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Medication nonadherence is a leading cause of graft loss. Adherence monitoring technologies-reminder texts, smart bottles, video-observed ingestion, and digestion-activated signaling pills-may support adherence. However, patient, care partner, and clinician perceptions of these tools are not well studied. We conducted qualitative individual semistructured interviews and focus groups among 97 participants at a single center: kidney and liver transplant recipients 2 weeks to 18 months posttransplant, their care partners, and transplant clinicians. We assessed adherence practices, reactions to monitoring technologies, and opportunities for care integration. One-size-fits-all approaches were deemed infeasible. Interviewees considered text messages the most acceptable approach; live video checks were the least acceptable and raised the most concerns for inconvenience and invasiveness. Digestion-activated signaling technology produced both excitement and apprehension. Patients and care partners generally aligned in perceptions of adherence monitoring integration into clinical care. Key themes were importance of routine, ease of use, leveraging technology for actionable medication changes, and aversion to surveillance. Transplant clinicians similarly considered text messages most acceptable and video checks least acceptable. Clinicians reported that early posttransplant use and real-time adherence tracking with patient feedback may facilitate successful implementation. The study provides initial insights that may inform future adherence technology implementation.
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Cuidadores , Transplante de Rim , Humanos , Transplantados , Adesão à MedicaçãoRESUMO
COVID Watch is a remote patient monitoring program implemented during the pandemic to support home dwelling patients with COVID-19. The program conferred a large survival advantage. We conducted semi-structured interviews of 85 patients and clinicians using COVID Watch to understand how to design such programs even better. Patients and clinicians found COVID Watch to be comforting and beneficial, but both groups desired more clarity about the purpose and timing of enrollment and alternatives to text-messages to adapt to patients' preferences as these may have limited engagement and enrollment among marginalized patient populations. Because inclusiveness and equity are important elements of programmatic success, future programs will need flexible and multi-channel human-to-human communication pathways for complex clinical interactions or for patients who do not desire tech-first approaches.
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Atitude do Pessoal de Saúde , Atitude Frente a Saúde , COVID-19 , Monitorização Ambulatorial , Pacientes , Telemedicina , Humanos , COVID-19/epidemiologia , COVID-19/terapia , Pandemias , Preferência do Paciente , Pacientes/psicologia , Pacientes/estatística & dados numéricos , Monitorização Ambulatorial/métodos , Avaliação de Programas e Projetos de Saúde , Pesquisa Qualitativa , Desenvolvimento de Programas , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , IdosoRESUMO
BACKGROUND: Pharmacogenetic (PGx) testing for germline variants in the DPYD and UGT1A1 genes can be used to guide fluoropyrimidine and irinotecan dosing, respectively. Despite the known association between PGx variants and chemotherapy toxicity, preemptive testing prior to chemotherapy initiation is rarely performed in routine practice. METHODS: We conducted a qualitative study of oncology clinicians to identify barriers to using preemptive PGx testing to guide chemotherapy dosing in patients with gastrointestinal malignancies. Each participant completed a semi-structured interview informed by the Consolidated Framework for Implementation Research (CFIR). Interviews were analyzed using an inductive content analysis approach. RESULTS: Participants included sixteen medical oncologists and nine oncology pharmacists from one academic medical center and two community hospitals in Pennsylvania. Barriers to the use of preemptive PGx testing to guide chemotherapy dosing mapped to four CFIR domains: intervention characteristics, outer setting, inner setting, and characteristics of individuals. The most prominent themes included 1) a limited evidence base, 2) a cumbersome and lengthy testing process, and 3) a lack of insurance coverage for preemptive PGx testing. Additional barriers included clinician lack of knowledge, difficulty remembering to order PGx testing for eligible patients, challenges with PGx test interpretation, a questionable impact of preemptive PGx testing on clinical care, and a lack of alternative therapeutic options for some patients found to have actionable PGx variants. CONCLUSIONS: Successful adoption of preemptive PGx-guided chemotherapy dosing in patients with gastrointestinal malignancies will require a multifaceted effort to demonstrate clinical effectiveness while addressing the contextual factors identified in this study.
