Feasibility study of microburst VNS therapy in drug-resistant focal and generalized epilepsy.

BACKGROUND: Vagus nerve stimulation (VNS) at low frequencies (≤30 Hz) has been an established treatment for drug-resistant epilepsy (DRE) for over 25 years. OBJECTIVE: To examine the initial safety and efficacy performance of an investigational, high-frequency (≥250 Hz) VNS paradigm herein called "Microburst VNS" (µVNS). µVNS consists of short, high-frequency bursts of electrical pulses believed to preferentially modulate certain brain regions. METHODS: Thirty-three (33) participants were enrolled into an exploratory feasibility study, 21 with focal-onset seizures and 12 with generalized-onset seizures. Participants were titrated to a personalized target dose of µVNS using an investigational fMRI protocol. Participants were then followed for up to 12 months, with visits every 3 months, and monitored for side-effects at all time points. This study was registered as NCT03446664 on February 27th, 2018. RESULTS: The device was well-tolerated. Reported adverse events were consistent with typical low frequency VNS outcomes and tended to diminish in severity over time, including dysphonia, cough, dyspnea, and implant site pain. After 12 months of µVNS, the mean seizure frequency reduction for all seizures was 61.3% (median reduction: 70.4%; 90% CI of median: 48.9%-83.3%). The 12-month responder rate (≥50% reduction) was 63.3% (90% CI: 46.7%-77.9%) and the super-responder rate (≥80% reduction) was 40% (90% CI: 25.0%-56.6%). Participants with focal-onset seizures appeared to benefit similarly to participants with generalized-onset seizures (mean reduction in seizures at 12 months: 62.6% focal [n = 19], versus 59.0% generalized [n = 11]). CONCLUSION: Overall, µVNS appears to be safe and potentially a promising therapeutic alternative to traditional VNS. It merits further investigation in randomized controlled trials which will help determine the impact of investigational variables and which patients are most suitable for this novel therapy.

Clinical Outcomes Associated with Amoxicillin Treatment for Acute Otitis Media in Children.

BACKGROUND: Acute otitis media (AOM) is the most common reason children are prescribed antibiotics. Bacteria that produce beta-lactamase are an increasingly frequent cause of AOM and may be resistant to amoxicillin, the currently recommended treatment for AOM. We aimed to evaluate the clinical outcomes of children treated with amoxicillin for AOM and assessed whether outcomes vary by infecting pathogen or beta-lactamase production. METHODS: 205 children 6-35 months old diagnosed with AOM and prescribed amoxicillin were included. Bacterial culture and qualitative multiplex real-time polymerase chain reaction were performed on nasopharyngeal swabs collected at enrollment. Parents completed surveys assessing symptoms, antibiotic adherence, and potential adverse events. The primary outcome was treatment failure with amoxicillin. Secondary outcomes included recurrence, symptom improvement, resolution, and adverse drug events (ADE). RESULTS: 8 children (5.4%) experienced treatment failure and 14 (6.8%) had recurrence. By day 5, 152 (74.1%) children had symptom improvement and 97 (47.3%) had resolution. Parents reported ADE for 56 (27.3%) children. Among 149 children who did not take any amoxicillin before enrollment, 98 (65.8%) had one or more beta-lactamase-producing bacteria. Common bacterial otopathogens were Moraxella catarrhalis (79, 53.0%), Streptococcus pneumoniae (51, 34.2%), Haemophilus influenzae (30, 20.1%), and Staphylococcus aureus (21, 14.1%). Treatment failure did not differ between children that did (5, 5.1%) and did not (3, 5.9%) have beta-lactamase-producing otopathogens (p = .05). CONCLUSIONS: Among children diagnosed with AOM treated with amoxicillin, treatment failure was uncommon and did not differ by pathogen or beta-lactamase production. These data support guidance recommending amoxicillin despite an increasing prevalence of beta-lactamase-producing bacteria.

Interventions to de-implement unnecessary antibiotic prescribing for ear infections (DISAPEAR Trial): protocol for a cluster-randomized trial.

