Mode of action studies confirm on-target engagement of lysyl-tRNA synthetase inhibitor and lead to new selection marker for Cryptosporidium.

Introduction: Cryptosporidiosis is a leading cause of diarrheal-associated morbidity and mortality, predominantly affecting children under 5 years old in low-and-middle-income countries. There is no effective treatment and no vaccine. New therapeutics are emerging from drug discovery efforts. It is critical that mode of action studies are performed alongside drug discovery to ensure the best clinical outcomes. Unfortunately, technology to identify and validate drug targets for Cryptosporidium is severely lacking. Methods: We used C. parvum lysyl-tRNA synthetase (CpKRS) and DDD01510706 as a target-compound pair to develop both chemical and genetic tools for mode of action studies for Cryptosporidium. We adapted thermal proteome profiling (TPP) for Cryptosporidium, an unbiased approach for target identification. Results: Using TPP we identified the molecular target of DDD01510706 and confirm that it is CpKRS. Genetic tools confirm that CpKRS is expressed throughout the life cycle and that this target is essential for parasite survival. Parasites genetically modified to over-express CpKRS or parasites with a mutation at the compound-binding site are resistant to treatment with DDD01510706. We leveraged these mutations to generate a second drug selection marker for genetic modification of Cryptosporidium, KRSR. This second selection marker is interchangeable with the original selection marker, NeoR, and expands the range of reverse genetic approaches available to study parasite biology. Due to the sexual nature of the Cryptosporidium life cycle, parental strains containing different drug selection markers can be crossed in vivo. Discussion: Selection with both drug markers produces highly efficient genetic crosses (>99% hybrid progeny), paving the way for forward genetics approaches in Cryptosporidium.

Risk factors for post sternotomy wound complications across the patient journey: A systematised review of the literature.

BACKGROUND: Around 36,000 cardiac operations are undertaken in the United Kingdom annually, with most procedures undertaken via median sternotomy. Wound complications occur in up to 8% of operations, with an associated mortality rate of around 47% in late or undetected cases. OBJECTIVE: To undertake a systematised literature review to identify pre-operative, peri-operative and post-operative risk factors associated with sternal wound complications. METHODS: Healthcare databases were searched for articles written in the English language and published between 2013 and 2021. Inclusion criteria were quantitative studies involving patients undergoing median sternotomy for cardiac surgery; sternal complications and risk factors. RESULTS: 1360 papers were identified, with 25 included in this review. Patient-related factors included: high BMI; diabetes; comorbidities; gender; age; presenting for surgery in a critical state; predictive risk scores; vascular disease; severe anaemia; medication such as steroids or α-blockers; and previous sternotomy. Peri-operative risk increased with specific types and combinations of surgical procedures. Sternal reopening was also associated with increased risk of sternal wound infection. Post-operative risk factors included a complicated recovery; the need for blood transfusions; respiratory complications; renal failure; non-diabetic hyperglycaemia; sternal asymmetry and sepsis. CONCLUSION: Pre, peri and post-operative risk factors increase the risk of sternal wound complications in cardiac surgery. Generic risk assessment tools are primarily designed to provide mortality risk scores, with their ability to predict risk of wound infection questionable. Tools that incorporate factors throughout the operative journey are required to identify patients at risk of surgical wound infection.

Observation of the non-linear Meissner effect.

A long-standing theoretical prediction is that in clean, nodal unconventional superconductors the magnetic penetration depth λ, at zero temperature, varies linearly with magnetic field. This non-linear Meissner effect is an equally important manifestation of the nodal state as the well studied linear-in-T dependence of λ, but has never been convincingly experimentally observed. Here we present measurements of the nodal superconductors CeCoIn5 and LaFePO which clearly show this non-linear Meissner effect. We further show how the effect of a small dc magnetic field on λ(T) can be used to distinguish gap nodes from non-nodal deep gap minima. Our measurements of KFe2As2 suggest that this material has such a non-nodal state.

The illogical logic of music torture.

This article draws on research into the use of music in the context of torture--both as a technique of torture and as a means of rehabilitation--to ask what types of musical activities and practices may constitute ill-treatment, up to and including torture. As well as providing information on the ways music is used in the context of torture and cruel, inhuman or degrading treatment or punishment (hereafter: CIDT), the article discusses responses to this issue in the scholarly, legal and therapeutic communities. Pointing to a widespread link between musical practices and humiliation of the prisoner and celebration of the power of those in charge over those held in detention, the author argues that coerced musical practices of any sort in detention are a cause for grave concern. She draws on research into post-traumatic stress disorder (hereafter: PTSD) and the torture-CIDT distinction to argue for an approach to the use of music in detention that places primacy on the dignity of the detained person.