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Antineoplásicos/administração & dosagem , Tomada de Decisão Clínica , Neoplasias Gastrointestinais/tratamento farmacológico , Testes Farmacogenômicos , Adulto , Idoso , Antineoplásicos/uso terapêutico , Feminino , Acessibilidade aos Serviços de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Oncologistas/estatística & dados numéricos , Padrões de Prática Médica , Pesquisa QualitativaRESUMO
PURPOSE: Oncologists may overestimate prognosis for patients with cancer, leading to delayed or missed conversations about patients' goals and subsequent low-quality end-of-life care. Machine learning algorithms may accurately predict mortality risk in cancer, but it is unclear how oncology clinicians would use such algorithms in practice. METHODS: The purpose of this qualitative study was to assess oncology clinicians' perceptions on the utility and barriers of machine learning prognostic algorithms to prompt advance care planning. Participants included medical oncology physicians and advanced practice providers (APPs) practicing in tertiary and community practices within a large academic healthcare system. Transcripts were coded and analyzed inductively using NVivo software. RESULTS: The study included 29 oncology clinicians (19 physicians, 10 APPs) across 6 practice sites (1 tertiary, 5 community) in the USA. Fourteen participants had previously had exposure to an automated machine learning-based prognostic algorithm as part of a pragmatic randomized trial. Clinicians believed that there was utility for algorithms in validating their own intuition about prognosis and prompting conversations about patient goals and preferences. However, this enthusiasm was tempered by concerns about algorithm accuracy, over-reliance on algorithm predictions, and the ethical implications around disclosure of an algorithm prediction. There was significant variation in tolerance for false positive vs. false negative predictions. CONCLUSION: While oncologists believe there are applications for advanced prognostic algorithms in routine care of patients with cancer, they are concerned about algorithm accuracy, confirmation and automation biases, and ethical issues of prognostic disclosure.
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Neoplasias , Oncologistas , Algoritmos , Humanos , Aprendizado de Máquina , Oncologia , Neoplasias/terapia , PrognósticoRESUMO
BACKGROUND: Assessing the postoperative recovery of pediatric patients is challenging as there is no validated comprehensive patient-centered recovery assessment tool for this population. A qualitative investigative approach with in-depth stakeholder interviews can provide insight into the recovery process and inform the development of a comprehensive patient-centered postoperative assessment tool for children. METHODS: We conducted open-ended, semistructured interviews with children 6-12 years old undergoing elective surgery (n = 35), their parents (n = 37), and clinicians (n = 23) who commonly care for this population (nurses, anesthesiologists, and surgeons). A codebook was developed and analyzed using NVivo 12 Plus. The codebook was iteratively developed using a qualitative content analysis approach with modifications made throughout to refine codes. We report the results of this thematic analysis of patient, parent, and clinician transcripts. RESULTS: Postoperative recovery priorities/concerns overlapped and also diverged across the 3 groups. Topics prioritized by children included mobility and self-care, as well as access to a strong social support network following surgery. The majority of children reported feeling anxious about the surgery and separating from their parents, as well as sadness about their inability to participate in activities while recovering. Although children highly valued familial support during recovery, there was variable awareness of the impact of surgery on family members and support network. In contrast, parents focused on the importance of clear and open communication among themselves and the health care team and being equipped with appropriate knowledge and resources on discharge. The immediate repercussions of the child's surgery, such as pain, confusion, and nausea, appeared to be a primary focus of both parents and clinicians when describing recovery. Clinicians had a comprehensive awareness of the possible psychological impacts of surgery in children, while parents reported varying degrees of awareness or concern regarding longer-term or more latent impacts of surgery and anesthesia (eg, anxiety and depression). Prior experience with pediatric surgery emerged as a distinguishing characteristic for parents and clinicians as parents without prior experience expressed less understanding of or comfort with managing a child's recovery following surgery. CONCLUSIONS: A patient-centered qualitative investigative approach yielded insights regarding the importance of various aspects of recovery in pediatric patients, their parents, and members of the health care team. Specifically, this investigation highlighted the importance of clear communication providing anticipatory guidance for families presenting for elective surgery in an effort to optimize patient recovery. This information will be used in the development of a patient-centered recovery assessment tool.
