Requirements for efficient correction of ΔF508 CFTR revealed by analyses of evolved sequences.

Misfolding of ΔF508 cystic fibrosis (CF) transmembrane conductance regulator (CFTR) underlies pathology in most CF patients. F508 resides in the first nucleotide-binding domain (NBD1) of CFTR near a predicted interface with the fourth intracellular loop (ICL4). Efforts to identify small molecules that restore function by correcting the folding defect have revealed an apparent efficacy ceiling. To understand the mechanistic basis of this obstacle, positions statistically coupled to 508, in evolved sequences, were identified and assessed for their impact on both NBD1 and CFTR folding. The results indicate that both NBD1 folding and interaction with ICL4 are altered by the ΔF508 mutation and that correction of either individual process is only partially effective. By contrast, combination of mutations that counteract both defects restores ΔF508 maturation and function to wild-type levels. These results provide a mechanistic rationale for the limited efficacy of extant corrector compounds and suggest approaches for identifying compounds that correct both defective steps.

Catching Those Who Fall Through the Cracks: Integrating a Follow-Up Process for Emergency Department Patients with Incidental Radiologic Findings.

STUDY OBJECTIVE: Abnormal findings unrelated to the indication for testing are identified on emergency department (ED) imaging studies. We report the design and implementation of an electronic health record-based interdisciplinary referral system and our experience from the first 13 months of ensuring that patients with incidental radiology findings were connected with the appropriate outpatient surveillance. METHODS: Our informatics team standardized the contemporaneous reporting of critical radiology alerts using our ED trackboard and created a companion follow-up request form for the treating ED clinicians to complete. The forms were routed to nurse case managers, who arranged follow-ups based on the findings and clinical significance. The primary outcome was the proportion of ED patient visits with identified incidental findings that had documented communication of the incidental findings and surveillance plans. RESULTS: Over the first 13 months after implementation, 932 ED patient visits had critical radiology alert referrals, for a total of 982 incidental findings. The primary outcome (confirmed post-ED communication and documented follow-up plan) was attained in 888 (95.3%, 95% confidence interval [CI] 93.9% to 96.6%) ED patient visits with confirmed post-ED communication and documented follow-up plans. The team was unable to contact or confirm follow-up with 44 (4.7%, 95% CI 3.4 to 6.1) patients by telephone or through the health care system's electronic communication tools. CONCLUSION: We report the implementation of a standardized notification and referral system for ED patients with incidental radiology findings. The development of a reliable notification and follow-up system is an important patient safety intervention given the opportunity to potentially identify undiagnosed malignancies.

Assessment of a Naloxone Coprescribing Alert for Patients at Risk of Opioid Overdose: A Quality Improvement Project.

BACKGROUND: Patients taking high doses of opioids, or taking opioids in combination with other central nervous system depressants, are at increased risk of opioid overdose. Coprescribing the opioid-reversal agent naloxone is an essential safety measure, recommended by the surgeon general, but the rate of naloxone coprescribing is low. Therefore, we set out to determine whether a targeted clinical decision support alert could increase the rate of naloxone coprescribing. METHODS: We conducted a before-after study from January 2019 to April 2021 at a large academic health system in the Southeast. We developed a targeted point of care decision support notification in the electronic health record to suggest ordering naloxone for patients who have a high risk of opioid overdose based on a high morphine equivalent daily dose (MEDD) ≥90 mg, concomitant benzodiazepine prescription, or a history of opioid use disorder or opioid overdose. We measured the rate of outpatient naloxone prescribing as our primary measure. A multivariable logistic regression model with robust variance to adjust for prescriptions within the same prescriber was implemented to estimate the association between alerts and naloxone coprescribing. RESULTS: The baseline naloxone coprescribing rate in 2019 was 0.28 (95% confidence interval [CI], 0.24-0.31) naloxone prescriptions per 100 opioid prescriptions. After alert implementation, the naloxone coprescribing rate increased to 4.51 (95% CI, 4.33-4.68) naloxone prescriptions per 100 opioid prescriptions (P < .001). The adjusted odds of naloxone coprescribing after alert implementation were approximately 28 times those during the baseline period (95% CI, 15-52). CONCLUSIONS: A targeted decision support alert for patients at risk for opioid overdose significantly increased the rate of naloxone coprescribing and was relatively easy to build.