What are the risk factors for renal failure following open elective abdominal aortic aneurysm repair?

OBJECTIVES: Renal failure following abdominal aortic aneurysm (AAA) repair is a common and significant complication. The objective of this study was to identify risk factors for renal failure following open elective AAA repair. DESIGN: A retrospective analysis of prospectively collected multi-centre data. MATERIALS: Consecutive data on patients undergoing open elective AAA repair were collected between January 2000 and December 2010. Patients with pre-operative serum creatinine >200 µmol/L were excluded. METHODS: Renal failure was reported by clinicians and included all patients requiring post-operative renal-replacement therapy. Univariate and multivariate analyses were used to identify renal failure risk factors. A simplified clinical risk score was developed. RESULTS: Post-operative renal failure occurred in 140 (6.0%) of 2347 patients and was associated with age >75 (OR = 1.58, 95%CI 1.11-2.26), symptomatic AAA (OR = 1.77, 95%CI 1.24-2.52), supra/juxta renal AAA (OR = 2.17, 95%CI 1.32-3.57) pre-operative serum creatinine >150 (OR = 2.75, 95%CI 1.69-4.50), treated hypertension (OR = 1.87, 95%CI 1.28-2.74), and respiratory disease (OR = 2.08, 95%CI 1.45-2.97). Patients with post-operative renal failure had significantly higher 30-day mortality (35.0% vs. 4.3%, p < 0.001). CONCLUSIONS: Renal failure following open elective AAA repair was associated with an increased risk of mortality. Risk factors for post-operative renal failure were identified and a simple clinical risk score developed to facilitate focussed care strategies for high-risk patients.

Synthesis and biological activities of 4-N-(anilinyl-n-[oxazolyl])-7-chloroquinolines (n=3' or 4') against Plasmodium falciparum in in vitro models.

The synthesis (Pd-mediated coupling strategy) and characterization (NMR, IR, elemental analysis, etc.) of a short series of quinoline-oxazole hybrid compounds has been carried out. These materials are found to be moderately active against Plasmodium falciparum in vitro, with activities in the sub-micromolar range, and to display acceptable cytotoxicity to mononuclear leukocytes. Chemical modification strategies, with the intention to increase the biological potency of this new class of anti-malarial agents, are discussed.

Delivery of enteral nutrition.

There is increasing evidence that enteral feeding is superior to parenteral nutrition with regard to maintaining gut structure and function. Selection of the enteral access route depends on the type and anticipated duration of nutrient delivery. At present, enteral feeding devices can be divided into two major categories: those entering the gastrointestinal tract through the oral or nasal cavity (oroenteric or nasoenteric tubes) and those entering through the abdominal wall including gastrostomy, duodenostomy, or jejunostomy tubes. This article provides a review of methods to insert and confirm gastric and intestinal feeding tube placement. Care of the patient with an enteric tube will be described.

Financial impact of elimination of routine chest radiographs in a pediatric intensive care unit.

OBJECTIVE: To determine the change in chest radiograph use if each chest radiograph requires a separate order and clinical indication. DESIGN: Prospective, nonrandomized, controlled design with an intervention. SETTING: The pediatric intensive care unit (PICU) at Primary Children's Medical Center, Salt Lake City, UT. PATIENTS: The study comprised 3,727 PICU patients treated between 1992 and 1996. INTERVENTIONS: A change in ordering practice: There will be no standing orders for routine daily morning chest radiographs. Each radiograph requires a written order and a clinical indication. MEASUREMENTS AND MAIN RESULTS: During a 29-month control phase when routine daily chest radiographs were obtained for all intubated patients, 1.026 chest radiographs per patient day were performed. After the intervention, the ratio dropped to 0.653 chest radiographs per patient day, a decrease of 36.4%. This resulted in a (projected) variable cost savings of $45,476. Data were also collected for quality assurance purposes. CONCLUSIONS: These results demonstrate the impact of an evaluation and subsequent change in radiology ordering practice in our PICU. The change resulted in decreased variability in ordering practice, fewer chest radiographs per patient, and an accompanying cost savings to our patients and payors.

A cost analysis of enterally administered lorazepam in the pediatric intensive care unit.

