Management Protocol for Uncomplicated Peritonsillar Abscess: Standardizing Care and Improving Emergency Medicine Resident Confidence.

INTRODUCTION: A peritonsillar abscess (PTA) is a frequent reason for a visit to the emergency department. As there are no current published guidelines for medical versus surgical management, attending physicians vary among management tendencies, generating uncertainty among resident physicians. This project established a standard of care for managing patients with PTA and provided clear management guidelines to the emergency department, in collaboration with the otolaryngology department, at a community academic hospital. METHODS: Pre- and post-interventional, anonymous surveys were given to assess resident physician confidence in the management of PTA. A proposed management protocol was developed based on existing literature and approved by both the emergency medicine (EM) and otolaryngology (ENT) departments. The protocol was then disseminated during in-person didactic sessions to EM residents and ENT residents for use over a four-month interventional period. RESULTS: The mean confidence level for all residents increased significantly after the implementation of the protocol (p<0.001). The increase in confidence level for "antibiotic selection for PTA" (p=0.72) and "inpatient PTA management" (p=0.20) was not statistically significant for the post-graduate year (PGY) 3 and 4 residents. The increase in confidence level was higher overall for PGY 1 and 2 residents (95% CI 2.25 ± 1.09, p<0.001) than for PGY 3 and 4 residents (95% CI 1.73 ± 1.09, p=0.003). CONCLUSION: The implementation of a standardized protocol for the management of PTA proved to be an effective tool in assisting residents and improving their confidence. This study highlights the importance of establishing guidelines in clinical practice to promote consistent and evidence-based management strategies for PTA. By providing clear guidelines, this protocol enhances communication among healthcare providers and contributes to the delivery of high-quality care to patients with PTA.

Disentangling top-down drivers of mortality underlying diel population dynamics of Prochlorococcus in the North Pacific Subtropical Gyre.

Photosynthesis fuels primary production at the base of marine food webs. Yet, in many surface ocean ecosystems, diel-driven primary production is tightly coupled to daily loss. This tight coupling raises the question: which top-down drivers predominate in maintaining persistently stable picocyanobacterial populations over longer time scales? Motivated by high-frequency surface water measurements taken in the North Pacific Subtropical Gyre (NPSG), we developed multitrophic models to investigate bottom-up and top-down mechanisms underlying the balanced control of Prochlorococcus populations. We find that incorporating photosynthetic growth with viral- and predator-induced mortality is sufficient to recapitulate daily oscillations of Prochlorococcus abundances with baseline community abundances. In doing so, we infer that grazers in this environment function as the predominant top-down factor despite high standing viral particle densities. The model-data fits also reveal the ecological relevance of light-dependent viral traits and non-canonical factors to cellular loss. Finally, we leverage sensitivity analyses to demonstrate how variation in life history traits across distinct oceanic contexts, including variation in viral adsorption and grazer clearance rates, can transform the quantitative and even qualitative importance of top-down controls in shaping Prochlorococcus population dynamics.

The impact of time to death in donors after circulatory death on recipient outcome in simultaneous pancreas-kidney transplantation.

The time to arrest donors after circulatory death is unpredictable and can vary. This leads to variable periods of warm ischemic damage prior to pancreas transplantation. There is little evidence supporting procurement team stand-down times based on donor time to death (TTD). We examined what impact TTD had on pancreas graft outcomes following donors after circulatory death (DCD) simultaneous pancreas-kidney transplantation. Data were extracted from the UK transplant registry from 2014 to 2022. Predictors of graft loss were evaluated using a Cox proportional hazards model. Adjusted restricted cubic spline models were generated to further delineate the relationship between TTD and outcome. Three-hundred-and-seventy-five DCD simultaneous kidney-pancreas transplant recipients were included. Increasing TTD was not associated with graft survival (adjusted hazard ratio HR 0.98, 95% confidence interval 0.68-1.41, P = .901). Increasing asystolic time worsened graft survival (adjusted hazard ratio 2.51, 95% confidence interval 1.16-5.43, P = .020). Restricted cubic spline modeling revealed a nonlinear relationship between asystolic time and graft survival and no relationship between TTD and graft survival. We found no evidence that TTD impacts pancreas graft survival after DCD simultaneous pancreas-kidney transplantation; however, increasing asystolic time was a significant predictor of graft loss. Procurement teams should attempt to minimize asystolic time to optimize pancreas graft survival rather than focus on the duration of TTD.

