversation, and triaging patients to psychosocial services. Barriers included perceived limited institutional support, commitment, and resources for psychosocial services, limited knowledge and appreciation of existing evidence-based validated tools, concerns about diverse family cultural backgrounds regarding psychosocial issues and language proficiency, and HCPs' personal values regarding psychosocial screening. Finally, practical issues of implementation including training in psychosocial risk screening, when and how to screen were discussed. CONCLUSIONS: These findings highlight the importance of addressing HCPs' perceptions of benefits, barriers, and practical issues regarding implementing psychosocial risk screening.

Cord Placement Model: An Instructional Guide for Preclinical Dental Students to Practice the Skill of Retraction Cord Placement.

Introduction: Gingival displacement is essential for ideal margin exposure and improved direct or indirect restorative outcome. Recent literature found many dentists prefer using retraction cord. Some contraindications of other displacement methods make retraction cord displacement preferred. It is necessary to teach dental students appropriate cord placement while minimizing gingival trauma. Methods: We developed a stone model using prepared typodont teeth and simulated gingiva that was made of polyvinylsiloxane material. Twenty-three faculty and 143 D2 students were briefed on the instructional guide. After faculty demonstration, D2 students practiced for 10-15 minutes under observation. The following year, former D2 (now D3) and D4 students were asked for feedback on the instructional experience. Results: Fifty-six percent of faculty rated the model and instructional guide good to excellent, and 65% rated the student experience as good to excellent, with only one participant rating it poor. Seventy-eight percent of D3 students strongly agreed or agreed the exercise increased their understanding of the technique in placing cord on a patient. Furthermore, 94% of D4 students strongly agreed or agreed having this exercise in preclinical D2 year would have been helpful. Discussion: Use of retraction cord to deflect gingiva is still preferred by most dentists. Completing the cord placement exercise on a model helps prepare students to perform the procedure on a patient before arriving at the clinic. Survey comments such as "useful exercise" support use of this instructional model. Overall, faculty and D3 and D4 students felt the exercise was beneficial to use in preclinical education.

Dental Bite-Sized Bits: A Module for Teaching Common Oral Health Conditions to Multidisciplinary Students.

The Surgeon General's report in the year 2000 highlighted the association between chronic diseases and oral health infections. Current healthcare education programs, regrettably, report only 1 to 3 h of oral health instruction within curricula. In the years 2020-2022, as part of their respective oral health curricula, 278 first-year physician assistant and 12 pre-clinical second-year pharmacy students were invited to participate in a voluntary survey examining the effectiveness of animated succinct, online video-based oral health units. Among all student responses for the post-use survey, respondents "strongly agreed" or "agreed" that learning objectives of the unit(s) were achieved after reviewing the videos. Of the participants, 97% "strongly agreed" or "agreed" that the videos helped them understand information of which they had no prior knowledge. Similarly, 98% "strongly agreed" or "agreed" the information was appropriate for their level of knowledge. Most students, 93%, "strongly agreed" or "agreed" the exercise was a valuable learning experience. Regarding the importance of future interprofessional collaboration pertaining to a mutual patient's oral health, 95% of participants "strongly agreed" or "agreed" that they would be likely to collaborate. This study demonstrates the importance of oral health as a critical area of focus in healthcare education. The study also confirms the hypothesis that Dental Bite-Sized Bits units deliver engaging, valuable oral health education for preclinical healthcare learners, incorporating interprofessional perspectives from the disciplines of dental, pharmacy, and physician assistant.

Creating Video-Based Education Modules for Parents of Newly Diagnosed Pediatric Patients With Cancer.

BACKGROUND: Parents of children newly diagnosed with cancer are required to understand a significant amount of new information during a time of distress. Parents of children with cancer have expressed that concise information with visual cues, which can be repeated, positively influences their ability to understand. OBJECTIVES: The primary objective was to develop 2 concise, video-based education modules that are understandable to parents of children with cancer. A secondary objective was to determine feasibility of a future trial evaluating efficacy of video-based education. METHODS: The study was conducted in phases: script development, video creation, and feasibility testing. Topics were "managing fever at home" and "giving medications at home." Content was developed by pediatric oncology experts and turned into video scripts. Scripts were refined through cognitive interviews with parents of children with cancer. Feasibility testing included recruitment of 20 parents of a child given a diagnosis of cancer within 4 weeks. Parents watched both videos and answered questions that assessed their understanding and perceived confidence. RESULTS: Final scripts were reviewed by 25 participants. Feasibility was achieved with 20 parents recruited within 7 weeks, with 100% watching both videos and answering knowledge and confidence questions. CONCLUSIONS: We successfully developed 2 educational videos for parents of children newly diagnosed with cancer. A future trial to test the efficacy of video-based education modules is feasible. IMPLICATIONS TO PRACTICE: Delivering quality education to parents of children newly diagnosed with cancer can decrease parental distress and improve safe care during a high-risk time for treatment-related morbidity and mortality.