Age-related patterns of cytomegalovirus antibodies accompanying Epstein-Barr virus co-infection.

OBJECTIVE: Cytomegalovirus (CMV) infection is associated with age-related chronic disease, and co-infection with Epstein-Barr virus (EBV) may compound disease risk. We aimed to assess the frequency of CMV infection and its relationship with age among EBV seropositive individuals in an Indigenous Amazonian population. METHODS: We report concentrations of CMV and EBV antibodies in dried blood spot samples collected from 157 EBV positive Shuar participants aged 15-86 years (60.5% female) to assess CMV infection rate. We used logistic and linear regression models to examine associations among CMV, EBV, and age, adjusting for sex, geographic region, and body mass index. RESULTS: Nearly two-thirds (63.1%) of EBV seropositive participants were also CMV seropositive. A 1-year increase in age was associated with 3.4% higher odds of CMV infection (OR [95% CI]: 1.034 [1.009-1.064], p = .012), but CMV antibody concentration was not significantly associated with age or EBV antibody concentration among co-infected individuals. CONCLUSIONS: Herpesvirus-related immunosenescence may be important to understanding chronic disease risk among Shuar. Future studies should further explore the role of co-infection in shaping age-related changes in immune function.

Transplant social worker and donor financial assistance to increase living donor kidney transplants among African Americans: The TALKS Study, a randomized comparative effectiveness trial.

Lack of donors hinders living donor kidney transplantation (LDKT) for African Americans. We studied the effectiveness of a transplant social worker intervention (TALK SWI) alone or paired with living donor financial assistance to activate African Americans' potential living kidney donors. African Americans (N = 300) on the transplant waiting list were randomly assigned to usual care; TALK SWI; or TALK SWI plus Living Donor Financial Assistance. We quantified differences in live kidney donor activation (composite rate of live donor inquiries, completed new live donor evaluations, or live kidney donation) after 12 months. Participants' mean age was 52 years, 56% were male, and 43% had annual household income less than $40,000. Most previously pursued LDKT. Participants were highly satisfied with TALK social workers, but they rarely utilized Financial Assistance. After 12 months, few (n = 39, 13%) participants had a new donor activation event (35 [12%] new donor inquiries; 17 [6%] new donor evaluations; 4 [1%] LDKT). There were no group differences in donor activation events (subdistribution hazard ratio [95% CI]: 1.09 [0.51-2.30] for TALK SWI and 0.92 [0.42-2.02] for TALK SWI plus Financial Assistance compared to Usual Care, p = 91). Alternative interventions to increase LDKT for African Americans on the waiting list may be needed. Trial registration: ClinicalTrials.gov (NCT02369354).

Characteristics and outcomes of atrial fibrillation in patients without traditional risk factors: an RE-LY AF registry analysis.