CyanoCyc cyanobacterial web portal.

CyanoCyc is a web portal that integrates an exceptionally rich database collection of information about cyanobacterial genomes with an extensive suite of bioinformatics tools. It was developed to address the needs of the cyanobacterial research and biotechnology communities. The 277 annotated cyanobacterial genomes currently in CyanoCyc are supplemented with computational inferences including predicted metabolic pathways, operons, protein complexes, and orthologs; and with data imported from external databases, such as protein features and Gene Ontology (GO) terms imported from UniProt. Five of the genome databases have undergone manual curation with input from more than a dozen cyanobacteria experts to correct errors and integrate information from more than 1,765 published articles. CyanoCyc has bioinformatics tools that encompass genome, metabolic pathway and regulatory informatics; omics data analysis; and comparative analyses, including visualizations of multiple genomes aligned at orthologous genes, and comparisons of metabolic networks for multiple organisms. CyanoCyc is a high-quality, reliable knowledgebase that accelerates scientists' work by enabling users to quickly find accurate information using its powerful set of search tools, to understand gene function through expert mini-reviews with citations, to acquire information quickly using its interactive visualization tools, and to inform better decision-making for fundamental and applied research.

Insulin independence following islet transplantation improves long-term metabolic outcomes.

AIMS: Pancreatic islet allotransplantation is an effective therapy for type 1 diabetes mellitus, restoring glycaemic control and hypoglycaemic awareness in patients with recurrent severe hypoglycaemia. Insulin independence following transplant is being increasingly reported; however, this is not a primary endpoint in the UK. Having surpassed 10 years of islet transplantation in Scotland, we aimed to evaluate the impact of insulin independence following transplant on metabolic outcomes and graft survival. METHODS: We conducted a retrospective analysis on data collected prospectively between 2011 and 2022. Patients who underwent islet transplantation in Scotland up to the 31st January 2020 were included. Primary endpoint was graft survival (stimulated C-peptide >50 pmol/L). Secondary endpoints included GOLD score, HbA1c, C-peptide and insulin requirement. Outcomes were compared between patients who achieved insulin independence at any point following transplant versus those who did not. RESULTS: 60 patients were included. 74.5% experienced >50 severe hypoglycaemic episodes in the year preceding transplant. There was a 55.0% decrease in insulin requirement following transplant and 30.0% achieved insulin independence. Mean graft survival time was 9.0 years (95% CI 7.2-10.9) in patients who achieved insulin independence versus 4.4 years (95% CI 3.4-5.3) in patients who did not. Insulin independence was associated with significantly improved graft function, glycaemic control and hypoglycaemic awareness at 1 year. CONCLUSIONS: This is the largest UK single-centre study on islet transplant to date. Our findings demonstrate significantly improved outcomes in patients who achieved insulin independence following islet transplantation.

Quality improvement review of O positive blood in emergency transfusion.

BACKGROUND: We recently introduced a policy to use O positive red cells in emergency transfusions for males >16 years of age and females >50 years of age. Here, we investigate changes in emergency transfusion practice and rates of red cell alloimmunization with the use of O positive blood for emergency transfusion. STUDY DESIGN AND METHODS: State-wide retrospective review of emergency transfusions between June 2020 and June 2021. The laboratory information system and patient medical records were used to collect demographic details, indications for transfusion, usage of O positive and O negative blood and rates of alloimmunization. RESULTS: There were 2354 red cell units transfused to 1013 patients (male = 59%, average age = 53 years) during the 12-month period. O positive units accounted for 46.9% (1103 units) of emergency transfusions. However, 726 (30.8%) O negative units were transfused to patients without a mandatory indication for O negative blood. Twenty-eight patients (2.9%) had a red cell alloantibody prior to transfusion including anti-E (n = 10), anti-D (n = 4), and anti-K (n = 4). One patient with prior anti-D had mild delayed hemolysis. There were 19 patients (4.3%, median follow-up 22 days) who developed a red cell alloantibody after emergency transfusion and include anti-E (n = 10), anti-D (n = 7), and anti-C (n = 5). DISCUSSION: The use of O positive blood for emergency transfusion has saved 1103 O negative red cell units with no detriment to patient outcome. There remains potential to optimize use of O positive blood in emergency transfusion and to understand red cell alloimmunization rates in a prospective fashion.

