Biomarker-Based Risk Stratification in Pediatric Sepsis From a Low-Middle Income Country.

OBJECTIVES: Most biomarker studies of sepsis originate from high-income countries, whereas mortality risk is higher in low- and middle-income countries. The second version of the Pediatric Sepsis Biomarker Risk Model (PERSEVERE-II) has been validated in multiple North American PICUs for prognosis. Given differences in epidemiology, we assessed the performance of PERSEVERE-II in septic children from Pakistan, a low-middle income country. Due to uncertainty regarding how well PERSEVERE-II would perform, we also assessed the utility of other select biomarkers reflecting endotheliopathy, coagulopathy, and lung injury. DESIGN: Prospective cohort study. SETTING: PICU in Aga Khan University Hospital in Karachi, Pakistan. PATIENTS: Children (< 18 yr old) meeting pediatric modifications of adult Sepsis-3 criteria between November 2020 and February 2022 were eligible. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Plasma was collected within 24 hours of admission and biomarkers quantified. The area under the receiver operating characteristic curve for PERSEVERE-II to discriminate 28-day mortality was determined. Additional biomarkers were compared between survivors and nonsurvivors and between subjects with and without acute respiratory distress syndrome. In 86 subjects (20 nonsurvivors, 23%), PERSEVERE-II discriminated mortality (area under the receiver operating characteristic curve, 0.83; 95% CI, 0.72-0.94) and stratified the cohort into low-, medium-, and high-risk of mortality. Biomarkers reflecting endotheliopathy (angiopoietin 2, intracellular adhesion molecule 1) increased across worsening risk strata. Angiopoietin 2, soluble thrombomodulin, and plasminogen activator inhibitor 1 were higher in nonsurvivors, and soluble receptor for advanced glycation end-products and surfactant protein D were higher in children meeting acute respiratory distress syndrome criteria. CONCLUSIONS: PERSEVERE-II performs well in septic children from Aga Khan University Hospital, representing the first validation of PERSEVERE-II in a low-middle income country. Patients possessed a biomarker profile comparable to that of sepsis from high-income countries, suggesting that biomarker-based enrichment strategies may be effective in this setting.

Total flucloxacillin plasma concentrations poorly reflect unbound concentrations in hospitalized patients with Staphylococcus aureus bacteraemia.

AIMS: Flucloxacillin dosing may be guided by measurement of its total plasma concentrations. Flucloxacillin is highly protein bound with fraction unbound in plasma (fu ) of around 0.04 in healthy individuals. The utility of measuring unbound flucloxacillin concentrations for patients outside the intensive care unit (ICU) is not established. We aimed to compare flucloxacillin fu in non-ICU hospitalised patients against healthy volunteers, and to examine the performance of a published model for predicting unbound concentrations, using total flucloxacillin and plasma albumin concentrations. METHODS: Data from 12 healthy volunteers (248 samples) and 47 hospitalized patients (61 samples) were examined. Plasma flucloxacillin concentrations were measured using a validated liquid chromatography-tandem mass spectrometry method. Flucloxacillin fu for the two groups was compared using a generalized estimating equation model to account for clustered observations. The performance of the single protein binding site prediction model in hospitalized patients was compared with measured unbound concentrations using Bland-Altman plots. RESULTS: The median (range) flucloxacillin fu for healthy (median albumin 45 g l-1 ) and hospitalized individuals (median albumin 30 g l-1 ) were 0.04 (0.02-0.07) and 0.10 (0.05-0.37), respectively (P < 0.0001). The prediction model underpredicted unbound flucloxacillin concentrations with a mean bias (95% limits of agreement) of -54% (-137%, +30%). CONCLUSIONS: The flucloxacillin fu values observed in our cohort of hospitalized patients had a wide range and were greater than those of healthy individuals. Unbound flucloxacillin plasma concentrations were predicted poorly by the model. Instead, unbound concentrations should be measured to guide dosing.

Management of ingested foreign bodies in children: a clinical report of the NASPGHAN Endoscopy Committee.

