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1.
J Bacteriol ; 2021 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-33753470

RESUMEN

By evolving strains of E. coli that hyper-resist sedimentation, we discovered an uncharacterized mechanism that bacteria can use to remain in suspension indefinitely without expending energy. This unusual phenotype was traced to the anchoring of long colanic acid polymers (CAP) that project from the cell surface. Although each characterized mutant activated this same mechanism, the genes responsible and the strengths of the phenotypes varied. Mutations in rcsC, lpp, igaA, or the yjbEFGH operon were sufficient to stimulate sedimentation resistance, while mutations altering the cps promoter, cdgI, or yjbF provided phenotypic enhancements. The sedimentation resistances changed in response to temperature, growth phase, and carbon source and each mutant exhibited significantly reduced biofilm formation. We discovered that the degree of colony mucoidy exhibited by these mutants was not related to the degree of Rcs pathways activation or to the amount of CAP that was produced; rather, it was related to the fraction of CAP that was shed as a true exopolysaccharide. Therefore, these and other mutations that activate this phenotype are likely to be absent from genetic screens that relied on centrifugation to harvest bacteria. We also found that this anchored CAP form is not linked to LPS cores and may not be attached to the outer membrane.IMPORTANCEBacteria can partition in aqueous environments between surface-dwelling, planktonic, sedimentary, and biofilm forms. Residence in each location provides an advantage depending on nutritional and environmental stresses and a community of a single species is often observed to be distributed throughout two or more of these niches. Another adaptive strategy is to produce an extracellular capsule, which provides an environmental shield for the microbe and can allow escape from predators and immune systems. We discovered that bacteria can either shed or stably anchor capsules to dramatically alter their propensity to sediment. The degree to which the bacteria anchor their capsule is controlled by a stress sensing system, suggesting that anchoring may be used as an adaptive response to severe environmental challenges.

2.
Headache ; 61(3): 438-454, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33594686

RESUMEN

BACKGROUND: Calcitonin gene-related peptide (CGRP) inhibitors were introduced in the United States (US) in 2018. To understand the changing patterns of preventive treatment following the introduction of these new agents, we must first characterize the patterns which preceded their introduction. OBJECTIVE: To characterize the burden, unmet need, and treatment patterns in patients with migraine initiating preventive migraine medications before the introduction of CGRP inhibitors in the US. METHODS: Between March 2016 and October 2017, we enrolled episodic (EM) and chronic migraine (CM) patients initiating or changing preventive treatment at primary care or neurology clinic visits in the US, in a real-world observational study using a prospective cohort design. At baseline and monthly thereafter for 6 months, we collected data from study sites and patients on migraine frequency, treatment modifications, migraine impact on functioning, and work productivity for a descriptive analysis of migraine patient experience and treatment patterns. RESULTS: From the sample of 234 completers, 118 had EM (50.4%) and 116 had CM (49.6%). Mean age at enrollment was 41 years (SD = 12) and mean age at first migraine diagnosis was 22 years (SD = 11). Most participants were females (n = 204/234; 87.2%) and white (n = 178/234; 76.1%). The majority (n = 164/234; 70.1%) had not used preventive migraine treatment in the 5 years prior to enrollment (treatment naïve). At baseline, mean monthly migraine days were 9.6 days (SD = 5.0) for the preventive treatment naïve group and 12.4 days (SD = 7.0) for treatment experienced patients. The majority had severe Migraine Disability Assessment (Grade IV, total score ≥21), including 67.1% (n = 110/164) of the preventive treatment naïve and 77.1% (n = 54/70) of the preventive treatment experienced patients. Headache Impact Test total scores indicating severe impairment (score >59) occurred in 88.4% (n = 145/164) of the treatment naïve and 88.6% (n = 62/70) of treatment experienced patients. Mean work productivity loss as measured by the Work Productivity and Activity Impairment questionnaire in the subsample of employed patients was 53.3% loss. The most used acute medications at baseline were nonsteroidal anti-inflammatory agents (n = 124/234; 53.0%), acetaminophen-based products (n = 112/234; 47.9%), and triptans (n = 105/234; 44.9%). The most commonly initiated preventive treatments were topiramate (n = 100/234; 42.7%), tricyclic antidepressants (n = 39/234; 16.7%), beta-blockers (n = 26/234; 11.1%), and onabotulinumtoxinA (n = 24/234; 10.3%). Over the 6-month follow-up period, almost half of patients (n = 116/234, 49.6%) modified their preventive treatment and discontinued treatment (n = 88/312 total modifications; 28.2%) or modified their pattern of use by increasing, decreasing, or skipping doses (n = 224/312 total modifications; 71.8%), often without seeking medical advice. Avoiding side effects was the main reason reported among patients who discontinued (n = 52/88; 59.1%), decreased frequency or dose (n = 37/89; 41.6%), and skipped doses (n = 29/86; 33.7%). Perceived lack of efficacy was another frequent reason reported among those who discontinued (n = 20/88; 22.7%), decreased frequency or dose (n = 15/89; 16.9%), and skipped doses (n = 18/86; 20.9%). Despite initiation of preventive treatment and improvements observed in number of headache and migraine days, migraine patients continued to experience substantial disability, headache impact, and reduced productivity throughout the 6-month follow-up period. CONCLUSIONS: Prior to 2018, the burden of migraine was high for patients initiating preventive treatments. Despite having more than 9 days of migraine per month on average, the majority (70.1%) of patients initiating prevention had been treatment naïve, indicating underuse of preventive treatments. The preventive treatments used in this study were poorly tolerated and were reported by patients to lack efficacy, resulting in suboptimal adherence. The high discontinuation rates suggest that the preventive medications being offered during the period of the study did not meet the treatment needs of patients. In addition, the decisions by about half of patients to alter their prescribed treatment plan without consulting their provider can pose substantial health risks. These findings pertain to the broad set of preventive treatments initiated in this study and do not support inferences about individual preventive treatments, due to limitations in sample size. These findings suggest the need for more effective and better tolerated preventive treatment options.

