Predicting Adverse Events Among Patients With COPD Exacerbations in the Emergency Department.

BACKGROUND: COPD exacerbations lead to excessive health care utilization, morbidity, and mortality. The Ottawa COPD Risk Scale (OCRS) was developed to predict short-term serious adverse events (SAEs) among patients in the emergency department (ED) with COPD exacerbations. We assessed the utility of the OCRS, its component elements, and other clinical variables for ED disposition decisions in a United States population. METHODS: We compared the OCRS and other factors in predicting SAEs among a retrospective cohort of ED patients with COPD exacerbations. We followed subjects for 30 d, and the primary outcome, SAE, was defined as any death, admission to monitored unit, intubation, noninvasive ventilation, major procedure, myocardial infarction, or revisit with hospital admission. RESULTS: A total of 246 subjects (median 61-y old, 46% male, total admission rate to ward 52%) were included, with 46 (18.7%) experiencing SAEs. Median OCRS scores did not differ significantly between those with and without an SAE (difference: 0 [interquartile range 0-1)]. The OCRS predicted SAEs poorly (Hosmer-Lemeshow goodness of fit [H-L GOF] P ≤ .001, area under the receiver operating characteristic [ROC] curve 0.519). Three variables were significantly related to SAEs in our final model (H-L GOF P = .14, area under the ROC curve 0.808): Charlson comorbidity index (odds ratio [OR] 1.3 [1.1-1.5] per 1-point increase); triage venous PCO2 (OR 1.7 [1.2-2.4] per 10 mm Hg increase); and hospitalization within previous year (OR 9.1 [3.3-24.8]). CONCLUSIONS: The OCRS did not reliably predict SAEs in our population. We found 3 risk factors that were significantly associated with 30-d SAE in our United States ED population: triage [Formula: see text] level, Charlson comorbidity index, and hospitalization within the previous year. Further studies are needed to develop generalizable decision tools to improve safety and resource utilization for this patient population.

COPD Care Bundle in Emergency Department Observation Unit Reduces Emergency Department Revisits.

BACKGROUND: COPD exacerbations lead to accelerated decline in lung function, poor quality of life, and increased mortality and cost. Emergency department (ED) observation units provide short-term care to reduce hospitalizations and cost. Strategies to improve outcomes in ED observation units following COPD exacerbations are needed. We sought to reduce 30-d ED revisits for COPD exacerbations managed in ED observation units through implementation of a COPD care bundle. The study setting was an 800-bed, academic, safety-net hospital with 700 annual ED encounters for COPD exacerbations. Among those discharged from ED observation unit, the 30-d all-cause ED revisit rate (ie, the outcome measure) was 49% (baseline period: August 2014 through September 2016). METHODS: All patients admitted to the ED observation unit with COPD exacerbations were included. A multidisciplinary team implemented the COPD bundle using iterative plan-do-study-act cycles with a goal adherence of 90% (process measure). The bundle, adopted from our inpatient program, was developed using care-delivery failures and unmet subject needs. It included 5 components: appropriate inhaler regimen, 30-d inhaler supply, education on devices available after discharge, standardized discharge instructions, and a scheduled 15-d appointment. We used statistical process-control charts for process and outcome measures. To compare subject characteristics and process features, we sampled consecutive patients from the baseline (n = 50) and postbundle (n = 83) period over 5-month and 7-month intervals, respectively. Comparisons were made using t tests and chi-square tests with P < .05 significance. RESULTS: During baseline and postbundle periods, 410 and 165 subjects were admitted to the ED observation unit, respectively. After iterative plan-do-study-act cycles, bundle adherence reached 90% in 6 months, and the 30-d ED revisit rate declined from 49% to 30% (P = .003) with a system shift on statistical process-control charts. There was no difference in hospitalization rate from ED observation unit (45% vs 51%, P = .16). Subject characteristics were similar in the baseline and postbundle periods. CONCLUSIONS: Reliable adherence to a COPD care bundle reduced 30-d ED revisits among those treated in the ED observation unit.

Subunit interfaces contribute differently to activation and allosteric modulation of neuronal nicotinic acetylcholine receptors.

