Motivations for and against Participation in Neonatal Research: Insights from Interviews of Diverse Parents Approached for Neonatal Research in the US.

OBJECTIVE: To describe parents' motivations for and against participation in neonatal research, including the views of those who declined participation. STUDY DESIGN: We performed 44 semi-structured, qualitative interviews of parents approached for neonatal research. Here we describe their motivations for and against participation. RESULTS: Altruism was an important reason parents chose to participate. Some hoped participation in research would benefit their infant. Burdens of participation to the family, such as transportation to follow up (distinct from risks/burdens to the infant), were often deciding factors among those who declined participation. Perceived risks to the infant were reasons against participation, but parents often did not differentiate between baseline risks and incremental risk of study participation. Concerns regarding their infant being treated like a "guinea pig" were common among those who declined. Finally, historical abuses and institutional racism were reported as important concerns by some research decliners from minoritized populations. CONCLUSIONS: Within a diverse sample of parents approached to enroll their infant in neonatal research, motivations for and against participation emerged, which may be targets of future interventions. These motivations included reasons for participation which we may hope to encourage, such as altruism. They also included reasons against participation, which we may hope to, as feasible, eliminate, mitigate, or at least acknowledge. These findings can help clinical trialists, regulators, and funders attempting to improve neonatal research recruitment processes.

Practical approaches for supporting informed consent in neonatal clinical trials.

The survival and health of preterm and critically ill infants have markedly improved over the past 50 years, supported by well-conducted neonatal research. However, newborn research is difficult to undertake for many reasons, and obtaining informed consent for research in this population presents several unique ethical and logistical challenges. In this article, we explore methods to facilitate the consent process, including the role of checklists to support meaningful informed consent for neonatal clinical trials. CONCLUSION: The authors provide practical guidance on the design and implementation of an effective consent checklist tailored for use in neonatal clinical research.

Impact of the COVID-19 pandemic on pediatric faculty: a report from nine academic institutions.

BACKGROUND: The COVID-19 pandemic affected home and work routines, which may exacerbate existing academic professional disparities. Objectives were to describe the impact of the pandemic on pediatric faculty's work productivity, identify groups at risk for widening inequities, and explore mitigation strategies. METHODS: A cross-sectional study of faculty members was conducted at nine U.S. pediatric departments. Responses were analyzed by demographics, academic rank, and change in home caregiving responsibility. RESULTS: Of 5791 pediatric faculty members eligible, 1504 (26%) completed the survey. The majority were female (64%), over 40 years old (60%), and assistant professors (47%). Only 7% faculty identified as underrepresented in medicine. Overall 41% reported an increase in caregiving during the pandemic. When comparing clinical, administrative, research, and teaching activities, faculty reported worse 1-year outlook for research activities. Faculty with increased caregiving responsibilities were more likely to report concerns over delayed promotion and less likely to have a favorable outlook regarding clinical and research efforts. Participants identified preferred strategies to mitigate challenges. CONCLUSIONS: The COVID-19 pandemic negatively impacted pediatric faculty productivity with the greatest effects on those with increased caregiving responsibilities. COVID-19 was particularly disruptive to research outlook. Mitigation strategies are needed to minimize the long-term impacts on academic pediatric careers. IMPACT: The COVID-19 pandemic most negatively impacted work productivity of academic pediatric faculty with caregiving responsibilities. COVID-19 was particularly disruptive to short-term (1-year) research outlook among pediatric faculty. Faculty identified mitigation strategies to minimize the long-term impacts of the pandemic on academic pediatric career pathways.

N-of-1 trials: The epitome of personalized medicine?

Observational studies are notoriously susceptible to bias, and parallel-group randomized trials are important to identify the best overall treatment for eligible patients. Yet, such trials can be expected to be a misleading indicator of the best treatment for some subgroups or individual patients. In selected circumstances, patients can be treated in n-of-1 trials to address the inherent heterogeneity of treatment response in clinical populations. Such trials help to accomplish the ultimate goal of all biomedical research, to optimize the care of individual patients.