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Anestesia , Procedimentos Cirúrgicos Eletivos , Necessidades e Demandas de Serviços de Saúde , Avaliação das Necessidades , Pais/psicologia , Equipe de Assistência ao Paciente , Assistência Centrada no Paciente , Cuidados Pós-Operatórios , Anestesia/efeitos adversos , Anestesia/psicologia , Anestesiologistas/psicologia , Atitude do Pessoal de Saúde , Criança , Comportamento Infantil , Procedimentos Cirúrgicos Eletivos/efeitos adversos , Procedimentos Cirúrgicos Eletivos/psicologia , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Entrevistas como Assunto , Masculino , Enfermeiras e Enfermeiros/psicologia , Educação de Pacientes como Assunto , Satisfação do Paciente , Pesquisa Qualitativa , Indicadores de Qualidade em Assistência à Saúde , Cirurgiões/psicologia , Resultado do TratamentoRESUMO
The burnout literature is replete with burnout score results from quantitative surveys. There is a paucity of qualitative research that seeks to understand the impact of physician stressors on work-life balance and burnout. This study aimed to identify factors that support and disrupt work-life balance, drivers of burnout, and potential solutions among academic dermatologists. The objective was to better understand factors that promote wellness and ameliorate burnout. Concurrent explanatory mixed methods consisted of scores on the Abbreviated Maslach Burnout Inventory and open-ended semi-structured telephone interviews. The results were that positive factors, such as supportive home life and satisfaction derived from academic endeavors, compete with ongoing feelings of exhaustion, frustration, and apathy. Negative stressors include the electronic medical record, insufficient staffing, administrative and clinical task burden, and perceived lack of interest from mid-level and senior health system leadership in addressing clinicians' needs. This was a single-center academic study. As with all qualitative studies, these results may not be generalizable to all dermatologists. In addition, some participants were concerned about their anonymity. Modifiable root causes of burnout require institutional commitment to sustain the pace required by academic dermatologists.
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Esgotamento Profissional , Médicos , Humanos , Dermatologistas , Esgotamento Profissional/prevenção & controle , Inquéritos e Questionários , Satisfação no EmpregoRESUMO
Opioid misuse represents a major public health issue in the United States. One driver is overprescription for acute pain, with the size of initial prescription associated with subsequent long-term use. However, little work has been done to elicit clinician feedback about interventions to reduce opioid prescribing. To address this knowledge gap, qualitative analyses were conducted with clinicians who participated in a randomized controlled trial in which clinicians received monthly emailed feedback notifications about their opioid prescribing behaviors. Semistructured telephone interviews were conducted (N = 12) with urgent care (N = 7) and emergency department (N = 5) clinicians who participated in the trial between November 2020 and April 2021. Clinicians appreciated feedback about their prescribing behavior and found comparative data with peer clinicians to be most useful. Sharing opioid prescribing feedback data with clinicians can be an acceptable way to address opioid prescribing among emergency and urgent care clinicians.
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Analgésicos Opioides , Transtornos Relacionados ao Uso de Opioides , Humanos , Estados Unidos , Analgésicos Opioides/uso terapêutico , Retroalimentação , Padrões de Prática Médica , Prescrições de MedicamentosRESUMO
BACKGROUND/OBJECTIVE: While positive airway pressure (PAP) is an efficacious intervention for the treatment of obstructive sleep apnea syndrome (OSAS) in children with Down syndrome (DS), implementation and consistent use can be difficult. Caregiver perspectives and experiences using PAP are described with the aim of informing clinical practice. METHODS: Qualitative semi-structured phone interviews were conducted with 40 caregivers (i.e., mothers) of children with DS and OSAS treated with PAP for at least 6 months. Content analysis was used to identify themes associated with adherence and non-adherence. RESULTS: Respondents indicated variability in caregiver experience with the adoption of PAP and observed benefits of PAP. Varied experiences were attributed to several themes including accessing supplies, interactions with the medical team and equipment company, and patients' unique needs and behaviors, including the child's willingness and ability to adapt to PAP, sensory sensitivities, keeping the mask on all night, and differences in daytime behavior. Many families reported that desensitization with a reward system and trust within the caregiver-patient relationship were helpful. Caregiver suggestions for improving PAP adherence for families of children with DS included improving communication with the medical team and medical equipment company, emphasizing patience, using visual supports, and social support and education for extended family. CONCLUSIONS: Although family experiences varied, several actionable strategies by both the medical team and families emerged for improving the experience of and adherence to PAP in children with DS.