Characterization of dihydrofolate reductases from multiple strains of Plasmodium falciparum using mathematical descriptors of their inhibitors.

Two classes of graph-theoretic molecular descriptors, viz., topological indices (TIs) and atom pairs (APs), have been used to derive high-quality quantitative structure-activity relationships (QSARs) for inhibitors of dihydrofolate reductases (DHFRs) isolated from the wild and four mutant strains of Plasmodium falciparum. Of the three methods used for QSAR formulation, viz., principal-components regression (PCR), partial least squares (PLS), and ridge regression (RR), the RR method outperformed the other two. Cohen's kappa values, based on the overlap of significant and insignificant structural descriptors calculated for the QSAR development, show that DHFR from the wild strain is substantially different from the four mutant strains. The differential QSAR approach reported in this study can be used in protocols for the development of drugs to combat drug-resistant pathogens arising continuously in nature due to mutations. The pairwise kappa values in conjunction with appropriate drug targets and their corresponding set of ligands may be a useful tool in gauging the evolving mutual similarities and dissimilarities of pathogenic organisms from purely computed mathematical descriptors of the ligands.

A community of practice in dental education: A phenomenon of newcomers becoming oldtimers.

OBJECTIVES: Community of practice (CoP) members develop cooperative learning history with shared cases, techniques, and concepts. A 2020 study was designed to explore participants' perceptions toward learning in the dental education CoP. METHODS: The Institutional Review Board exempted (AZ #1355) study involved an incidental population of third- and fourth-year dental students (N = 285) and resulted in a 43.5% response rate. The online Community of Practice Assessment Scale, consisted of Likert-style, check box items, and one open-ended question. Survey responses were categorized as Strongly Agree (1), Agree (2), No opinion (3), Disagree (4), and Strongly Disagree (5). Univariate analyses and descriptive statistics were used to analyze study variables (domain, community, and practice). RESULTS: Overall the learning domain is most strongly perceived by participants with mean scores ranging from 1.59 to 1.61. Responses assessing practices within the CoP had mean scores ranging from 1.72 to 1.90. Similarly, responses assessing the community ranged from 1.65 to 1.81. "Builds Knowledge and Shared Learning" was the characteristic participants most strongly agreed as beneficial with a 1.58 mean score. Participants agree that the CoP "Captures and Stores Tacit and Explicit Knowledge" with a mean score of 1.90. There was a 25.6% response rate to the open-ended question. Two themes evolved: the need for calibration and more shared learning. CONCLUSION: Based on study results, participants strongly agreed or agreed in opinions about CoP learning resources (faculty, staff, technology, and other students) benefitting their learning. The CoP provides an optimal environment for preparing competent new dental professionals.

Protocol for mapping psychosocial screening to resources in pediatric oncology: a pilot randomized controlled trial.

BACKGROUND: A pediatric cancer diagnosis and its treatment can have a detrimental effect on the mental health of children and their families. Screening to identify psychosocial risk in families has been recognized as a standard of care in pediatric oncology, but there has been limited clinical application of this standard thus far. A significant impediment to the implementation of psychosocial screening is the dearth of information on how to translate psychosocial screening to clinical practice, and specifically, how to follow-up from screening results. This manuscript aims to describe a protocol of a new intervention examining the feasibility and acceptability of mapping via a Psychosocial Navigator (PSN) psychosocial screening results to specific recommendations of resources for families based on measured risk for psychosocial distress and mental health symptoms. METHODS: The pilot randomized control trial (RCT) consists of dyads of youth (10-17 years) newly diagnosed with cancer and their primary caregiver. This RCT includes two arms (intervention and control group), with each group completing measurements near diagnosis and 1 year later. After the initial assessment, dyads in the intervention group receive monthly screening results and recommendations from the study PSN that are tailored to these results. The patient's primary healthcare team (nurse, social worker, oncologist) also receive the risk, distress, and mental health results as well as the recommendations from the PSN. DISCUSSION: This study addresses a significant barrier to the implementation of psychosocial screening in pediatric oncology: specifically, the limited knowledge of how to follow-up from screening results. Findings from this pilot will inform a future definitive RCT to test the effectiveness of the intervention on patient and family mental health outcomes. This project has implications for enhancing clinical care in pediatric oncology, as well as other pediatric populations. STRENGTHS AND LIMITATIONS OF THIS STUDY: This is the first study of screening and follow-up using a psychosocial navigator. This study involves both patient and caregiver report. The small sample size necessitates a future larger study to investigate the effects of intervention. TRIAL REGISTRATION: NCT04132856 , Registered 10 October 2019-retrospectively registered.