BACKGROUND: Watchful waiting management for acute otitis media (AOM), where an antibiotic is used only if the child's symptoms worsen or do not improve over the subsequent 2-3 days, is an effective approach to reduce antibiotic exposure for children with AOM. However, studies to compare the effectiveness of interventions to promote watchful waiting are lacking. The objective of this study is to compare the effectiveness and implementation outcomes of two pragmatic, patient-centered interventions designed to facilitate use of watchful waiting in clinical practice. METHODS: This will be a cluster-randomized trial utilizing a hybrid implementation-effectiveness design. Thirty-three primary care or urgent care clinics will be randomized to one of two interventions: a health systems-level intervention alone or a health systems-level intervention combined with use of a shared decision-making aid. The health systems-level intervention will include engagement of a clinician champion at each clinic, changes to electronic health record antibiotic orders to facilitate delayed antibiotic prescriptions as part of a watchful waiting strategy, quarterly feedback reports detailing clinicians' use of watchful waiting individually and compared with peers, and virtual learning sessions for clinicians. The hybrid intervention will include the health systems-level intervention plus a shared decision-making aid designed to inform decision-making between parents and clinicians with best available evidence. The primary outcomes will be whether an antibiotic was ultimately taken by the child and parent satisfaction with their child's care. We will explore the differences in implementation effectiveness by patient population served, clinic type, clinical setting, and organization. The fidelity, acceptability, and perceived appropriateness of the interventions among different clinician types, patient populations, and clinical settings will be compared. We will also conduct formative qualitative interviews and surveys with clinicians and administrators, focus groups and surveys of parents of patients with AOM, and engagement of two stakeholder advisory councils to further inform the interventions. DISCUSSION: This study will compare the effectiveness of two pragmatic interventions to promote use of watchful waiting for children with AOM to reduce antibiotic exposure and increase parent satisfaction, thus informing national antibiotic stewardship policy development. CLINICAL TRIAL REGISTRATION: NCT06034080.

Associations between air pollution and the risk of first admission and multiple readmissions for cardiovascular diseases.

OBJECTIVES: We aimed to investigate the associations between air pollutants and the risk of admission and multiple readmission events for cardiovascular disease (CVD). METHODS: A total of 285 009 participants free of CVD at baseline from the UK Biobank were included in this analysis. Four major cardiovascular admission events were identified during the follow-up: chronic ischaemic heart disease (CIHD), cerebrovascular disease, atrial fibrillation and heart failure. We used Prentice, Williams and Peterson-Total Time model to examine the association between ambient air pollution and first admission, as well as multiple readmissions for these CVDs. RESULTS: During a median follow-up of 12 years, 17 176 (6.03%) participants were hospitalised with CVDs, and 6203 (36.11%) patients with CVD had subsequent readmission events for CVDs. We observed significant associations between air pollution and both first admission and readmission for CVDs, with generally stronger associations on readmission for cardiovascular events. For example, the adjusted HRs for the first admission and subsequent readmission for cerebrovascular disease were 1.130 (95% CI 1.070 to 1.194) and 1.270 (95% CI 1.137 to 1.418) for each IQR increase of particulate matter with a diameter ≤2.5 µm. The corresponding HRs for CIHD were 1.060 (95% CI 1.008 to 1.114) and 1.120 (95% CI 1.070 to 1.171). Sex stratified analyses showed that the associations were generally more pronounced among females than males. CONCLUSION: This study provides evidence that ambient air pollutants might play an important role in both first admission and readmission for cardiovascular events. In addition, patients with pre-existing CVDs may be more vulnerable to air pollution compared with healthy population.

Reducing length of antibiotics for children with ear infections: protocol for a cluster-randomized trial in the USA.