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Síndrome de Down , Apneia Obstrutiva do Sono , Humanos , Criança , Cuidadores , Síndrome de Down/complicações , Pressão Positiva Contínua nas Vias Aéreas , Cooperação do PacienteRESUMO
Blood cultures are fundamental in diagnosing and treating sepsis in the pediatric intensive care unit (PICU), but practices vary widely. Overuse can lead to false positive results and unnecessary antibiotics. Specific factors underlying decisions about blood culture use and overuse are unknown. Therefore, we aimed to identify perceived determinants of blood culture use in the PICU. Methods: We conducted semistructured interviews of clinicians (M.D., D.O., R.N., N.P., P.A.) from 6 PICUs who had participated in a quality improvement collaborative about blood culture practices. We developed interview questions by combining elements of the Consolidated Framework for Implementation Research and behavioral economics. We conducted telephone interviews, open-coded the transcripts, and used modified content analysis to determine key themes and mapped themes to elements of Consolidated Framework for Implementation Research and behavioral economics. Results: We reached thematic saturation in 24 interviews. Seven core themes emerged across 3 Consolidated Framework for Implementation Research domains: individual characteristics [personal belief in the importance of blood cultures, the perception that blood cultures are a low-risk test]; inner setting [adherence to site-specific usual practices, site-specific overall approach to PICU care (collaborative versus hierarchical), influence of non-PICU clinicians on blood culture decisions]; and outer setting [patient-specific risk factors, sepsis guidelines]. In addition, outcome bias, default bias, and loss aversion emerged as salient behavioral economics concepts. Conclusions: Determinants of blood culture use include individual clinician characteristics, inner setting, and outer setting, as well as default bias, outcome bias, and loss aversion. These determinants will now inform the development of candidate strategies to optimize culture practices.
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BACKGROUND: There is a lack of racial, ethnic, and sex diversity in recruitment research registries and Alzheimer's disease (AD) research studies and trials. Theory-based recruitment messages may provide an opportunity to increase study participant diversity in AD research studies and trials. OBJECTIVE: To identify behavioral, normative, and control beliefs that are associated with joining an AD-focused recruitment registry among historically underrepresented groups. METHOD: Using a Reasoned Action Approach, we conducted 60 semi-structured phone interviews in 2020 among White, Black, and Hispanic adults ages 49-79 years in Philadelphia, PA. Underlying beliefs were elicited for the target behavior of "signing up to be on a registry for brain health research studies in the next month." Percentages based on counts are reported for the overall sample and by race and ethnicity and sex. RESULTS: Participants were most concerned that if they were to sign up for a registry, they would be asked to participate in experimental studies. Advancing science to help others was a commonly reported positive belief about signing up. Participants' children and friends/neighbors were important from a normative perspective. Barriers to enrollment focused on logistical concerns and inconvenient sign-up processes, including using a computer. Results show generally few racial and ethnic or sex group differences. CONCLUSION: The elicited beliefs from underrepresented groups offer a basis for understanding the behavior of signing up for research registries. However, there were few differences between the groups. Implications for outreach and recruitment are discussed.
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Doença de Alzheimer , Idoso , População Negra , Etnicidade , Hispânico ou Latino , Humanos , Masculino , Sistema de RegistrosRESUMO
Home pulse oximeters prescribed for infants with cardiorespiratory conditions generate many false alarms, which create caregiver stress and sleep disturbance and can lead to unsafe practices. Additionally, relationships among oximeters, alarms, and everyday living demands are not well understood. Therefore, we aimed to gather parent perspectives on home pulse oximetry monitoring during the problem analysis phase of a quality improvement (QI) initiative. Methods: We purposively sampled and interviewed parents of infants prescribed home pulse oximeters and receiving local home care company services. We based questions on systems engineering frameworks previously used in healthcare. Data were coded iteratively and analyzed deductively (theoretical frameworks) and inductively (emerging themes). Results: Generally, themes aligned with theoretical frameworks. Parents expressed dissatisfaction with the number of false alarms home pulse oximeters generate, which parents primarily attributed to poor probe adhesiveness and the inability of oximeters to account for infant movement. Interviews highlighted the burden associated with poor device tones and portability. Device-related issues had negative repercussions for the entire family related to sleep quality, mobility, and social interactions. Universally, parents developed workarounds, including cessation of monitoring. Conclusions: Parents of infants monitored at home using pulse oximetry face many challenges, resulting in compromises in safety. Continuing to instruct parents to comply with prescribed monitoring recommendations may be unrealistic. Instead, we suggest re-engineering the home monitoring system with the needs and goals of children and their families at the center. Our description of adapting qualitative research and systems engineering methods may benefit others developing QI work.