3.
Artículo en Inglés | MEDLINE | ID: mdl-33608970

RESUMEN

The purpose of this study was to determine if locally applied insulin has a dose-responsive effect on posterolateral lumbar fusion. Adult male New Zealand White rabbits underwent posterolateral intertransverse spinal fusions (PLFs) at L5-L6 using suboptimal amounts of autograft. Fusion sites were treated with collagen sponge soaked in saline (control, n = 11), or with insulin at low (5 or 10 units, n = 13), mid (20 units, n = 11), and high (40 units, n = 11) doses. Rabbits were euthanized at 6 weeks. The L5-L6 spine segment underwent manual palpation and radiographic evaluation performed by two fellowship trained spine surgeons blinded to treatment. Differences between groups were evaluated by analysis of variance on ranks followed by post-hoc Dunn's tests. Forty-three rabbits were euthanized at the planned 6 weeks endpoint, while three died or were euthanized prior to the endpoint. Radiographic evaluation found bilateral solid fusion in 10%, 31%, 60%, and 60% of the rabbits from the control and low, mid, and high-dose insulin-treated groups, respectively (p < 0.05). As per manual palpation, 7 of 10 rabbits in the mid-dose insulin group were fused as compared to 1 of 10 rabbits in the control group (p < 0.05). This study demonstrates that insulin enhanced the effectiveness of autograft to increase fusion success in the rabbit PLF model. The study indicates that insulin or insulin-mimetic compounds can be used to promote bone regeneration.

4.
J Patient Exp ; 7(5): 653-656, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-33294594

RESUMEN

The experience of pregnant and postpartum patients continues to evolve during the COVID-19 pandemic. Limited clinical data and the unknown nature of the virus' impact and transmission routes have forced constant changes to traditional care delivery. Dependence on telehealth technology such as telephonic and videoconferencing has surged, and patients' willingness to visit traditional health care facilities has plummeted. We set out to create an ongoing surveillance system to monitor changes to prenatal and obstetric care and the patient experience during the COVID-19 pandemic.