Aim: Preventing unnecessarily long durations of antibiotic therapy is a key opportunity to reduce antibiotic overuse in children 2 years of age and older with acute otitis media (AOM). Pragmatic interventions to reduce durations of therapy that can be effectively scaled and sustained are urgently needed. This study aims to fill this gap by evaluating the effectiveness and implementation outcomes of two low-cost interventions of differing intensities to increase guideline-concordant antibiotic durations in children with AOM. Methods: The higher intensity intervention will consist of clinician education regarding guideline-recommended short durations of antibiotic therapy; electronic health record (EHR) prescription field changes to promote prescribing of recommended short durations; and individualized clinician audit and feedback on adherence to recommended short durations of therapy in comparison to peers, while the lower intensity intervention will consist only of clinician education and EHR changes. We will explore the differences in implementation effectiveness by patient population served, clinician type, clinical setting and organization as well as intervention type. The fidelity, feasibility, acceptability and perceived appropriateness of the interventions among different clinician types, patient populations, clinical settings and intervention type will be compared. We will also conduct formative qualitative interviews with clinicians and administrators and focus groups with parents of patients to further inform the interventions and study. The formative evaluation will take place over 1.5 years, the interventions will be implemented over 2 years and evaluation of the interventions will take place over 1.5 years. Discussion: The results of this study will provide a framework for other healthcare systems to address the widespread problem of excessive durations of therapy for AOM and inform national antibiotic stewardship policy development. Clinical Trial Registration: NCT05608993 (ClinicalTrials.gov).

Reducing Ophthalmic Antibiotic Use for Non-severe Conjunctivitis in Children.

BACKGROUND: Antibiotics are often overprescribed for pediatric conjunctivitis. We implemented a system-level quality improvement (QI) intervention to reduce unnecessary ophthalmic antibiotic use. METHODS: The multi-faceted intervention in Denver, CO comprised a clinical care pathway, nurse protocol modifications, electronic health record (EHR) changes, parent education materials, and clinician education. We evaluated children aged 6 months-17 years with conjunctivitis seen between November 2018 and December 2022. A multi-interrupted time series model evaluated the effectiveness of the intervention over three time periods: Pre-COVID, Pre-Intervention (November 2018-February 2020), COVID, Pre-Intervention (March 2020-March 2021), and Post-Intervention (April 2021-December 2022). Fisher's exact tests compared treatment failure and healthcare utilization rates between time periods and among children receiving or not receiving ophthalmic antibiotics. RESULTS: Among 6960 eligible encounters, ophthalmic antibiotic use was reduced by 18.8% (95% CI: 16.3, 21.3) from Pre-COVID, Pre-Intervention to Post-Intervention. During the Pre-Intervention period following the onset of COVID, a reduction of 16.1% (95% CI: 12.9, 19.3) was observed. Implementation of the intervention resulted in an additional 2.7% (95% CI: -0.4, 5.7) reduction in antibiotic prescribing, primarily in younger children (ages 6 months-5 years). The greatest reduction in prescribing occurred for nurse triage encounters with an 82.1% (95% CI: 76.8, 87.5) reduction in prescribing rates (92.6%-10.5%). Treatment failure occurred in 1301 (18.7%) children and was more common among children that received an ophthalmic antibiotic than those that did not (20.0 vs 17.9%; P = .03). CONCLUSION: The QI intervention significantly reduced ophthalmic antibiotic prescribing for pediatric conjunctivitis without increasing treatment failure rates or health care utilization.

Reliability of nasopharyngeal PCR for the detection of otopathogens in children with uncomplicated acute otitis media compared to culture.

Otopathogens in acute otitis media (AOM) have implications for care because the likelihood of resolution without antibiotics and optimal antibiotic agent varies by microorganism. We aimed to determine the sensitivity, specificity, positive predictive value, and negative predictive value of nasopharyngeal (NP) qualitative polymerase chain reaction (PCR) for common bacterial otopathogens in children with AOM compared to NP culture. NP flocked swabs collected from enrolled children aged 6 to 35 months with uncomplicated AOM in Denver, CO were tested by culture and multiplex PCR. The sensitivity and negative predictive value of PCR using culture as a reference were high (H. influenzae 93.3%, 98.0%; S. pneumoniae 94.2%, 95.1%; M. catarrhalis 92.3%, 86.4%); whereas the specificity and positive predictive value were lower and varied by organism (54.2%-84.1%, 55.1%-69.2%, respectively). PCR detected 1.5 times more organisms than culture. NP PCR has a high predictive value for excluding otopathogens compared to culture and warrants exploration as a diagnostic tool.

Dietary Diversity and Inflammatory Diet Associated with All-Cause Mortality and Incidence and Mortality of Type 2 Diabetes: Two Prospective Cohort Studies.