AIMS: Data on patient characteristics, prevalence, and outcomes of atrial fibrillation (AF) patients without traditional risk factors, often labelled 'lone AF', are sparse. METHODS AND RESULTS: The RE-LY AF registry included 15 400 individuals who presented to emergency departments with AF in 47 countries. This analysis focused on patients without traditional risk factors, including age ≥60 years, hypertension, coronary artery disease, heart failure, left ventricular hypertrophy, congenital heart disease, pulmonary disease, valve heart disease, hyperthyroidism, and prior cardiac surgery. Patients without traditional risk factors were compared with age- and region-matched controls with traditional risk factors (1:3 fashion). In 796 (5%) patients, no traditional risk factors were present. However, 98% (779/796) had less-established or borderline risk factors, including borderline hypertension (130-140/80-90 mmHg; 47%), chronic kidney disease (eGFR < 60 mL/min; 57%), obesity (body mass index > 30; 19%), diabetes (5%), excessive alcohol intake (>14 units/week; 4%), and smoking (25%). Compared with patients with traditional risk factors (n = 2388), patients without traditional risk factors were more often men (74% vs. 59%, P < 0.001) had paroxysmal AF (55% vs. 37%, P < 0.001) and less AF persistence after 1 year (21% vs. 49%, P < 0.001). Furthermore, 1-year stroke occurrence rate (0.6% vs. 2.0%, P = 0.013) and heart failure hospitalizations (0.9% vs. 12.5%, P < 0.001) were lower. However, risk of AF-related re-hospitalization was similar (18% vs. 21%, P = 0.09). CONCLUSION: Almost all patients without traditionally defined AF risk factors have less-established or borderline risk factors. These patients have a favourable 1-year prognosis, but risk of AF-related re-hospitalization remains high. Greater emphasis should be placed on recognition and management of less-established or borderline risk factors.

A model for rapid emergency department expansion for the COVID-19 pandemic.

COVID-19 has caused global dramatic change in medical practices including the introduction of temporary screening and assessment areas outside the footprint of the main hospital structures. Following the initial surge of patients with novel coronavirus (2019-nCoV) in the United States, our medical center rapidly designed and constructed an alternative assessment and treatment site in a converted parking garage deck for emergency department patients with suspected or confirmed 2019-nCoV. During the first month after opening, 651 patients were treated in this alternative assessment area including 54 patients who tested positive for 2019-nCoV. This accounted for 55% of the 98 patients with confirmed novel coronavirus (2019-nCoV) who were treated in our ED. This report provides a blueprint for the necessary steps, materials, labor needs and barriers, both anticipated and unanticipated, to rapidly construct an alternative ED treatment site during a pandemic.

Ankle brachial index (ABI) in a cohort of older women in the Philippines: Prevalence of peripheral artery disease and predictors of ABI.

OBJECTIVE: Cardiovascular disease (CVD) is rising in low and middle-income countries, but studies of CVD epidemiology in such settings often focus on risk factors rather than measures of disease progression. Here we use the ankle brachial index (ABI) to assess the prevalence of peripheral artery disease (PAD) among older women living in Metropolitan Cebu, Philippines, and relationships between ABI and CVD risk factors and body composition. METHODS: ABI was measured using the Doppler technique in 538 female participants in the 2015 Cebu Longitudinal Health and Nutrition Survey (mean age 58 years, range 47-78 years). ABI was related to a panel of CVD risk factors measured in 2005 and 2012, and to 2012 body composition measures. RESULTS: The prevalence of PAD (1.8%) was among the lowest reported in any comparably-aged sample, and only 9.9% of participants had an ABI indicating borderline PAD risk. Smoking (P < 0.011) and use of CVD medications (P < 0.0001) predicted lower ABI (indicating higher PAD risk), which was also lower in relation to 2012 systolic blood pressure (P < 0.054). ABI was unrelated to other CVD risk factors. An apparent protective relationship between body mass index (BMI) and ABI, noted in previous studies, was found to be confounded by protective relationships between ABI and fat free mass, height, and grip strength (all P < 0.05). CONCLUSIONS: The prevalence of PAD is low in Cebu Longitudinal Health and Nutrition Survey participants, and ABI was related to few CVD risk factors. Past reports of lower PAD risk in relation to BMI may reflect confounding by lean mass, which has protective relationships with ABI.

Impact of revised triage to improve throughput in an ED with limited traditional fast track population.