Beta-cell death and dysfunction drives hyperglycaemia in organ donors.

BACKGROUND: Donor hyperglycaemia following brain death has been attributed to reversible insulin resistance. However, our islet and pancreas transplant data suggest that other mechanisms may be predominant. We aimed to determine the relationships between donor insulin use and markers of beta-cell death and beta-cell function in pancreas donors after brain death. METHODS: In pancreas donors after brain death, we compared clinical and biochemical data in 'insulin-treated' and 'not insulin-treated donors' (IT vs. not-IT). We measured plasma glucose, C-peptide and levels of circulating unmethylated insulin gene promoter cell-free DNA (INS-cfDNA) and microRNA-375 (miR-375), as measures of beta-cell death. Relationships between markers of beta-cell death and islet isolation outcomes and post-transplant function were also evaluated. RESULTS: Of 92 pancreas donors, 40 (43%) required insulin. Glycaemic control and beta-cell function were significantly poorer in IT donors versus not-IT donors [median (IQR) peak glucose: 8 (7-11) vs. 6 (6-8) mmol/L, p = .016; C-peptide: 3280 (3159-3386) vs. 3195 (2868-3386) pmol/L, p = .046]. IT donors had significantly higher levels of INS-cfDNA [35 (18-52) vs. 30 (8-51) copies/ml, p = .035] and miR-375 [1.050 (0.19-1.95) vs. 0.73 (0.32-1.10) copies/nl, p = .05]. Circulating donor miR-375 was highly predictive of recipient islet graft failure at 3 months [adjusted receiver operator curve (SE) = 0.813 (0.149)]. CONCLUSIONS: In pancreas donors, hyperglycaemia requiring IT is strongly associated with beta-cell death. This provides an explanation for the relationship of donor IT with post-transplant beta-cell dysfunction in transplant recipients.

Whole-Organ Pancreas and Islets Transplantations in UK: An Overview and Future Directions.

Whole-organ pancreas and islets transplantations are two therapeutic options to treat type 1 diabetic patients resistant to optimised medical treatment in whom severe complications develop. Selection of the best option for ß-cell replacement depends on several factors such as kidney function, patient comorbidities, and treatment goals. For a patient with end-stage kidney disease, the treatment of choice is often a simultaneous transplant of the pancreas and kidney (SPK). However, it remains a major surgical procedure in patients with multiple comorbidities and therefore it is important to select those who will benefit from it. Additionally, in view of the organ shortage, new strategies to improve outcomes and reduce immune reactions have been developed, including dynamic organ perfusion technologies, pancreas bioengineering, and stem cell therapies. The purpose of this article is to review the indications, surgical techniques, outcomes, and future directions of whole-organ pancreas and islets transplantations.

Primary Adrenal Lymphoma as a Rare Cause of Primary Adrenal Insufficiency: Challenges in Management and a Review of the Literature.

Background/Objective: Primary adrenal lymphoma (PAL) is an aggressive form of lymphoma associated with adrenal insufficiency (AI) in most cases. It requires a histologic confirmation unlike other cases of primary AI. Case Report: We report a case of a 66-year-old man who presented with AI with symptomatic hypotension and hypo-osmolar hyponatremia. Ultrasound and computed tomography scans revealed bilateral bulky adrenal masses that were avid on fluorodeoxyglucose positron emission tomography scan. The diagnosis of PAL was confirmed with adrenal biopsy. He was treated with rituximab-based chemotherapy, which was complicated by several endocrine challenges, including worsening diabetes, multiple adrenal crises, prolonged hyponatremia, and refractory hypokalemia requiring spironolactone. He eventually developed central nervous system disease and was treated with palliative intent. Discussion: AI in the setting of PAL can constitute both diagnostic and therapeutic challenges, including significant electrolyte imbalances as discussed in this case report. Conclusion: It is important to have a high suspicion for PAL, especially in the presence of bilateral adrenal masses and AI. Early adrenal biopsy is required for diagnosis. Multidisciplinary care is vital to manage complications that arise during the disease course and treatment.

Maternal iron deficiency anaemia in pregnancy: Lessons from a national audit.