OBJECTIVE: To determine the cost savings of replacing intravenous midazolam with enterally administered lorazepam in mechanically ventilated children who require long-term continuous sedation. DESIGN: Retrospective review of patients treated according to a preestablished pediatric intensive care unit (ICU) sedation protocol. SETTING: Twenty-six-bed pediatric ICU in a tertiary care children's hospital. PATIENTS: The records of 30 mechanically ventilated children were analyzed. The median age was 1.5 yrs and the median weight was 8.0 kg. Patients required continuous sedation for a total of 16 days (median). INTERVENTIONS: According to our pediatric ICU sedation protocol, midazolam infusion was continued until the hourly midazolam requirement was stable for at least 24 hrs. Thereafter, patients with a nasojejunal tube who were likely to require a minimum of three additional days of continuous sedation were transitioned from intravenous midazolam to enterally administered lorazepam. The goal in transitioning therapy was to titrate the lorazepam dose and reduce midazolam administration while maintaining an unchanged level of sedation. MEASUREMENTS AND MAIN RESULTS: The rate of midazolam administration was significantly (p<.05) reduced beginning on day 1 of lorazepam treatment. Midazolam was successfully discontinued in 24 (80%) patients in 3 days (median), and adequate and appropriate sedation was maintained with lorazepam monotherapy. Six patients in whom midazolam could not be discontinued experienced a 52% reduction in the rate of midazolam administration as a result of adding lorazepam. Total projected midazolam utilization was defined as the sum of midazolam administration before initiating lorazepam and the projected midazolam requirement after initiating lorazepam. Projected midazolam cost was calculated as the product of total projected midazolam utilization and midazolam acquisition cost. Actual expenditures for both midazolam and lorazepam were subtracted from the projected midazolam cost to calculate the estimated cost savings. Overall, midazolam utilization (in milligrams) was reduced by 46.7+/-27.6% (median 52). Total projected midazolam cost for the 30 patients was $90,771. The actual cost of midazolam and lorazepam combined was $47,867, resulting in a cost savings of $42,904. CONCLUSIONS: Transitioning from intravenous midazolam to enterally administered lorazepam in critically ill children who require long-term sedation results in significant cost savings. The oral formulation of lorazepam was convenient to use, inexpensive, and effective in maintaining a continuous and appropriate level of sedation once midazolam was discontinued.

Searching for information on outcomes: do you need to be comprehensive?

The concepts of evidence-based practice and clinical effectiveness are reliant on up to date, accurate, high quality, and relevant information. Although this information can be obtained from a range of sources, computerised databases such as MEDLINE offer a fast, effective means of bringing up to date information to clinicians, as well as health service and information professionals. Common problems when searching for information from databases include missing important relevant papers or retrieving too much information. Effective search strategies are therefore necessary to retrieve a manageable amount of relevant information. This paper presents a range of strategies which can be used to locate information on MEDLINE efficiently and effectively.

Reviewing and selecting outcome measures for use in routine practice.

For the successful achievement of evidence-based practice, clinicians, managers and purchasers need evidence on whether a particular intervention works and ways to judge the appropriateness of the outcome criteria and measures used. Guidance is needed on what outcome measure to use, especially within routine clinical care settings. Beginning with a reclarification of the difference between a health status and an outcome measure, the paper presents an evaluative checklist for use by clinical audit and research staff to review outcome measures for use in routine care settings. Central features include the user-centredness of the measure, its psychometric properties, feasibility of use and utility. The applicability of the checklist is illustrated for outcome measurement in diabetes and stroke care. A modified form of the checklist is proposed for use by the busy clinician as an aid to the critical review of research papers within the context of evidence-based practice and to aid health care practitioners' choice of which outcome measure(s) to use within routine clinical care.

Nonradiographic assessment of enteral feeding tube position.

OBJECTIVE: To determine whether a clinical, nonradiographic criterion can be used to predict when the tip of a blindly placed feeding tube is in the small intestine. DESIGN: Prospective sample. SETTING: Pediatric intensive care unit at a tertiary care children's hospital. PATIENTS: Critically ill children requiring transpyloric feeding. INTERVENTIONS: The small bowel was intubated, using a blind, bedside transpyloric feeding tube placement protocol. The feeding tube was considered to be in the small bowel when <2 mL of a 10- mL aliquot of insufflated air could be aspirated from the feeding tube. This clinical criterion was confirmed with an abdominal radiograph. MEASUREMENTS AND MAIN RESULTS: Patient age ranged from 1 month to 19 yrs (median 6 months). Weight ranged from 2.2 to 60 kg (median 4.9). Median time to feeding tube placement was 10 mins (range 5 to 60). Eighty-nine percent of the patients were mechanically ventilated, while 28% of these patients were pharmacologically paralyzed. Seventy-five feeding tubes were inserted. There were no known complications. Ninety-nine (74/75) percent of the feeding tubes were positioned in the small bowel. The inability to aspirate insufflated air correctly predicted small bowel intubation with 99% certainty (Sequential Probability Ratio Test, p = .05 and power = .80). This test incorrectly predicted the position of only one feeding tube, the 26th, which was in the stomach. Of the 74 feeding tubes positioned in the small bowel, 13 feeding tubes were in the duodenum and 61 were in the jejunum. CONCLUSIONS: The inability to aspirate insufflated air confirms the transpyloric position of a feeding tube. Other clinical criteria did not successfully predict small bowel intubation. Use of this single test may obviate confirmatory abdominal radiographs in carefully selected patients and may lead to more cost-effective and timely initiation of enteral feedings.