BACKGROUND: Emergency department (ED) crowding is associated with patient safety concerns, increased patients left without being seen (LWBS), low patient satisfaction, and lost ED revenue. The objective was to measure the impact of a revised triage process on ED throughput. METHODS: This study took place at an urban, university-affiliated, adult ED with an annual census of 70,000 and admission rate of 34%. The revised triage approach included: identifying eligible patients at triage based on complaint, comorbidities, and illness acuity; and reallocating a nurse practitioner (NP) into our triage area. We trialed the intervention from 1100-2300 on weekdays from January 13-26, 2016. Adult patients who were not likely to require intensive evaluations were eligible. Primary outcomes were throughput measures including: time to provider, ED length of stay (LOS), and LWBS. Pre- and post-intervention metrics were compared using the Mann-Whitney U test, given the non-normal distribution of the metrics. RESULTS: The NP evaluated 120 patients of which 101 (84%) were discharged, 3 (2.5%) admitted, and 16 (13%) required more intense evaluation. Time to provider decreased from a median (IQR) of 42 (16, 114) to 27 (12.4, 81.5) minutes (p<0.01) and ED LOS from 290 (194.8, 405.6) to 257 (171.2, 363.4) minutes (p<0.01) for all patients not admitted and not requiring a consult. LWBS decreased from a pre-trial 4.6% to 2.2% (p<0.01). CONCLUSION: The revised triage intervention was associated with improvements in several ED throughput metrics and a reduction in LWBS.

Chronic Noncommunicable Diseases in 6 Low- and Middle-Income Countries: Findings From Wave 1 of the World Health Organization's Study on Global Ageing and Adult Health (SAGE).

In this paper, we examine patterns of self-reported diagnosis of noncommunicable diseases (NCDs) and prevalences of algorithm/measured test-based, undiagnosed, and untreated NCDs in China, Ghana, India, Mexico, Russia, and South Africa. Nationally representative samples of older adults aged ≥50 years were analyzed from wave 1 of the World Health Organization's Study on Global Ageing and Adult Health (2007-2010; n = 34,149). Analyses focused on 6 conditions: angina, arthritis, asthma, chronic lung disease, depression, and hypertension. Outcomes for these NCDs were: 1) self-reported disease, 2) algorithm/measured test-based disease, 3) undiagnosed disease, and 4) untreated disease. Algorithm/measured test-based prevalence of NCDs was much higher than self-reported prevalence in all 6 countries, indicating underestimation of NCD prevalence in low- and middle-income countries. Undiagnosed prevalence of NCDs was highest for hypertension, ranging from 19.7% (95% confidence interval (CI): 18.1, 21.3) in India to 49.6% (95% CI: 46.2, 53.0) in South Africa. The proportion untreated among all diseases was highest for depression, ranging from 69.5% (95% CI: 57.1, 81.9) in South Africa to 93.2% (95% CI: 90.1, 95.7) in India. Higher levels of education and wealth significantly reduced the odds of an undiagnosed condition and untreated morbidity. A high prevalence of undiagnosed NCDs and an even higher proportion of untreated NCDs highlights the inadequacies in diagnosis and management of NCDs in local health-care systems.

Surface ECG f Wave Analysis at Initial Onset of Paroxysmal and Persistent Atrial Fibrillation.

INTRODUCTION: Dominant frequency (DF) analysis of electrocardiograms (ECGs) from patients with paroxysmal (PAF) and persistent (PeAF) atrial fibrillation has identified higher DFs in PeAF. We therefore hypothesized that among patients initially presenting to the emergency department (ED) with new onset AF, surface ECG features could differentiate PeAF from PAF. METHODS AND RESULTS: Initial 12-lead ECGs from patients presenting to the ED with a first episode of symptomatic AF were analyzed. Following QRS-T subtraction, fast Fourier transform (FFT) analysis of the AF fibrillatory waves was performed to measure DF and organization index (OI). Median DF of all leads and the DF in the lead with maximum OI were determined. Maximum f wave amplitude and vector magnitudes were measured. One hundred sixty-one patients (age 59 ± 16 years, 68% men) were included in this analysis, of whom 96 (58%) spontaneously converted to sinus rhythm within 7 days (PAF group). The remaining 65 patients underwent cardioversion or remained in AF (PeAF group). ECG features (DF, OI, f wave amplitude, and vector magnitude) did not differ among PAF and PeAF patients. CONCLUSIONS: ECG features (DF, OI, amplitude, vector magnitude) do not differ among patients with PAF versus PeAF when the ECGs are obtained at the initial onset of symptoms. Thus, prior data showing higher DF in PeAF likely reflect electrophysiologic remodeling rather than a marker for any specific type of AF or extent of underlying substrate.