6.
Spine Surg Relat Res ; 4(4): 314-319, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33195855

RESUMEN

Introduction: The effect of pelvic fixation on postoperative medical complications, blood transfusion, length of hospital stay, and discharge disposition is poorly understood. Determining factors that predispose patients to increased complications after spinopelvic fusion will help surgeons to plan these complex procedures and optimize patients preoperatively. Methods: We conducted a retrospective cohort study using data from the ACS-NSQIP database between 2006 and 2016 of patients who underwent lumbar fusion with and without spinopelvic fixation. Data regarding demographics, complications, hospital stay, and discharge disposition were collected. Results: A total of 57,417 (98.5%) cases of lumbar fusion without spinopelvic fixation (LF) and 887 (1.5%) cases of lumbar fusion with spinopelvic fixation (SPF) were analyzed. The transfusion rate in the SPF group was 59.3% vs 13% in the LF group (p < 0.001). The mean length of stay (LOS) and discharge to skilled nursing facility (SNF) were significantly different (LOS: SPF 6.5 days vs LF 3.5 days p < 0.001; SNF: SPF 21.3% vs LF 10.4% p < 0.001). After controlling for demographic differences, the overall complication rates were not significantly different between the groups (p = 0.531). The odds ratio for transfusion in the SPF group was 2.9 (p < 0.001). The odds ratio for increased LOS and increased care discharge disposition were elevated in the SPF group (LOS OR: 1.3, p < 0.012, Discharge disposition OR: 1.8, p < 0.001). Conclusions: Patients who underwent SPF had increased complications, transfusion rate, LOS, and discharge to SNF or subacute rehab facilities as compared with patients who underwent LF. SPF remains an effective technique for achieving lumbosacral arthrodesis. Surgeons should consider the implications of the associated complication profile for SPF and the value of preoperative optimization in a select cohort of patients.

8.
Life (Basel) ; 10(11)2020 Oct 24.
Artículo en Inglés | MEDLINE | ID: mdl-33114423

RESUMEN

Both Staphylococcus aureus and Staphylococcus epidermidis are commonly associated with periprosthetic joint infections (PJIs). The treatment of PJI can be challenging because biofilms are assumed to have an increased intolerance to antibiotics. This makes the treatment of PJI challenging from a clinical perspective. Although S. aureus has been previously demonstrated to have increased biofilm antibiotic tolerance, this has not been well established with Staphylococcus epidermidis. A prospective registry of PJI S. epidermidis isolates was developed. The efficacy of clinically relevant antibiotics was quantified against these isolates. S. epidermidis planktonic minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were collected using clinical laboratory standard index (CLSI) assays for eight antibiotics (doxycycline, vancomycin, daptomycin, clindamycin, rifampin, nafcillin, and trimethoprim/sulfamethoxazole). Mature biofilms were grown in vitro, after which minimum biofilm inhibitory concentration (MBIC) and minimum biofilm bactericidal concentration (MBBC) were quantified. Only rifampin and doxycycline had a measurable MBIC across all tested isolates. Based on MBBC, 64% of S. epidermidis biofilms could be eliminated by rifampin, whereas only 18% by doxycycline. S. epidermidis biofilm was observed to have a high tolerance to antibiotics as compared to planktonic culture. Isolate biofilm antibiotic tolerance varied to a larger degree than was seen in planktonic cultures.

9.
J Gen Intern Med ; 35(12): 3478-3484, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-32989714

RESUMEN

IMPORTANCE: As prescription drug costs rise, it is important to understand attitudes among primary care physicians and nurse practitioners (NPs) towards generic drugs. OBJECTIVE: We aimed to examine the generic skepticism index (GSI) among primary care clinicians, and their willingness to discuss and prescribe generic antidepressants (ADs) and generic oral contraceptives (OCPs). DESIGN: We used a factorial vignette design survey to test 4 factors: message source, message, brand preference, and drug class. Participants were randomized to different combinations of factors. SETTING: This was a cross-sectional study. PARTICIPANTS: Physicians registered with the American College of Physicians (ACP) and NPs registered with the American Association of Nurse Practitioners (AANP) participated in the study. MAIN MEASURES: The primary outcomes were generic skepticism as measured using the generic skepticism index (GSI), and clinician willingness to discuss and prescribe generics. RESULTS: Surveys were completed by 56% of physicians (n = 369/661) and 60% of NPs (n = 493/819). Compared with physicians, NPs were younger (p < 0.001), predominantly female (p < 0.001), and differed in the race (p < 0.001). According to the GSI, 16% (n = 138/862) were identified as generic skeptics (18.5% of NPs and 12.7% of physicians, p = 0.023). Generic skeptics had lower odds of willingness to discuss switching (OR 0.22, 95% CI (0.14-0.35), p < 0.001) or prescribe (OR 0.18, 95% CI (0.11-0.28), p < 0.001) generic OCPs. Participants had lower odds of willingness to prescribe generic drugs to patients with brand preference compared with brand-neutral patients (OR 0.64, 95% CI 0.50-0.82, p < 0.001). CONCLUSIONS AND RELEVANCE: Generic skepticism was associated with lower willingness to discuss or prescribe generic drugs. Clinicians reported lower willingness to discuss switching or prescribe generics for OCPs than for ADs. Patient brand preference hindered generic prescribing. Message source and message type were not significantly associated with outcomes.