A higher dietary diversity score (DDS) and a lower energy-adjusted dietary inflammatory index (E-DII) may be associated with lower risks of type 2 diabetes (T2D) and mortality. This cohort study aimed to investigate the associations of DDS and E-DII with all-cause mortality, incidence of T2D, and mortality of T2D, as well as the joint effects of these two dietary factors. A total of 181,360 participants without all types of diabetes at baseline from the UK Biobank and 42,139 participants from the US NHANES were included. Cox proportional hazards models were used to assess the associations of DDS and E-DII with outcomes. In the UK Biobank data, 8338 deaths, 3416 incident T2D cases, and 353 T2D deaths occurred during a median follow-up of 12.5 years. In the US NHANES data, 6803 all-cause deaths and 248 T2D-specific deaths were recorded during a median follow-up of 9.6 years. We observed that higher DDS and lower E-DII were significantly associated with lower risks of total mortality and incident T2D. Compared with low DDS, the hazard ratios (HRs) and 95% confidence intervals (CIs) of high DDS were 0.69 (0.64, 0.74) for all-cause mortality, 0.79 (0.70, 0.88) for incident T2D in the UK Biobank, and 0.69 (0.61, 0.78) for all-cause mortality in the US NHANES. Compared with participants in tertile 3 of E-DII, those in tertile 1 had a lower risk of overall death [HR 0.86 (95% CI: 0.81, 0.91) in UK Biobank; 0.83 (0.77, 0.88) in US NHANES] and incident T2D [0.86 (0.79, 0.94)] in UK Biobank. No evidence was observed of the interactive effects of DDS and E-DII on either all-cause mortality or the incidence and mortality of T2D. There was no significant association found between any exposure and T2D mortality in this study. In conclusion, our results revealed that higher DDS and lower E-DII were associated with both total mortality and incident T2D in UK and US adults.

Genetic deletion of skeletal muscle iPLA2γ results in mitochondrial dysfunction, muscle atrophy and alterations in whole-body energy metabolism.

Skeletal muscle is the major site of glucose utilization in mammals integrating serum glucose clearance with mitochondrial respiration. To mechanistically elucidate the roles of iPLA2γ in skeletal muscle mitochondria, we generated a skeletal muscle-specific calcium-independent phospholipase A2γ knockout (SKMiPLA2γKO) mouse. Genetic ablation of skeletal muscle iPLA2γ resulted in pronounced muscle weakness, muscle atrophy, and increased blood lactate resulting from defects in mitochondrial function impairing metabolic processing of pyruvate and resultant bioenergetic inefficiency. Mitochondria from SKMiPLA2γKO mice were dysmorphic displaying marked changes in size, shape, and interfibrillar juxtaposition. Mitochondrial respirometry demonstrated a marked impairment in respiratory efficiency with decreases in the mass and function of oxidative phosphorylation complexes and cytochrome c. Further, a pronounced decrease in mitochondrial membrane potential and remodeling of cardiolipin molecular species were prominent. Collectively, these alterations prevented body weight gain during high-fat feeding through enhanced glucose disposal without efficient capture of chemical energy thereby altering whole-body bioenergetics.

Sustainability of Interventions to Increase Guideline-Concordant Durations of Antibiotic Therapy for Children with Acute Otitis Media.

Two low-cost pragmatic interventions (change in the options in the electronic health record; change in the electronic health record plus education plus feedback comparing prescribing with peers) to improve prescribing of guideline-concordant short antibiotic durations for children 2 years and older with uncomplicated acute otitis media were highly effective and results were sustained 18 months after discontinuation of the active components of the interventions.

COVID-19 and Acute Otitis Media in Children: A Case Series.