Renal Function and Scaled Troponin in Patients Presenting to the Emergency Department with Symptoms of Myocardial Infarction.

BACKGROUND: Cardiac troponins are often found to be elevated in patients with renal dysfunction, even in the absence of acute myocardial injury. The objective of this report was to characterize the scaled troponin values and proportion of adjudicated acute myocardial infarction (AMI) among patients with and without renal dysfunction. METHODS: The data was from a multicenter prospective study including patients presenting to the emergency department with symptoms of AMI. Troponin measurements were standardized across various assays by calculating the observed results as multiples of the assay-specific 99th percentile upper limit of normal. Patients with an estimated glomerular filtration rate (eGFR; calculated by the Chronic Kidney Disease Epidemiology Collaboration formula) <60 mL/min/1.73 m2 were considered to have renal dysfunction. RESULTS: Of 430 included patients, 249 (58%) were male and 181 (42%) were female, with a mean age of 55.9 ± 12.3 and 57.3 ± 12.8 years, respectively. Eighty-seven (20.2%) had renal dysfunction. The proportions of patients with at least one scaled troponin value above the 99th percentile cut-off point among patients with and without renal dysfunction were 40 (45.9%) and 81 (23.6%) respectively (p < 0.001). The proportions of patients with an adjudicated diagnosis of AMI among those with and without renal dysfunction were 20.7 and 18.7%, respectively (p = 0.67). Using scaled troponins, by the second test there was >5X and by the third test >15X separation in the excursion of troponin among those with AMI compared to those without. CONCLUSIONS: One or more elevated troponin values are common in those with renal dysfunction. Scaled troponins for eGFR groups were similar, indicating that the use of this interpretative technique is applicable in discerning AMI for those with and without renal dysfunction.

Comparison of Etomidate and Ketamine for Induction During Rapid Sequence Intubation of Adult Trauma Patients.

STUDY OBJECTIVE: Induction doses of etomidate during rapid sequence intubation cause transient adrenal dysfunction, but its clinical significance on trauma patients is uncertain. Ketamine has emerged as an alternative for rapid sequence intubation induction. Among adult trauma patients intubated in the emergency department, we compare clinical outcomes among those induced with etomidate and ketamine. METHODS: The study entailed a retrospective evaluation of a 4-year (January 2011 to December 2014) period spanning an institutional protocol switch from etomidate to ketamine as the standard induction agent for adult trauma patients undergoing rapid sequence intubation in the emergency department of an academic Level I trauma center. The primary outcome was hospital mortality evaluated with multivariable logistic regression, adjusted for age, vital signs, and injury severity and mechanism. Secondary outcomes included ICU-free days and ventilator-free days evaluated with multivariable ordered logistic regression using the same covariates. RESULTS: The analysis included 968 patients, including 526 with etomidate and 442 with ketamine. Hospital mortality was 20.4% among patients induced with ketamine compared with 17.3% among those induced with etomidate (adjusted odds ratio [OR] 1.41; 95% confidence interval [CI] 0.92 to 2.16). Patients induced with ketamine had ICU-free days (adjusted OR 0.80; 95% CI 0.63 to 1.00) and ventilator-free days (adjusted OR 0.96; 95% CI 0.76 to 1.20) similar to those of patients induced with etomidate. CONCLUSION: In this analysis spanning an institutional protocol switch from etomidate to ketamine as the standard rapid sequence intubation induction agent for adult trauma patients, patient-centered outcomes were similar for patients who received etomidate and ketamine.