Pertussis and influenza immunization: perceived attitude and decision of postpartum patients.

BACKGROUND: Vaccination of pregnant patients with tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) and influenza vaccine during influenza season can reduce maternal and fetal morbidity and mortality; nevertheless, vaccination rates remain suboptimal in this patient population. To investigate the effect of a brief educational counseling session on maternal Tdap and influenza vaccination and determine factors influencing women's decision in regards to receiving Tdap and or influenza vaccine during their pregnancy. METHODS: A face-to-face semi-structured cross-sectional survey was administered to postpartum patients on their anticipated day of discharge (June 11-August 21, 2018). A brief educational counseling session about maternal pertussis and Tdap vaccine was provided to interested patients after which the Tdap vaccine was offered to eligible patients who did not receive it during their pregnancy or upon hospital admission. Medical records were reviewed to determine if surveyed patients were vaccinated prior to discharge. RESULTS: Two hundred postpartum patients were surveyed on their day of anticipated discharge. Of those who were surveyed, 103 (51.5%) had received Tdap and 80 (40.0%) had received influenza vaccinations prior to hospitalization. Among immunized patients, the common facilitators were doctor's recommendation (Tdap: 68, 54.4%; influenza: 3, 6.0%), to protect their baby (Tdap: 57, 45.6%; influenza: 17, 34.0%) and for self-protection (Tdap: 17, 13.6%; Influenza: 17, 34.0%). Of the 119 participants who had not received either Tdap or influenza vaccine prior to the survey, the barriers cited were that the vaccine was not offered by the provider (Tdap: 36, 52.2%; influenza: 29, 27.6%), belief that vaccination was unnecessary (Tdap: 5, 7.2%; influenza: 9, 8.5%), safety concerns for baby (Tdap: 4, 5.8%; influenza: 2, 1.9%). Of 97 patients who were not immunized with Tdap prior to admission but were eligible to receive vaccine, 24 (25%) were vaccinated prior to survey as part of routine hospital-based screening and vaccination program, 29 (38.2%) after our survey. CONCLUSION: Interventions to educate pregnant patients about the benefits of vaccination for their baby, addressing patient safety concerns, and vaccine administration in obstetricians' offices may significantly improve maternal vaccination rates.

A scoping review of randomized trials assessing the impact of n-of-1 trials on clinical outcomes.

BACKGROUND: The single patient (n-of-1) trial can be used to resolve therapeutic uncertainty for the individual patient. Treatment alternatives are systematically tested against each other, generating patient-specific data used to inform an individualized treatment plan. We hypothesize that clinical decisions informed by n-of-1 trials improve patient outcomes compared to usual care. Our objective was to provide an overview of the clinical trial evidence on the effect of n-of-1 trials on clinical outcomes. METHODS: A systematic search of medical databases, trial registries, and gray literature was performed to identify trials assessing clinical outcomes in a group of patients undergoing an n-of-1 trial compared to those receiving usual care for any clinical condition. We abstracted elements related to study design and results and assessed risk of bias for both the overall randomized trials and the n-of-1 trials. The review was registered on PROSPERO. (CRD: 42020166490). FINDINGS: Twelve randomized trials of the n-of-1 approach were identified in conditions spanning chronic pain, osteoarthritis, chronic irreversible airflow limitation, attention-deficit hyperactivity disorder, hyperlipidemia, atrial fibrillation, statin intolerance, and hypertension. One trial showed a statistically significant benefit in the primary outcome. Only one reached the pre-specified sample size target. Secondary outcomes showed modest benefits, including decreasing medication use, fewer atrial fibrillation episodes, and improved patient satisfaction. INTERPRETATION: Very few trials have been undertaken to assess the effectiveness of n-of-1 trials in improving clinical outcomes, and most trials were underpowered for the primary outcome. Barriers to enrollment and retention in these trials should be explored, as well-powered randomized trials are needed to clarify the clinical impact of n-of-1 trials and assess their utility in clinical practice.