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Background: Early serious illness conversations (SICs) about goals of care and prognosis improve mood, quality of life, and end-of-life care quality. Algorithm-based behavioral nudges to oncologists increase the frequency and timeliness of such conversations. However, clinicians' perspectives on such nudges are unknown. Design: Qualitative study consisting of semistructured interviews among medical oncology clinicians who participated in a stepped-wedge cluster randomized trial of Conversation Connect, an algorithm-based intervention consisting of behavioral nudges to promote early SICs in the outpatient oncology setting. Results: Of 79 eligible oncology clinicians, 56 (71%) were approached to participate in interviews and 25 (45%) accepted. Key facilitators to algorithm-based nudges included prompting documentation of conversations, peer comparisons, performance reports, and validating norms around early conversations. Barriers included cancer-specific heterogeneity in algorithm performance and the frequency and tone of text messages. Areas of improvement included utilizing different information channels, identifying patients earlier in the disease trajectory, and incorporating patient-targeted messaging that emphasizes the value of early conversations. Conclusions: Oncology clinicians identified key facilitators and barriers to Conversation Connect. These insights inform future algorithm-based supportive care interventions in oncology. Controlled trial (NCT03984773).
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Planejamento Antecipado de Cuidados , Oncologistas , Humanos , Qualidade de Vida , Comunicação , AlgoritmosRESUMO
INTRODUCTION: Pulse oximetry monitoring is prescribed to children receiving home oxygen for chronic medical conditions associated with hypoxemia. Although home pediatric pulse oximetry is supported by national organizations, there is a lack of guidelines outlining indications and prescribing parameters. METHODS: A mixed-methods analysis of pediatric home pulse oximetry orders prescribed through the institutional home healthcare provider at a large US children's hospital 6/2018-7/2019 was retrospectively reviewed to determine prescribed alarm parameter limits and recommended interventions. Semi-structured qualitative interviews with pediatric providers managing patients receiving home oxygen and pulse oximetry were conducted to identify opportunities to improve home pulse oximetry prescribing practices. Interviews were analyzed using a modified content analysis approach to identify recurring themes. RESULTS: A total of 368 children received home pulse oximetry orders. Orders were most frequently prescribed on noncardiac medical floors (32%). Attending physicians were the most frequent ordering providers (52%). Frequency of use was prescribed in 96% of orders, however, just 70% were provided with specific instructions for interventions when alarms occurred. Provider role and clinical setting were significantly associated with the presence of a care plan. Provider interviews identified opportunities for improvement with the device, management of alarm parameter limits, and access to home monitor data. DISCUSSION: This study demonstrated significant variability in home pulse oximetry prescribing practices. Provider interviews highlighted the importance of the provider-patient relationship and areas for improvement. There is an opportunity to create standardized guidelines that optimize the use of home monitoring devices for patients, families, and pulmonary providers.
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Oximetria , Alta do Paciente , Criança , Hospitais Pediátricos , Humanos , Monitorização Fisiológica , Estudos RetrospectivosRESUMO
BACKGROUND: We previously conducted a prospective cohort study (n=1610) demonstrating that the implementation of a validated calculator to predict likelihood of cesarean delivery during labor induction was associated with reduced maternal morbidity, reduced cesarean delivery rate, and improved birth satisfaction. OBJECTIVE: To optimize future implementation, we used qualitative interviews to understand the clinician perspective on: (1) the cesarean delivery risk calculator implementation and (2) the mechanisms by which the use of the calculator resulted in the observed improved outcomes. STUDY DESIGN: After completion of the prospective study (June 30, 2019), 20 trainees and attending clinicians (including nurse-midwives, obstetrical physicians, and family medicine physicians) at the study site participated in a single, brief semistructured interview from March 1, 2020, to June 30, 2020. Transcriptions were coded using a systematic approach. RESULTS: Overall, clinicians had favorable perspectives regarding the cesarean delivery risk calculator. Clinicians described the calculator as offering "objective data" and a "standardized snapshot of the labor trajectory." Concerns were raised regarding "overreliance" on calculator output. Barriers to use included time for patient counseling and "awkwardness" around the interactions and perceived patient misunderstanding of the calculator result. Although most senior clinicians (n=8) reported that the calculator did not impact patient management, trainee clinicians (n=12) more often felt that the calculator influenced care at the extremes of cesarean delivery risk. Furthermore, more senior clinicians felt "neutral" regarding any impact of counseling patients on cesarean delivery risk compared with trainee clinicians, who felt that the counseling "built [patient-clinician] trust." CONCLUSION: This qualitative evaluation characterized the generally positive clinician perspective around the cesarean delivery risk calculator, while identifying specific facilitators and barriers to implementation. In addition, we elucidated potential mechanisms by which the calculator may have been related to clinician decision making and patient-clinician interactions, leading to reduced maternal morbidity and improved patient birth satisfaction. This information is important as widespread implementation of the cesarean delivery risk calculator begins.