Foreign body ingestions in children are some of the most challenging clinical scenarios facing pediatric gastroenterologists. Determining the indications and timing for intervention requires assessment of patient size, type of object ingested, location, clinical symptoms, time since ingestion, and myriad other factors. Often the easiest and least anxiety-producing decision is the one to proceed to endoscopic removal, instead of observation alone. Because of variability in pediatric patient size, there are less firm guidelines available to determine which type of object will safely pass, as opposed to the clearer guidelines in the adult population. In addition, the imprecise nature of the histories often leaves the clinician to question the timing and nature of the ingestion. Furthermore, changes in the types of ingestions encountered, specifically button batteries and high-powered magnet ingestions, create an even greater potential for severe morbidity and mortality among children. As a result, clinical guidelines regarding management of these ingestions in children remain varied and sporadic, with little in the way of prospective data to guide their development. An expert panel of pediatric endoscopists was convened and produced the present article that outlines practical clinical approaches to the pediatric patient with a variety of foreign body ingestions. This guideline is intended as an educational tool that may help inform pediatric endoscopists in managing foreign body ingestions in children. Medical decision making, however, remains a complex process requiring integration of clinical data beyond the scope of these guidelines. These guidelines should therefore not be considered to be a rule or to be establishing a legal standard of care. Caregivers may well choose a course of action outside of those represented in these guidelines because of specific patient circumstances. Furthermore, additional clinical studies may be necessary to clarify aspects based on expert opinion instead of published data. Thus, these guidelines may be revised as needed to account for new data, changes in clinical practice, or availability of new technology.

An analysis of the learning curve to achieve competency at colonoscopy using the JETS database.

OBJECTIVE: The number of colonoscopies required to reach competency is not well established. The primary aim of this study was to determine the number of colonoscopies trainees need to perform to attain competency, defined by a caecal intubation rate (CIR) ≥90%. As competency depends on completion, we also investigated trainee factors that were associated with colonoscopy completion. DESIGN: The Joint Advisory Group on GI Endoscopy in the UK has developed a trainee e-portfolio from which colonoscopy data were retrieved. Inclusion criteria were all trainees who had performed a total of ≥20 colonoscopies and had performed ≤50 colonoscopies prior to submission of data to the e-portfolio. The primary outcome measure was colonoscopy completion. The number of colonoscopies required to achieve CIR ≥90% was calculated by the moving average method and learning curve cumulative summation (LC-Cusum) analysis. To determine factors which determine colonoscopy completion, a mixed effect logistic regression model was developed which allowed for nesting of patients within trainees and nesting of patients within hospitals, with various patient, trainee and training factors entered as fixed effects. RESULTS: 297 trainees undertook 36 730 colonoscopies. By moving average analysis, the cohort of trainees reached a CIR of 90% at 233 procedures. By LC-Cusum analysis, 41% of trainees were competent after 200 procedures. Of the trainee factors, the number of colonoscopies, intensity of training and previous flexible sigmoidoscopy experience were significant factors associated with colonoscopy completion. CONCLUSIONS: This is the largest study to date investigating the number of procedures required to achieve competency in colonoscopy. The current training certification benchmark in the UK of 200 procedures does not appear to be an inappropriate minimum requirement. The LC-Cusum chart provides real time feedback on individual learning curves for trainees. The association of training intensity and flexible sigmoidoscopy experience with colonoscopy completion could be exploited in training programmes.

Bowel preparation for pediatric colonoscopy: report of the NASPGHAN endoscopy and procedures committee.

Pediatric bowel preparation protocols used before colonoscopy vary greatly, with no identified standard practice. The present clinical report reviews the evidence for several bowel preparations in children and reports on their use among North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition members. Publications in the pediatric literature for bowel preparation regimens are described, including mechanisms of action, efficacy and ease of use, and pediatric studies. A survey distributed to pediatric gastroenterology programs across the country reviews present national practice, and cleanout recommendations are provided. Finally, further areas for research are identified.

Pulmonary valve infective endocarditis in an adult patient with atrial septal defect presenting with multiple pulmonary emboli - A case report.

Isolated pulmonary valve (PV) infective endocarditis (IE) is a rare entity accounting for <2 % of all cases of IE. Risk of PV IE in patients with atrial septal defect (ASD) is considered negligible and there have only been a few cases reported to date. We describe a case of a 51-year-old woman with an ostium secundum ASD with associated PV endocarditis, who presented with multiple pulmonary septic emboli. Initially we tried antibiotic therapy and later she underwent successful surgery with ASD closure, vegetectomy, and PV repair. We want to draw attention to the possibility of IE of PV in a patient with ASD and report successful management with surgery and good recovery following treatment. Learning objective: In this study, we highlight the importance of keeping a strong clinical suspicion of infective endocarditis (IE) in patients presenting with fever and a pulmonary focus, especially in the setting of congenital heart disease (including even atrial septal defect). We also discuss the possible indications for surgical management in patients with pulmonary valve IE.

Taking the next steps to implement polygenic risk scoring for improved risk stratification and primary prevention of coronary artery disease.