Personalized Trial Ethics and Institutional Review Board Submissions.

The ethical and regulatory oversight of any clinical activity related to human subjects is commonly determined based on its categorization as either clinical practice or research. Prominent bioethicists have criticized the traditional distinctions used to delineate these categories, calling them counterproductive and outmoded, and arguing that learning and clinical practice should be deliberately and appropriately integrated. Personalized trials represent a clinical activity with characteristics that overlap both categories, making ethical and regulatory oversight requirements less straightforward. When the primary intent of the personalized trial is to assist in the conduct of individualized patient care with an emphasis on protecting the clinical decision from the biases inherent in usual clinical practice, how should this activity be regulated? In this article, we will explore the ethical underpinnings of personalized trials and propose various approaches to meeting regulatory requirements. Instead of imposing standard research regulations on the conduct of all personalized trials, we recommend that personalized trialists and IRB panels should consider whether participation in a personalized trial results in any foreseeable incremental increase in risk to the participant compared with usual care. This approach may reduce regulatory barriers, which could promote more widespread uptake of personalized trials.

Long-Term Compassionate Use of Cefiderocol To Treat Chronic Osteomyelitis Caused by Extensively Drug-Resistant Pseudomonas aeruginosa and Extended-Spectrum-ß-Lactamase-Producing Klebsiella pneumoniae in a Pediatric Patient.

We report a 15 year-old Nigerian adolescent male with chronic osteomyelitis caused by an extensively drug-resistant (XDR) Pseudomonas aeruginosa strain of sequence type 773 (ST773) carrying blaNDM-1 and an extended spectrum ß-lactamase (ESBL)-producing Klebsiella pneumoniae strain. The patient developed neurological side effects in the form of circumoral paresthesia with polymyxin B and asymptomatic elevation of transaminases with aztreonam (used in combination with ceftazidime-avibactam). Cefiderocol treatment for 14 weeks plus bone implantation resulted in apparent cure and avoided amputation.

Impact of Antibiotic Therapy in the Microbiological Yield of Healthcare-Associated Ventriculitis and Meningitis.

The impact of antibiotic therapy on the diagnosis of healthcare-associated ventriculitis and meningitis (HCAVM) is unknown. Antibiotics were administered before obtaining cerebrospinal fluid (CSF) in 217 out of 326 (66%) patients with HCAVM, and they impacted the sensitivity of the cerebrospinal fluid Gram stain and culture (P ≤ .004).

Epidemiology of Meningitis and Encephalitis in Infants and Children in the United States, 2011-2014.

BACKGROUND: Large epidemiologic studies evaluating the etiologies, management decisions and outcomes of infants and children with meningitis and encephalitis in the United States are lacking. METHODS: Children 0-17 years of age with meningitis or encephalitis as assessed by International Classification of Diseases, Ninth Revision, codes available in the Premier Healthcare Database during 2011-2014 were analyzed. RESULTS: Six thousand six hundred sixty-five patients with meningitis or encephalitis were identified; 3030 (45.5%) were younger than 1 year of age, 295 (4.4%) were 1-2 years of age, 1460 (21.9%) were 3-9 years of age, and 1880 (28.2%) were 10-17 years of age. Etiologies included enterovirus (58.4%), unknown (23.7%), bacterial (13.0%), noninfectious (3.1%), herpes simplex virus (1.5%), other viruses (0.7%), arboviruses (0.5%) and fungal (0.04%). The majority of patients were male [3847 (57.7%)] and healthy [6094 (91.4%)] with no reported underlying conditions. Most underwent a lumbar puncture in the emergency department [5363 (80%)] and were admitted to the hospital [5363 (83.1%)]. Antibiotic therapy was frequent (92.2%) with children younger than 1 year of age with the highest rates (97.7%). Antiviral therapy was less common (31.1%). Only 539 (8.1%) of 6665 of patients received steroids. Early administration of adjunctive steroids was not associated with a reduction in mortality (P = 0.266). The overall median length of stay was 2 days. Overall mortality rate (0.5%) and readmission rates (<1%) was low for both groups. CONCLUSION: Meningitis and encephalitis in infants and children in the United States are more commonly caused by viruses and are treated empirically with antibiotic therapy and antiviral therapy in a significant proportion of cases. Adjunctive steroids are used infrequently and are not associated with a benefit in mortality.