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Trabalho de Parto , Enfermeiros Obstétricos , Cesárea , Feminino , Humanos , Trabalho de Parto Induzido , Gravidez , Estudos ProspectivosRESUMO
INTRODUCTION: Acne often persists into adulthood in women. However, few studies have specifically explored the lived experience of acne in adult populations. OBJECTIVE: To examine the lived experience of acne and its treatment among a cohort of adult women. DESIGN, SETTING, AND PARTICIPANTS: A qualitative analysis was conducted from free listing and open-ended, semistructured interviews of patients at a large academic health care system (University of Pennsylvania Health System) and a private practice (Dermatologists of Southwest Ohio). Fifty women 18 to 40 years of age with moderate to severe acne participated in interviews conducted between August 30, 2019, and December 31, 2020. MAIN OUTCOMES AND MEASURES: Free-listing data from interviews were used to calculate the Smith S, a measure of saliency for each list item. Semistructured interviews were examined to detect themes about patient perspectives regarding their acne and its treatment. RESULTS: Fifty participants (mean [SD] age, 28 [5.38] years; 24 [48%] White) described acne-related concerns about their appearance that affected their social, professional, and personal lives, with many altering their behavior because of their acne. Depression, anxiety, and social isolation were commonly reported. Participants described successful treatment as having completely clear skin over time or a manageable number of blemishes. Many participants described frustration with finding a dermatologist with whom they were comfortable and with identifying effective treatments for their acne. CONCLUSIONS AND RELEVANCE: The results of this qualitative study suggest that women with acne have strong concerns about appearance and experience mental and emotional health consequences and disruption of their personal and professional lives. In addition, many patients describe challenges finding effective treatments and accessing care. Future trials to understand the optimal treatment approaches for women with acne are needed to improve outcomes in this population.
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Acne Vulgar , Acne Vulgar/psicologia , Acne Vulgar/terapia , Adulto , Estudos de Coortes , Feminino , Humanos , Pesquisa Qualitativa , Pele , Resultado do TratamentoRESUMO
Dihydroorotate dehydrogenases (DHODs) oxidize dihydroorotate (DHO) to orotate using the FMN prosthetic group to abstract a hydride equivalent from C6 and a protein residue (Ser for Class 2 DHODs) to deprotonate C5. The fundamental question of whether the scission of the two DHO C-H bonds is concerted or stepwise was addressed for two Class 2 enzymes, those from Escherichia coli and Homo sapiens, by determining kinetic isotope effects on flavin reduction in anaerobic stopped-flow experiments. Isotope effects were determined for the E. coli enzyme at two pH values below a previously reported pKa controlling reduction [Palfey, B. A., Björnberg, O., and Jensen K. F. (2001) Biochemistry 40, 4381-4390] and were about 3-fold for DHO labeled at the 5-position, about 4-fold for DHO labeled at the 6-position, and about 6-7-fold for DHO labeled at both the 5- and 6-positions. These isotope effects are consistent with either a stepwise oxidation of DHO or a concerted mechanism with significant quantum mechanical tunneling. At a pH value above the pKa controlling reduction, no isotope effect was observed in E. coli DHOD for DHO deuterated at the 5-position (the proton donor in the reaction). This is consistent with a stepwise reaction; above the (kinetic) pKa, the deprotonation of C5 is fast enough that it does not contribute to the observed rate constant and, therefore, is not isotopically sensitive. All available information points to Ser acting as a component in a proton relay network which allows its transient deprotonation. The H. sapiens DHOD also appears to have a pKa near 9.4 controlling reduction, similar to that previously reported for the E. coli enzyme. Similar KIEs were obtained with the H. sapiens enzyme at a pH value below the pKa.