11.
Support Care Cancer ; 2020 Sep 03.
Artículo en Inglés | MEDLINE | ID: mdl-32880732

RESUMEN

OBJECTIVES: To evaluate the use of granulocyte colony-stimulating factor (G-CSF) prophylaxis in US patients with selected metastatic cancers and chemotherapy-induced febrile neutropenia (FN) incidence and associated outcomes among the subgroup who did not receive prophylaxis. METHODS: This retrospective cohort study was conducted at four US health systems and included adults with metastatic cancer (breast, colorectal, lung, non-Hodgkin lymphoma [NHL]) who received myelosuppressive chemotherapy (2009-2017). Patients were stratified by FN risk level based on risk factors and chemotherapy (low/unclassified risk, intermediate risk without any risk factors, intermediate risk with ≥ 1 risk factor [IR + 1], high risk [HR]). G-CSF use was evaluated among all patients stratified by FN risk, and FN/FN-related outcomes were evaluated among patients who did not receive first-cycle G-CSF prophylaxis. RESULTS: Among 1457 metastatic cancer patients, 20.5% and 28.1% were classified as HR and IR + 1, respectively. First-cycle G-CSF prophylaxis use was 48.5% among HR patients and 13.9% among IR + 1 patients. In the subgroup not receiving first-cycle G-CSF prophylaxis, FN incidence in cycle 1 was 7.8% for HR patients and 4.8% for IR + 1 patients; during the course, corresponding values were 16.9% and 15.9%. Most (> 90%) FN episodes required hospitalization, and mortality risk ranged from 7.1 to 26.9% across subgroups. CONCLUSION: In this retrospective study, the majority of metastatic cancer chemotherapy patients for whom G-CSF prophylaxis is recommended did not receive it; FN incidence in this subgroup was notably high. Patients with elevated FN risk should be carefully identified and managed to ensure appropriate use of supportive care.

12.
Cancer Res ; 80(21): 4612-4619, 2020 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-32934023

RESUMEN

The TMPRSS2-ERG fusion is the most common genomic rearrangement in human prostate cancer. However, in established adenocarcinoma, it is unknown how the ERG oncogene promotes a cancerous phenotype and maintains downstream androgen receptor (AR) signaling pathways. In this study, we utilized a murine prostate organoid system to explore the effects of ERG on tumorigenesis and determined the mechanism underlying prostate cancer dependence on ERG. Prostate organoids lacking PTEN and overexpressing ERG (Pten-/- R26-ERG) faithfully recapitulated distinct stages of prostate cancer disease progression. In this model, deletion of ERG significantly dampened AR-dependent gene expression. While ERG was able to reprogram the AR cistrome in the process of prostate carcinogenesis, ERG knockout in established prostate cancer organoids did not drastically alter AR binding, H3K27ac enhancer, or open chromatin profiles at these reprogrammed sites. Proteomic analysis of DNA-bound AR complexes demonstrated that ERG deletion causes a loss of recruitment of critical AR coregulators and basal transcriptional machinery, including NCOA3 and RNA polymerase II, but does not alter AR binding itself. Together, these data reveal a novel mechanism of ERG oncogene addiction in prostate cancer, whereby ERG facilitates AR signaling by maintaining coregulator complexes at AR bound sites across the genome. SIGNIFICANCE: These findings exploit murine organoid models to uncover the mechanism of ERG-mediated tumorigenesis and subsequent oncogenic dependencies in prostate cancer.