Neuronal nicotinic acetylcholine receptors (nAChRs) are widely distributed in the nervous system and are implicated in many normal and pathological processes. The structural determinants of allostery in nAChRs are not well understood. One class of nAChR allosteric modulators, including the small molecule morantel (Mor), acts from a site that is structurally homologous to the canonical agonist site but exists in the ß(+)/α(-) subunit interface. We hypothesized that all nAChR subunits move with respect to each other during channel activation and allosteric modulation. We therefore studied five pairs of residues predicted to span the interfaces of α3ß2 receptors, one at the agonist interface and four at the modulator interface. Substituting cysteines in these positions, we used disulfide trapping to perturb receptor function. The pair α3Y168-ß2D190, involving the C loop region of the ß2 subunit, mediates modulation and agonist activation, because evoked currents were reduced up to 50% following oxidation (H2O2) treatment. The pair α3S125-ß2Q39, below the canonical site, is also involved in channel activation, in accord with previous studies of the muscle-type receptor; however, the pair is differentially sensitive to ACh activation and Mor modulation (currents decreased 60% and 80%, respectively). The pairs α3Q37-ß2A127 and α3E173-ß2R46, both in the non-canonical interface, showed increased currents following oxidation, suggesting that subunit movements are not symmetrical. Together, our results from disulfide trapping and further mutation analysis indicate that subunit interface movement is important for allosteric modulation of nAChRs, but that the two types of interfaces contribute unequally to receptor activation.

Feedback to achieve improved sign-out technique.

To maximize the quality of sign-out documents within the internal medicine residency, a quality improvement intervention was developed and implemented. Written sign-outs were collected from general medicine ward teams and graded using an 11-point checklist; in-person feedback was then given directly to the ward teams. Documentation of many of the 11 elements improved: mental status (22% to 66%, P < .0001), decisionality (40% to 66%, P < .0001), lab/test results (63% to 69%, P < .0001), level of acuity (34% to 50%, P < .0001), anticipatory guidance (69% to 82%, P < .0001), and future plans (35% to 38%, P < .0005). The use of vague language declined (41% to 26%, P < .0001). The mean total scores improved from 7.0 to 8.2 out of a possible 11 (P < .0001). As new house staff rotated onto the services, improvement over time was sustained with 1 feedback session per team, per month. Similar interventions could be made in other programs and other institutions.

iPSC-derived forebrain neurons from FXS individuals show defects in initial neurite outgrowth.

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and is closely linked with autism. The genetic basis of FXS is an expansion of CGG repeats in the 5'-untranslated region of the FMR1 gene on the X chromosome leading to the loss of expression of the fragile X mental retardation protein (FMRP). The cause of FXS has been known for over 20 years, yet the full molecular and cellular consequences of this mutation remain unclear. Although mouse and fly models have provided significant understanding of this disorder and its effects on the central nervous system, insight from human studies is limited. We have created human induced pluripotent stem cell (iPSC) lines from fibroblasts obtained from individuals with FXS to enable in vitro modeling of the human disease. Three young boys with FXS who came from a well-characterized cohort representative of the range of affectedness typical for the syndrome were recruited to aid in linking cellular and behavioral phenotypes. The FMR1 mutation is preserved during the reprogramming of patient fibroblasts to iPSCs. Mosaicism of the CGG repeat length in one of the patient's fibroblasts allowed for the generation of isogenic lines with differing CGG repeat lengths from the same patient. FXS forebrain neurons were differentiated from these iPSCs and display defective neurite initiation and extension. These cells provide a well-characterized resource to examine potential neuronal deficits caused by FXS as well as the function of FMRP in human neurons.

Deficits in human trisomy 21 iPSCs and neurons.

Down syndrome (trisomy 21) is the most common genetic cause of intellectual disability, but the precise molecular mechanisms underlying impaired cognition remain unclear. Elucidation of these mechanisms has been hindered by the lack of a model system that contains full trisomy of chromosome 21 (Ts21) in a human genome that enables normal gene regulation. To overcome this limitation, we created Ts21-induced pluripotent stem cells (iPSCs) from two sets of Ts21 human fibroblasts. One of the fibroblast lines had low level mosaicism for Ts21 and yielded Ts21 iPSCs and an isogenic control that is disomic for human chromosome 21 (HSA21). Differentiation of all Ts21 iPSCs yielded similar numbers of neurons expressing markers characteristic of dorsal forebrain neurons that were functionally similar to controls. Expression profiling of Ts21 iPSCs and their neuronal derivatives revealed changes in HSA21 genes consistent with the presence of 50% more genetic material as well as changes in non-HSA21 genes that suggested compensatory responses to oxidative stress. Ts21 neurons displayed reduced synaptic activity, affecting excitatory and inhibitory synapses equally. Thus, Ts21 iPSCs and neurons display unique developmental defects that are consistent with cognitive deficits in individuals with Down syndrome and may enable discovery of the underlying causes of and treatments for this disorder.