We describe the management and the prevalence of iron deficiency anaemia (IDA) during pregnancy by comparison to standards. A cross-sectional national cohort study of women who had given birth six weeks prior to data collection was conducted at maternity units in the UK and Ireland. Participating centres collected data from 10 consecutive pregnant women. Analysis was descriptive to define the prevalence of IDA in pregnancy and the puerperium, and to compare the outcomes in women who had IDA with women who did not have anaemia anytime during pregnancy. Eighty-six maternity units contributed data on 860 pregnancies and births. The overall prevalence of IDA during pregnancy was 30.4% and in the puerperium 20%. Anaemic women were more likely to be from ethnic minorities, odds ratio 2.23 (1.50, 3.32). Adherence to national guidance was suboptimal, and the prevalence of anaemia in pregnancy remains very high. There is pressing need to explore barriers to early identification and effective management of iron deficiency. IDA should be considered a major public health problem in the UK.

Kidney Transplantation From Deceased Donors With Vaccine-induced Immune Thrombocytopenia and Thrombosis: An Updated Analysis of the UK Experience.

BACKGROUND: The emergence and attendant mortality of vaccine-induced immune thrombocytopenia and thrombosis (VITT) as a consequence of vaccination against severe acute respiratory syndrome coronavirus 2 have resulted in some patients with VITT being considered as deceased organ donors. Outcomes after kidney transplantation in this context are poorly described. Because the disease seems to be mediated by antiplatelet factor 4 antibodies, there is a theoretical risk of transmission via passenger leukocytes within the allograft. METHODS: We analyzed the experience of kidney transplantation from donors with VITT in the United Kingdom between January and June 2021. We followed-up all recipients of kidney-only transplants from donors with VITT to detect major postoperative complications or features of disease transmission and assess graft survival and function. RESULTS: There were 16 kidney donors and 30 single kidney transplant recipients in our study period. Of 11 preimplantation biopsies, 4 showed widespread glomerular microthrombi. After a median of 5 mo, patient and graft survival were 97% and 90%, respectively. The median 3-mo estimated glomerular filtration rate was 51 mL/min/1.73 m 2 . Two recipients had detectable antiplatelet factor 4 antibodies but no evidence of clinical disease after transplantation. Major hemorrhagic complications occurred in 3 recipients, all of whom had independent risk factors for bleeding, resulting in the loss of 2 grafts. The involvement of VITT could not be completely excluded in one of these cases. CONCLUSIONS: The UK experience to date shows that favorable outcomes are possible after kidney transplantation from donors with VITT but highlights the need for ongoing vigilance for donor-related complications in these patients.

Acute Generalized Exanthematous Pustulosis: A Painful and Pruritic Presentation of Pustulosis Following Pharmacotherapy for Pharyngeal Phlegmon.

Acute generalized exanthematous pustulosis (AGEP) is primarily a drug-induced skin eruption, which typically presents within two days of starting an offending medication; it is often self-limiting with spontaneous resolution within two weeks upon medication cessation. We report the case of a patient who presented with generalized desquamation, characteristic pustules, and several morbilliform rashes on the body surface in association with recent amoxicillin-clavulanic acid exposure. This was associated with significant pruritus, which was the associated chief complaint. A multimodal approach to symptomatic management with topical corticosteroids, barrier ointments, oral antihistamines, and analgesics was required, in addition to the cessation of the offending medication.

Effectiveness of Enhanced Performance Feedback on Appropriate Use of Blood Transfusions: A Comparison of 2 Cluster Randomized Trials.