13.
J Clin Med ; 9(9)2020 Aug 22.
Artículo en Inglés | MEDLINE | ID: mdl-32842683

RESUMEN

Brain injury is a significant source of morbidity and mortality for pediatric patients treated with Extracorporeal Membrane Oxygenation (ECMO). Our objective was to utilize neural networks to predict radiographic evidence of brain injury in pediatric ECMO-supported patients and identify specific variables that can be explored for future research. Data from 174 ECMO-supported patients were collected up to 24 h prior to, and for the duration of, the ECMO course. Thirty-five variables were collected, including physiological data, markers of end-organ perfusion, acid-base homeostasis, vasoactive infusions, markers of coagulation, and ECMO-machine factors. The primary outcome was the presence of radiologic evidence of moderate to severe brain injury as established by brain CT or MRI. This information was analyzed by a neural network, and results were compared to a logistic regression model as well as clinician judgement. The neural network model was able to predict brain injury with an Area Under the Curve (AUC) of 0.76, 73% sensitivity, and 80% specificity. Logistic regression had 62% sensitivity and 61% specificity. Clinician judgment had 39% sensitivity and 69% specificity. Sequential feature group masking demonstrated a relatively greater contribution of physiological data and minor contribution of coagulation factors to the model's performance. These findings lay the foundation for further areas of research directions.

14.
Health Serv Res ; 2020 Aug 26.
Artículo en Inglés | MEDLINE | ID: mdl-32844455

RESUMEN

OBJECTIVE: To examine the variability in the cesarean delivery (CD) rates of individual labor and delivery nurses compared with physicians at three attribution time points. DATA SOURCES: Medical record data from nine hospitals in Washington State from January 2016 through September 2018. STUDY DESIGN: Retrospective, observational cohort design using an aggregated database of birth records. DATA COLLECTION/EXTRACTION METHODS: Chart-abstracted clinical data from a subset of nulliparous, term, singleton, vertex births attributed at admission, labor management, and delivery to nurses and physicians. Two classification methods were used to categorize nurse- and physician-level CD rates at three attribution time points and the reliability of these methods compared. PRINCIPAL FINDINGS: The sample included 12 556 births, 319 nurses, and 126 physicians. Overall, variation in nurse-level CD rates did not differ significantly across the three attribution time points, and the extent of variation was similar to that observed in physicians. However, agreement between attribution time points varied between 35 percent and 65 percent when classifying individual nurses into the top and bottom deciles. The average reliability of nurse-level CD rates was 32 percent at admission (IQR 22.0 percent to 38.7 percent), 32.6 percent at labor (IQR 23.1 percent to 40.9 percent), and 29.3 percent (IQR 20.9 percent to 35.8 percent) at delivery. The average reliability of physician-level CD rates was higher: 54.2 percent (IQR 38.7 percent to 71.4 percent) at admission, 62.5 percent (IQR 49.0 percent to 79.6 percent) at labor management, and 66.1 percent (IQR 53.7 percent to 81.2 percent) at delivery. CONCLUSION: Feedback on nurse-level CD rates as part of routine clinical quality audits can provide insight into nurse performance in the context of other individual-level and unit-level information. To reliably distinguish individual nurse performance, larger sample sizes are needed.

15.
Ticks Tick Borne Dis ; 11(5): 101468, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32723647

RESUMEN

Anaplasmosis is an emerging infection in the United States and remains under-recognized in many areas including Pennsylvania. Presenting signs and symptoms are often nonspecific, but fulminant infection can occur in vulnerable populations. We present two cases of severe anaplasmosis that progressed to secondary hemophagocytic lymphohistiocytosis (HLH). This severe immune dysregulation syndrome has an extremely high mortality, but anaplasmosis represents one of the few treatable underlying etiologies. It is imperative for physicians to recognize this complication and start empiric doxycycline, as early treatment improves mortality. We also present a case of anaplasmosis-induced HLH successfully treated with a combination of doxycycline, steroids, and anakinra (an IL-1 receptor antagonist), highlighting that this primarily immune-mediated complication is amenable to treatment with both antibiotics and immune suppression.