The value of an outcomes information resource. An evaluation of the UK Clearing House on Health Outcomes.

Reports on the first phase of an evaluation of the UK Clearing House on Health Outcomes (UKCHHO) undertaken by a sample survey of purchasers and providers on its mailing list and users of its enquiry service. Explores user satisfaction with the services and publications of the project, uses made of the information provided and perceptions of the future role of a UKCHHO. Reports overwhelming satisfaction with the enquiry service and agreement about the usefulness of Outcomes Briefing. States that the main areas of use for the information provided were within clinical audit, guidelines and the exploration of outcomes within routine clinical practice. Also that the findings provide evidence of the need for an expanded brief for a UKCHHO, to include the provision of an enquiry service on study design and demonstrations of the value of the collection of outcomes data. Notes there is an urgent need to show that the systematic collection and use of outcomes data makes a difference to the quality of care provided to patients and to the purchase of services.

Reasoning in middle childhood: a dynamic model of performance on transitivity tasks.

An overview of the models and data relevant to children's transitive reasoning is provided. We propose a new conceptual framework, one which is embedded in a dynamic model that accounts for children's failures to reason transitively. It is assumed that rather than reasoning in a transitive manner, children often encode both relational and absolute stimulus information and use stimulus generalization as a transfer mechanism. The model is applied to new and extant data. The model provides an adequate and parsimonious account of children's failures on these tasks. We conclude that progress in understanding children's reasoning is dependent on operationalizing constructs in formal models so that assumptions can be evaluated and rejected.

On measuring (in)dependence of cognitive processes.

The authors provide a critical evaluation of the use of stochastic independence in psychological research. Specifically, they consider problems of confirming the null hypothesis, power of the statistical test, Simpson's paradox, and between-subjects and within-subject correlations. These problems are discussed in the context of research on theories of memory and cognitive development and illustrated with data on reasoning-remembering relationships. The authors conclude that demonstrations of response independence do not, by themselves, provide sufficient grounds for deciding whether a single process or multiple processes are necessary to account for performance. Instead, they argue that formal models are necessary if findings of (in)dependence are to be interpreted meaningfully in terms of underlying theoretical processes.

Dietary fat reduction strategies.

In this study, we used computer modeling to identify which techniques designed to achieve dietary fat reduction were the most effective in meeting the dietary recommendations of the American Heart Association Step-One diet. Menus were developed for men and nonpregnant, nonlactating women, 25 to 50 years old, according to the Continuing Survey of Food Intakes by Individuals (with 36% and 37% of energy from fat for men and women respectively). The menus were modified realistically using the Minnesota Nutrition Data System. The following five strategies were applied: skim milk replaced whole milk and 2%-fat milk (SKM); medium-fat meat exchanges replaced higher-fat ones (MMtEx); lean meat exchanges replaced higher-fat ones (LMtEx); fat-modified products were used (FMP); and 2%-fat milk replaced whole milk (LFM). For men, strategies LMtEx, SKM + LMtEx, SKM + LMtEx + FMP, LMtEx + FMP, LMtEx + FMP + LFM, and LMtEx + LFM reduced energy by 195 to 415 kcal and achieved the targeted level of energy from fat (less than or equal to 30 +/- 1%) and cholesterol (less than 300 mg) while maintaining 67% or more of the Recommended Dietary Allowances for other nutrients. For women, however, no single strategy achieved the goal. Certain combinations of strategies, SKM + LMtEx, SKM + FMP, SKM + MMtEx + FMP, reduced energy by 150 to 268 kcal and achieved the targeted dietary fat and cholesterol goals while maintaining 67% or more of the Recommended Dietary Allowances for other nutrients. All strategies led to a reduction in both saturated fatty acids (to 9% to 10% of energy) and monounsaturated fatty acids.(ABSTRACT TRUNCATED AT 250 WORDS)