Importance: Auditing and feedback are frequently used to improve patient care. However, it remains unclear how to optimize feedback effectiveness for the appropriate use of treatments such as blood transfusion, a common but costly procedure that is more often overused than underused. Objective: To evaluate 2 theoretically informed feedback interventions to improve the appropriate use of blood transfusions. Design, Setting, and Participants: Two sequential, linked 2 × 2 cluster randomized trials were performed in hospitals in the UK participating in national audits of transfusion for perioperative anemia and management of hematological disorders. Data were collected for a surgical trial from October 1, 2014, to October 31, 2016, with follow-up completed on October 31, 2016. Data were collected for a hematological trial through follow-up from July 1, 2015, to June 30, 2017. Trial data were analyzed from November 1, 2016, to June 1, 2019. Interventions: Hospitals were randomized to standard content or enhanced content to improve feedback clarity and usability and to standard support or enhanced support for staff to act on feedback. Main Outcomes and Measures: The primary end point was appropriateness of transfusions audited at 12 months. Secondary end points included volume of transfusions (aiming for reductions at patient and cluster levels) and transfusion-related adverse events and reactions. Results: One hundred thirty-five of 152 eligible clusters participated in the surgical audit (2714 patients; mean [SD] age, 74.9 [14.0] years; 1809 women [66.7%]), and 134 of 141 participated in the hematological audit (4439 patients; median age, 72.0 [IQR, 64.0-80.0] years; 2641 men [59.5%]). Fifty-seven of 69 clusters (82.6%) in the surgical audit randomized to enhanced content downloaded reports compared with 52 of 66 clusters (78.8%) randomized to standard reports. Fifty-nine of 68 clusters (86.8%) randomized to enhanced support logged onto the toolkit. The proportion of patients with appropriate transfusions was 0.184 for standard content and 0.176 for enhanced content (adjusted odds ratio [OR], 0.91 [97.5% CI, 0.61-1.36]) and 0.181 for standard support and 0.180 for enhanced support (adjusted OR, 1.05 [97.5% CI, 0.68-1.61]). For the hematological audit, 53 of 66 clusters (80.3%) randomized to enhanced content downloaded the reports compared with 53 of 68 clusters (77.9%) randomized to standard content. Forty-nine of 67 clusters sites (73.1%) assigned to enhanced support logged into the toolkit at least once. The proportion of patients with appropriate transfusions was 0.744 for standard content and 0.714 for enhanced content (adjusted OR, 0.81 [97.5% CI, 0.56-1.12]), and 0.739 for standard support and 0.721 for enhanced support (adjusted OR, 0.96 [97.5% CI, 0.67-1.38]). Conclusions and Relevance: This comparison of cluster randomized trials found that interventions to improve feedback usability and guide local action were no more effective than standard feedback in increasing the appropriate use of blood transfusions. Auditing and feedback delivered at scale is a complex and costly program; therefore, effective responses may depend on developing robust local quality improvement arrangements, which can be evaluated using rigorous experimental designs embedded within national programs. Trial Registration: isrctn.org Identifier: ISRCTN15490813.

Basin-scale biogeography of marine phytoplankton reflects cellular-scale optimization of metabolism and physiology.

Extensive microdiversity within Prochlorococcus, the most abundant marine cyanobacterium, occurs at scales from a single droplet of seawater to ocean basins. To interpret the structuring role of variations in genetic potential, as well as metabolic and physiological acclimation, we developed a mechanistic constraint-based modeling framework that incorporates the full suite of genes, proteins, metabolic reactions, pigments, and biochemical compositions of 69 sequenced isolates spanning the Prochlorococcus pangenome. Optimizing each strain to the local, observed physical and chemical environment along an Atlantic Ocean transect, we predicted variations in strain-specific patterns of growth rate, metabolic configuration, and physiological state, defining subtle niche subspaces directly attributable to differences in their encoded metabolic potential. Predicted growth rates covaried with observed ecotype abundances, affirming their significance as a measure of fitness and inferring a nonlinear density dependence of mortality. Our study demonstrates the potential to interpret global-scale ecosystem organization in terms of cellular-scale processes.

Bothsiderism.

This paper offers an account of a fallacy we will call bothsiderism, which is to mistake disagreement on an issue for evidence that either a compromise on, suspension of judgment regarding, or continued discussion of the issue is in order. Our view is that this is a fallacy of a unique and heretofore untheorized type, a fallacy of meta-argumentation. The paper develops as follows. After a brief introduction, we examine a recent bothsiderist case in American politics. We use this as a pivot point to survey the theoretical literature on the fallacy. The most prominent theory is that bothsiderism is a case of dialogue-shifting. This view fails, we maintain, to explain how bothsiderism might be persuasive. We argue, rather, bothsiderism is a kind of meta-argumentative fallacy.

A Bayesian approach to modeling phytoplankton population dynamics from size distribution time series.