16.
J Med Syst ; 44(9): 150, 2020 Jul 29.
Artículo en Inglés | MEDLINE | ID: mdl-32728888

RESUMEN

Technological advancements in wearable devices have revolutionized smart shoes. Smart shoes are sometimes referred to as intelligent shoes or computer-based shoes. They are capable of recognizing and recording data from day-to-day activities by the user. Such smart shoes are designed with sensors, vibrating motors, GPS, wireless systems, and various other sensors/actuators for the comfort and benefit of the wearer. In the current manuscript, we are reviewing various technologies that are implemented in smart shoes.

18.
Ann Intern Med ; 172(11 Suppl): S130-S136, 2020 06 02.
Artículo en Inglés | MEDLINE | ID: mdl-32479182

RESUMEN

Electronic health records (EHRs) are now widely adopted in the United States, but health systems have barely begun using them to deliver high-value care. More directed and rigorous research is needed to fulfill the promise of EHRs to not only store information but also support the delivery of better care. This article describes 4 potential benefits of EHR-based research: improving clinical decisions, supporting triage decisions, enabling collaboration among the care team (including patients), and increasing productivity via automation of tasks. Six recommendations are made for conducting and reporting research to catalyze value creation: develop interventions systematically by using user-centered design and a building-block approach; assess value in terms of cost, quality, outcomes, and work required of providers and patients; consider the time horizon for the intervention; test best practices for implementation in a range of real-world contexts; assess subtleties of behavior change tools used to improve high-value behaviors; and report the intervention in enough detail that it can be replicated, including context. Just as research played a critical role in developing early EHR prototypes and demonstrating their value to justify dissemination, research will continue to be essential in the next phase: expanding EHR-based interventions and maximizing their role in creating value.


Asunto(s)
Prestación de Atención de Salud/normas , Registros Electrónicos de Salud/organización & administración , Mejoramiento de la Calidad , Recolección de Datos , Humanos
19.
Obstet Gynecol ; 135(5): 1027-1037, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32282594

RESUMEN

Prenatal care is one of the most widely used preventive care services in the United States, yet prenatal care delivery recommendations have remained largely unchanged since just before World War II. The current prenatal care model can be improved to better serve modern patients and the health care providers who care for them in three key ways: 1) focusing more on promotion of health and wellness as opposed to primarily focusing on medical complications, 2) flexibly incorporating patient preferences, and 3) individualizing care. As key policymakers and stakeholders grapple with higher maternity care costs and poorer outcomes, including lagging access, equity, and maternal and infant morbidity and mortality in the United States compared with other high-income countries, the opportunity to improve prenatal care has been given insufficient attention. In this manuscript, we present a new conceptual model for prenatal care that incorporates both patients' medical and social needs into four phenotypes, and use human-centered design methods to describe how better matching patient needs with prenatal services can increase the use of high-value services and decrease the use of low-value services. Finally, we address some of the key challenges to implementing right-sized prenatal care, including capturing outcomes through research and payment.


Asunto(s)
Servicios de Salud Materna/normas , Obstetricia/métodos , Medicina de Precisión/normas , Atención Prenatal/normas , Mejoramiento de la Calidad , Femenino , Necesidades y Demandas de Servicios de Salud , Humanos , Embarazo , Estados Unidos
20.
Methods Mol Biol ; 2133: 31-54, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32144662

RESUMEN

In recent years, split inteins have seen widespread use as molecular platforms for the design of a variety of peptide and protein chemistry technologies, most notably protein ligation. The development of these approaches is dependent on the identification and/or design of split inteins with robust activity, stability, and solubility. Here, we describe two approaches to characterize and compare the activities of newly identified or engineered split inteins. The first assay employs an E. coli-based selection system to rapidly screen the activities of many inteins and can be repurposed for directed evolution. The second assay utilizes reverse-phase high-performance liquid chromatography (RP-HPLC) to provide insights into individual chemical steps in the protein splicing reaction, information that can guide further engineering efforts. These techniques provide useful alternatives to common assays that utilize SDS-PAGE to analyze splicing reaction progress.

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