Myeloablative Busulfan/Melphalan Consolidation following Induction Chemotherapy for Patients with Newly Diagnosed High-Risk Neuroblastoma: Children's Oncology Group Trial ANBL12P1.

Consolidation using high-dose chemotherapy with autologous stem cell transplantation (ASCT) is an important component of frontline therapy for children with high-risk neuroblastoma. The optimal preparative regimen is uncertain, although recent data support a role for busulfan/melphalan (BuMel). The Children's Oncology Group (COG) conducted a trial (ANBL12P1) to assess the tolerability and feasibility of BuMel ASCT following a COG induction. Patients with newly diagnosed high-risk neuroblastoma who did not progress during induction therapy and met organ function requirements received i.v. busulfan (every 24 hours for 4 doses based on age and weight) and melphalan (140 mg/m2 for 1 dose), followed by ASCT. Busulfan doses were adjusted to achieve to an average daily area under the curve (AUC) <5500 µM × minute. The primary endpoint was the occurrence of severe sinusoidal obstruction syndrome (SOS) or grade ≥4 pulmonary complications within the first 28 days after completion of consolidation therapy. A total of 146 eligible patients were enrolled, of whom 101 underwent BuMel ASCT. The overall incidence of protocol-defined unacceptable toxicity during consolidation was 6.9% (7 of 101). Six patients (5.9%) developed SOS, with 4 (4%) meeting the criteria for severe SOS. An additional 3 patients (3%) experienced grade ≥4 pulmonary complications during consolidation. The median busulfan AUC was 4558 µM × min (range, 3462 to 5189 µM × minute) for patients with SOS and 3512 µM × min (2360 to 5455 µM × minute) (P = .0142). No patients died during consolidation. From the time of study enrollment, the mean 3-year event-free survival for all 146 eligible patients was 55.6 ± 4.2%, and the mean 3-year overall survival was 74.5 ± 3.7%. The BuMel myeloablative regimen following COG induction was well tolerated, with acceptable pulmonary and hepatic toxicity.

Prediction of Anticancer Activity of 2-phenylindoles: Comparative Molecular Field Analysis Versus Ridge Regression using Mathematical Molecular Descriptors.

Topological indices (TIs) and atom pairs (APs) were used to develop quantitative structure-activity relationships (QSARs) for anticancer activity for a set of 43 derivatives of 2-phenylindole. Results show that QSARs formulated using TI+AP outperform those using either TI or AP alone. The q2 of the ridge regression model using TI+AP was 0.867 as compared to 0.705 reported in the literature using the comparative molecular field analysis (CoMFA) method.

Psychosocial screening and mental health in pediatric cancer: A randomized controlled trial.

OBJECTIVE: Diagnosis and treatment of childhood cancer can impact the mental health of the family. Early psychosocial risk screening may help guide interventions. The primary aim of this study was to evaluate if an intervention (providing psychosocial risk information to the patient's treating team) would result in decreased depression symptoms in caregivers, in general, and relative to initial psychosocial risk. A secondary aim was to examine intervention effects in a small sample of patient and sibling self-reported outcomes. METHODS: We randomly allocated families to the intervention group (IG, treating team received PAT summary) or control group (CG, no summary). One hundred and twenty-two caregivers of children newly diagnosed with cancer completed measures of depression and anxiety and psychosocial risk 2-4 weeks from diagnosis (T1) and 6 months later (T2). Patients and siblings completed self-report measures of depression and anxiety. RESULTS: There was no significant difference in caregiver depression symptoms between the IG and CG at T2. However, in the context of psychosocial risk, caregivers in the IG showed improvement in depression scores compared to CG when risk was high near diagnosis (Ms = 6.68 vs. 9.76, respectively, d = .60). Similar results were found in anxiety scores. Intervention effects with patients and siblings were inconclusive. CONCLUSIONS: Sharing psychosocial risk information with the treating team had measurable impact on mental health outcomes only if caregivers had initial high psychosocial risk. This study contributes to our understanding of mapping psychosocial screening and resources to improve outcomes in families managing childhood cancer. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Prevention of cisplatin-induced ototoxicity in children and adolescents with cancer: a clinical practice guideline.

Despite ototoxicity being a prevalent consequence of cisplatin chemotherapy, little guidance exists on interventions to prevent this permanent and progressive adverse event. To develop a clinical practice guideline for the prevention of cisplatin-induced ototoxicity in children and adolescents with cancer, we convened an international, multidisciplinary panel of experts and patient advocates to update a systematic review of randomised trials for the prevention of cisplatin-induced ototoxicity. The systematic review identified 27 eligible adult and paediatric trials that evaluated amifostine, sodium diethyldithiocarbamate or disulfiram, systemic sodium thiosulfate, intratympanic therapies, and cisplatin infusion duration. Regarding systemic sodium thiosulfate, the panel made a strong recommendation for administration in non-metastatic hepatoblastoma, a weak recommendation for administration in other non-metastatic cancers, and a weak recommendation against its routine use in metastatic cancers. Amifostine, sodium diethyldithiocarbamate, and intratympanic therapy should not be routinely used. Cisplatin infusion duration should not be altered as a means to reduce ototoxicity. Further research to determine the safety of sodium thiosulfate in patients with metastatic cancer is encouraged.