Randomized Quality Improvement Trial of Opting-In Versus Opting-Out to Increase Influenza Vaccination Rates during Pregnancy.

Introduction Despite strong recommendations, only 40.6% of pregnant women attending two prenatal clinics were vaccinated against influenza during the 2009 pandemic. We tested whether an opting-out approach would improve vaccine uptake. Methods We conducted a randomized quality improvement (QI) trial to compare opting-out with conventional opting-in consent for influenza immunization. Women age ≥ 18 years attending the University of Texas Health Science Center at Houston (UTHealth) or UT-Medical Branch (UTMB) prenatal clinics during the 2010-2011 influenza season, were eligible. Results We enrolled 280 women (140 UTHealth, 140 UTMB). Both groups had similar mean age (26.0 ± 5.5 years), mean gestational age (19.4 ± 9.5 weeks), and percent with underlying health conditions (20.7%). Vaccination rates with opting-in and opting-out were similar among all (83 vs. 84%), UTHealth (87 vs. 93%), and UTMB patients (79 vs.76%) ( p > 0.05). In subsamples of patients assessed, consent strategy did not significantly affect maternal recall of information provided. Conclusion While prenatal influenza vaccination uptake doubled from the 2009-2010 influenza season, opting-out did not perform better than opting-in, a conclusion opposite that we would have reached had this been a nonconcurrent trial. Vaccination rates dropped posttrial; hence, continued research is needed to increase the prenatal influenza immunizations.

Voriconazole Treatment for an Infant With Intractable Candida glabrata Meningitis.

We report voriconazole levels in an infant with disseminated Candida glabrata infection who received combination antifungal therapy and rescue voriconazole treatment. Serum and cerebrospinal fluid voriconazole levels were higher than anticipated and above target. Dose reduction did not lead to a reduction in the blood or cerebrospinal fluid levels. The patient did not exhibit identifiable drug toxicity.

Risk Classification for Enteroviral Infection in Children With Meningitis and Negative Gram Stain.

OBJECTIVES: Enterovirus is the most common cause of aseptic meningitis in children. This study aimed at identifying baseline variables associated with a positive cerebrospinal fluid (CSF) Enterovirus polymerase chain reaction (PCR) to aid clinicians in targeting patients who could be tested and treated as outpatients. METHODS: We performed a retrospective review of children (2 months to 17 years old) admitted to the Children's Memorial Hermann Hospital in Houston, TX, between January 2005 and December 2010 with symptoms of meningitis, CSF white cell count of greater than 5 cells/mm, and a negative CSF Gram stain, who had a CSF Enterovirus PCR. RESULTS: One hundred thirty-seven children were reviewed; median age was 4.7 (0.1-17.1) years, and 79 (58%) were male. Fifty patients (37%) had positive CSF Enterovirus PCR. Only 13 (15%) of the Enterovirus PCR-negative patients had an identifiable etiology. All patients were hospitalized. The mean hospital stay for patients with Enterovirus was 2.9 days; 88% received empiric antibiotics. Rates of antibiotic administration were not different between PCR-positive and PCR-negative groups (P > 0.05). All patients with Enterovirus had a favorable clinical outcome.A predictive model was created using 3 baseline variables independently associated with a positive Enterovirus PCR (P < 0.05): May to November presentation, CSF protein of less than 100 mg/dL, and absence of focal neurologic signs. The model classified patients into 2 risk categories for a positive Enterovirus PCR (low risk, 0% [0/17 patients]; high risk, 42% [50/120 patients]; P < 0.001). CONCLUSIONS: Our predictive model can be used to identify children for whom Enterovirus PCR testing is warranted. Such testing could avoid unnecessary hospitalization and antibiotic administration.