The rates of cell growth, division, and carbon loss of microbial populations are key parameters for understanding how organisms interact with their environment and how they contribute to the carbon cycle. However, the invasive nature of current analytical methods has hindered efforts to reliably quantify these parameters. In recent years, size-structured matrix population models (MPMs) have gained popularity for estimating division rates of microbial populations by mechanistically describing changes in microbial cell size distributions over time. Motivated by the mechanistic structure of these models, we employ a Bayesian approach to extend size-structured MPMs to capture additional biological processes describing the dynamics of a marine phytoplankton population over the day-night cycle. Our Bayesian framework is able to take prior scientific knowledge into account and generate biologically interpretable results. Using data from an exponentially growing laboratory culture of the cyanobacterium Prochlorococcus, we isolate respiratory and exudative carbon losses as critical parameters for the modeling of their population dynamics. The results suggest that this modeling framework can provide deeper insights into microbial population dynamics provided by size distribution time-series data.

Complex marine microbial communities partition metabolism of scarce resources over the diel cycle.

Complex assemblages of microbes in the surface ocean are responsible for approximately half of global carbon fixation. The persistence of high taxonomic diversity despite competition for a small suite of relatively homogeneously distributed nutrients, that is, 'the paradox of the plankton', represents a long-standing challenge for ecological theory. Here we find evidence consistent with temporal niche partitioning of nitrogen assimilation processes over a diel cycle in the North Pacific Subtropical Gyre. We jointly analysed transcript abundances, lipids and metabolites and discovered that a small number of diel archetypes can explain pervasive periodic dynamics. Metabolic pathway analysis of identified diel signals revealed asynchronous timing in the transcription of nitrogen uptake and assimilation genes among different microbial groups-cyanobacteria, heterotrophic bacteria and eukaryotes. This temporal niche partitioning of nitrogen uptake emerged despite synchronous transcription of photosynthesis and central carbon metabolism genes and associated macromolecular abundances. Temporal niche partitioning may be a mechanism by which microorganisms in the open ocean mitigate competition for scarce resources, supporting community coexistence.

The impact of islet mass, number of transplants, and time between transplants on graft function in a national islet transplant program.

The UK islet allotransplant program is nationally funded to deliver one or two transplants over 12 months to individuals with type 1 diabetes and recurrent severe hypoglycemia. Analyses were undertaken 10 years after program inception to evaluate associations between transplanted mass; single versus two transplants; time between two transplants and graft survival (stimulated C-peptide >50 pmol/L) and function. In total, 84 islet transplant recipients were studied. Uninterrupted graft survival over 12 months was attained in 23 (68%) single and 47 (94%) (p = .002) two transplant recipients (separated by [median (IQR)] 6 (3-8) months). 64% recipients of one or two transplants with uninterrupted function at 12 months sustained graft function at 6 years. Total transplanted mass was associated with Mixed Meal Tolerance Test stimulated C-peptide at 12 months (p < .01). Despite 1.9-fold greater transplanted mass in recipients of two versus one islet infusion (12 218 [9291-15 417] vs. 6442 [5156-7639] IEQ/kg; p < .0001), stimulated C-peptide was not significantly higher. Shorter time between transplants was associated with greater insulin dose reduction at 12 months (beta -0.35; p = .02). Graft survival over the first 12 months was greater in recipients of two versus one islet transplant in the UK program, although function at 1 and 6 years was comparable. Minimizing the interval between 2 islet infusions may maximize cumulative impact on graft function.

Molecular targeting of vulnerable RNA sequences in SARS CoV-2: identifying clinical feasibility.

Covid-19 (SARS CoV-2) has become a deadly, world-wide pandemic. Although most who are infected survive, complications from the virus can be pronounced and long-lasting. To date, of all the respiratory viruses including influenza and coronaviruses, only influenza has had a drug (i.e., Tamiflu) specifically targeted to treat and prevent infection. As a result, additional agents that specifically target viral production and are clinically feasible are needed to alleviate respiratory viral infections. The idea of using a miRNA/siRNA molecular approach for treating various diseases was postulated over a decade ago; however, only within the past few years has it become feasible. One technological advancement has been the molecular linkage of lipophilic moieties to mi/siRNAs in order to bypass the need for enveloping these inhibitory RNAs in lipid-based transfection reagents, which could irritate the airway if inhaled. Here we show that siRNAs and miRNAs inhibit SARS CoV-2 spike protein production in a dose-dependent manner in both HEK293 cells and a primary human airway tracheal cell line. We also show that this inhibition is equally robust using a clinically relevant siRNA that does not need to be prepped with a transfection reagent.