Redox-dependent conformational changes in cytochrome C oxidase suggest a gating mechanism for proton uptake.

A role for conformational change in the coupling mechanism of cytochrome c oxidase is the subject of controversy. Relatively small conformational changes have been reported in comparisons of reduced and oxidized crystal structures of bovine oxidase but none in bacterial oxidases. Comparing the X-ray crystal structures of the reduced (at 2.15 A resolution) and oxidized forms of cytochrome c oxidase from Rhodobacter sphaeroides, we observe a displacement of heme a(3) involving both the porphyrin ring and the hydroxyl farnesyl tail, accompanied by protein movements in nearby regions, including the mid part of helix VIII of subunit I which harbors key residues of the K proton uptake path, K362 and T359. The conformational changes in the reduced form are reversible upon reoxidation. They result in an opening of the top of the K pathway and more ordered waters being resolved in that region, suggesting an access path for protons into the active site. In all high-resolution structures of oxidized R. sphaeroides cytochrome c oxidase, a water molecule is observed in the hydrophobic region above the top of the D path, strategically positioned to facilitate the connection of residue E286 of subunit I to the active site or to the proton pumping exit path. In the reduced and reduced plus cyanide structures, this water molecule disappears, implying disruption of proton conduction from the D path under conditions when the K path is open, thus providing a mechanism for alternating access to the active site.

Quantitative structure-activity relationship (QSAR) modeling of human blood: air partitioning with proper statistical methods and validation.

Blood: air partition coefficient (BApc) is important in assessing toxicokinetics of chemicals. Since very few experimental data are available, quantitative structure-activity relationship (QSAR) models based on calculated molecular descriptors can be useful in estimating BApc. Since all descriptors used in the analysis are computed strictly from structure, they can be applied to any chemical, real or hypothetical. In this article, we report models for BApc estimation using four methods, including stepwise ordinary least-squares regression, which is commonly used in QSAR studies but often results in an inflated 'naïve' q2, over-representing the predictive ability of the model. The models developed using proper statistical techniques had q2 values of 0.825 and 0.841, and may be used to reliably predict BApc values for new compounds that are structurally similar to those upon which the models are based. The models developed using improper techniques had associated q2 values, as computed using naïve methods, of 0.920 and 0.934, severely overstating their actual quality.

A conserved steroid binding site in cytochrome C oxidase.

Micromolar concentrations of the bile salt deoxycholate are shown to rescue the activity of an inactive mutant, E101A, in the K proton pathway of Rhodobacter sphaeroides cytochrome c oxidase. A crystal structure of the wild-type enzyme reveals, as predicted, deoxycholate bound with its carboxyl group at the entrance of the K path. Since cholate is a known potent inhibitor of bovine oxidase and is seen in a similar position in the bovine structure, the crystallographically defined, conserved steroid binding site could reveal a regulatory site for steroids or structurally related molecules that act on the essential K proton path.

Proton-dependent electron transfer from CuA to heme a and altered EPR spectra in mutants close to heme a of cytochrome oxidase.

Eukaryotic cytochrome c oxidase (CcO) and homologous prokaryotic forms of Rhodobacter and Paraccocus differ in the EPR spectrum of heme a. It was noted that a histidine ligand of heme a (H102) is hydrogen bonded to serine in Rhodobacter (S44) and Paraccocus CcOs, in contrast to glycine in the bovine enzyme. Mutation of S44 to glycine shifts the heme a EPR signal from g(z) = 2.82 to 2.86, closer to bovine heme a at 3.03, without modifying other properties. Mutation to aspartate, however, results in an oppositely shifted and split heme a EPR signal of g(z) = 2.72/2.78, accompanied by lower activity and drastically inhibited intrinsic electron transfer from CuA to heme a. This intrinsic rate is biphasic; the proportion that is slow is pH dependent, as is the relative intensity of the two EPR signal components. At pH 8, the heme a EPR signal at 2.72 is most intense, and the electron transfer rate (CuA to heme a) is 10-130 s(-1), compared to wild-type at 90,000 s(-1). At pH 5.5, the signal at 2.78 is intensified, and a biphasic rate is observed, 50% fast (approximately wild type) and 50% slow (90 s(-1)). The data support the prediction that the hydrogen-bonding partner of the histidine ligand of heme a is one determinant of the EPR spectral difference between bovine and bacterial CcO. We further demonstrate that the heme a redox potential can be dramatically altered by a nearby carboxyl, whose protonation leads to a proton-coupled electron transfer process.