BACKGROUND: The association of SARS-CoV-2 with acute otitis media (AOM) in children is poorly understood. METHODS: Cases were identified as a subpopulation within the NO TEARS prospective AOM study in Denver, CO from March to December 2020. Children enrolled were 6 to 35 months of age with uncomplicated AOM; those with AOM and SARS-CoV-2 were included. Data was obtained from electronic medical records and research case report forms. RESULTS: A total of 108 patients enrolled in the NO TEARS study from May 2019 through December 2020 (all subsequently tested for SARS CoV-2). During the COVID-19 pandemic study period (March-December 2020), 16 patients enrolled, and 7 (43.6%) were identified with AOM/COVID-19 co-infection. Fever was present in 3 of 7 children (29%). Four children (57%) attended daycare. Only 2 children (29%) had SARS CoV-2 testing as part of their clinical workup. Mean AOM-SOS© scores were similar among SARS CoV-2 positive and negative patients with no statistical significance with two-sided t-tests: 13.6 (±4.5) versus 14.2 (±4.9) at enrollment, 1.4 (±1.8) versus 4.2 (±4.9) on Day 5, and 0.6 (±0.9) versus 2.5 (±6.1) on Day 14. Among the 7 cases, no child had an AOM treatment failure or recurrence within 3 to 14 or 15 to 30 days respectively. Of the 6 patients with completed bacterial and viral testing, a bacterial pathogen was identified in all 6, and a viral pathogen in 3 (50%). CONCLUSIONS: COVID-19 and AOM can co-exist. Providers should maintain a high index of suspicion for COVID-19 even in patients with clinical AOM and should not use a diagnosis of AOM to exclude COVID-19.

Increasing Guideline-Concordant Durations of Antibiotic Therapy for Acute Otitis Media.

OBJECTIVE: To compare the effectiveness of 2 interventions in improving prescribing of guideline-concordant durations of therapy for acute otitis media (AOM). STUDY DESIGN: This was a quasi-experimental mixed methods analysis that compared a bundled quality improvement intervention consisting of individualized audit and feedback, education, and electronic health record (EHR) changes to an EHR-only intervention. The bundle was implemented in 3 pediatric clinics from January to August 2020 and an EHR-only intervention was implemented in 6 family medicine clinics. The primary outcome measure was prescription of an institutional guideline-concordant 5-day duration of therapy for children ≥2 years of age with uncomplicated AOM. Propensity score matching and differences-in-differences analysis weighted with inverse probability of treatment were completed. Implementation outcomes were assessed using the Reach, Effectiveness, Adoption, Implementation, Maintenance Framework. Balance measures included treatment failure and recurrence. RESULTS: In total, 1017 encounters for AOM were included from February 2019 to August 2020. Guideline-concordant prescribing increased from 14.4% to 63.8% (difference = 49.4%) in clinics that received the EHR-only intervention and from 10.6% to 85.2% (difference = 74.6%) in clinics that received the bundled intervention. In the adjusted analysis, the bundled intervention improved guideline-concordant durations by an additional 26.4% (P < .01) compared with the EHR-only intervention. Providers identified EHR-prescription field changes as the most helpful components. There were no differences in treatment failure or recurrence rates between baseline and either intervention. CONCLUSIONS: Both interventions resulted in improved prescribing of guideline-concordant durations of antibiotics. The bundled intervention improved prescribing more than an EHR-only intervention and was acceptable to providers.

Caregiver perspectives and preferences for acute otitis media management.

Surveyed caregivers of children in Denver, Colorado, with acute otitis media (AOM) preferred immediate antibiotics over delayed antibiotics or observation. Overall, 77% stated that they would immediately fill a prescription written as delayed. In contrast, 86% of caregivers favored whichever duration was recommended by the provider or the shortest duration necessary.

Keap1/Cullin3 Modulates p62/SQSTM1 Activity via UBA Domain Ubiquitination.

p62/SQSTM1 (p62) is a scaffolding protein that facilitates the formation and degradation of ubiquitinated aggregates via its self-interaction and ubiquitin binding domains. The regulation of this process is unclear but may relate to the post-translational modification of p62. In the present study, we find that Keap1/Cullin3 ubiquitinates p62 at lysine 420 within its UBA domain. Substitution of lysine 420 with an arginine diminishes p62 sequestration and degradation activity similar what is seen when the UBA domain is deleted. Overexpression of Keap1/Cullin3 in p62-WT-expressing cells increases ubiquitinated inclusion formation and p62's association with LC3 and rescues proteotoxicity. This effect is not seen in cells expressing a mutant p62 that fails to interact with Keap1. Interestingly, p62 disease mutants have diminished or absent UBA domain ubiquitination. These data suggest that the ubiquitination of p62's UBA domain at lysine 420 may regulate p62's function and be disrupted in p62-associated disease.