Aseptic meningitis in adults and children: Diagnostic and management challenges.

BACKGROUND: Aseptic meningitis represents a common diagnostic and management dilemma to clinicians. OBJECTIVES: To compare the clinical epidemiology, diagnostic evaluations, management, and outcomes between adults and children with aseptic meningitis. STUDY DESIGN: We conducted a retrospective study from January 2005 through September 2010 at 9 Memorial Hermann Hospitals in Houston, TX. Patients age≥2months who presented with community-acquired aseptic meningitis with a CSF white blood cell count >5cells/mm3 and a negative Gram stain and cultures were enrolled. Patients with a positive cryptococcal antigen, positive blood cultures, intracranial masses, brain abscesses, or encephalitis were excluded. RESULTS: A total of 509 patients were included; 404 were adults and 105 were children. Adults were most likely to be female, Caucasian, immunosuppressed, have meningeal symptoms (headache, nausea, stiff neck, photophobia) and have a higher CSF protein (P <0.05). In contrast, children were more likely to have respiratory symptoms, fever, and leukocytosis (P <0.05). In 410 (81%) patients, the etiologies remained unknown. Adults were more likely to be tested for and to have Herpes simplex virus and West Nile virus while children were more likely to be tested for and to have Enterovirus (P <0.001). The majority of patients were admitted (96.5%) with children receiving antibiotic therapy more frequently (P <0.001) and adults receiving more antiviral therapy (P=0.001). A total of 384 patients (75%) underwent head CT scans and 125 (25%) MRI scans; all were normal except for meningeal enhancement. All patients had a good clinical outcome at discharge. DISCUSSION: Aseptic meningitis in adults and children represent a management challenge as etiologies remained unknown for the majority of patients due to underutilization of currently available diagnostic techniques.

The clinical significance of neutrophilic pleocytosis in cerebrospinal fluid in patients with viral central nervous system infections.

BACKGROUND: Viral central nervous system (CNS) infections are typically characterized by a cerebrospinal fluid (CSF) lymphocytic pleocytosis. A CSF neutrophilic pleocytosis presentation has been described, but its prognostic and clinical significance is unknown. The objectives of this study were to (1) compare the clinical and laboratory characteristics of viral CNS infections with a CSF neutrophilic pleocytosis to those with a lymphocytic pleocytosis, and (2) evaluate factors associated with an adverse clinical outcome. METHODS: A retrospective study of patients with confirmed viral CNS infections was conducted. The patients were divided into those with CSF neutrophilic pleocytosis and those with CSF lymphocytic pleocytosis. Clinical findings and outcomes were compared between the two groups. RESULTS: Of the 182 patients included in the study, 45 (24.7%) had CSF neutrophilic pleocytosis. Enterovirus infections were the cause of 64% of neutrophil-predominant CSF and 33% of lymphocyte-predominant CSF (p<0.001), while herpes infections were the cause of 46% of lymphocytic pleocytosis and 20% of neutrophilic pleocytosis (p=0.003). Moreover, neutrophilic pleocytosis was seen more commonly in younger patients (p=0.001), patients with respiratory symptoms (p=0.04), and patients with higher CSF white cell counts (p=0.004). Twenty-nine patients had an adverse clinical outcome (15.9%); the only predictor independently associated with an adverse clinical outcome on multivariable logistic regression analysis was an encephalitis presentation (p=0.01). CONCLUSIONS: The results of a study exploring the association between CSF neutrophilic pleocytosis and clinical and prognostic significance are presented here. This study suggests that CSF neutrophilic pleocytosis is not associated with higher adverse clinical outcomes.