Coronary artery disease (CAD) remains the leading cause of death worldwide. The role of hypertension, cholesterol, diabetes mellitus, and smoking in driving disease has been well recognized at a population level and has been the target of primary prevention strategies for over 50 years with substantial impact. However, in many cases, these factors alone do not provide enough precision at the individual level to allow physicians and patients to take appropriate preventive measures and many patients continue to suffer acute coronary syndromes in the absence of these risk factors. Recent advances in user-friendly chip designs, high speed throughput, and economic efficiency of genome-wide association studies complemented by advances in statistical analytical approaches have facilitated the rapid development of polygenic risk scores (PRSs). The latest PRSs combine data regarding hundreds of thousands of single-nucleotide polymorphisms to predict chronic diseases including CAD. Novel CAD PRSs are strong predictors of risk and may have application, in a complementary manner with existing risk prediction algorithms. However, there remain substantial controversies, and ultimately, we need to move forward from observational studies to prospectively and rigorously assess the potential impact if widespread implementation is to be aspired to. Consideration needs to be made of ethnicity, sex, as well as age, and risk estimate based on existing non-genomic algorithms. We provide an overview and commentary on the important advances in deriving and validating PRSs, as well as pragmatic considerations that will be required for implementation of the new knowledge into clinical practice.

The health digital twin to tackle cardiovascular disease-a review of an emerging interdisciplinary field.

Potential benefits of precision medicine in cardiovascular disease (CVD) include more accurate phenotyping of individual patients with the same condition or presentation, using multiple clinical, imaging, molecular and other variables to guide diagnosis and treatment. An approach to realising this potential is the digital twin concept, whereby a virtual representation of a patient is constructed and receives real-time updates of a range of data variables in order to predict disease and optimise treatment selection for the real-life patient. We explored the term digital twin, its defining concepts, the challenges as an emerging field, and potentially important applications in CVD. A mapping review was undertaken using a systematic search of peer-reviewed literature. Industry-based participants and patent applications were identified through web-based sources. Searches of Compendex, EMBASE, Medline, ProQuest and Scopus databases yielded 88 papers related to cardiovascular conditions (28%, n = 25), non-cardiovascular conditions (41%, n = 36), and general aspects of the health digital twin (31%, n = 27). Fifteen companies with a commercial interest in health digital twin or simulation modelling had products focused on CVD. The patent search identified 18 applications from 11 applicants, of which 73% were companies and 27% were universities. Three applicants had cardiac-related inventions. For CVD, digital twin research within industry and academia is recent, interdisciplinary, and established globally. Overall, the applications were numerical simulation models, although precursor models exist for the real-time cyber-physical system characteristic of a true digital twin. Implementation challenges include ethical constraints and clinical barriers to the adoption of decision tools derived from artificial intelligence systems.

Effect of massage therapy on stress levels and quality of life in brain tumor patients--observations from a pilot study.

BACKGROUND: Patients with brain tumors report experiencing elevated levels of stress across the disease continuum. Massage therapy is a commonly used complementary therapy and is employed in cancer care to reduce psychological stress and to improve quality of life (QoL). The purpose of this pilot study was to obtain a preliminary assessment of the efficacy of massage therapy on patient reported psychological outcomes and QoL. MATERIALS AND METHODS: The design of the study was a prospective, single-arm intervention. Participants were newly diagnosed primary brain tumor patients who reported experiencing stress and who received a total of eight massages over a period of 4 weeks. Participants completed the Perceived Stress Scale (PSS-10) and the Functional Assessment of Cancer Therapy-Brain to assess their stress level and QoL. RESULTS: As a group, levels of stress dropped significantly between weeks 2 and 3 (M = 12.3, SD = 3.09, P ≤ 0.010). A trend for the reduction in stress continued through week 4 (P ≤ 0.063). At the end of week 4, PSS-10 scores of all participants were below the threshold for being considered stressed. By the end of the intervention, participants reported significant improvements in three test domains, emotional well-being, additional brain tumor concerns, and social/family well-being. CONCLUSION: This study indicates that participation in a massage therapy program is both feasible and acceptable to newly diagnosed brain tumor patients experiencing stress. Furthermore, participants in this study reported improvements in stress and their QoL while receiving massage therapy.

Severe stridor and profound weakness after cerebral malaria.

Cerebral malaria (CM) is defined by WHO as coma (Blantyre Coma Score 2 or less) in a patient with Plasmodium falciparum parasitaemia and no alternative cause of coma identified. Mortality is approximately 15%-30% in African children and up to one-third of survivors have neurological sequelae. We present a patient with severe stridor and prolonged profound weakness during an intensive care admission with CM. These complications initially presented a diagnostic dilemma in our limited resourced setting. The stridor failed to improve with empiric steroids and a subsequent opportunistic ENT consult diagnosed vocal cord paresis. The weakness was so profound that the patient was unable to lift his head during the acute illness. The child received intensive physiotherapy, and at 1-month follow-up, the stridor and weakness had resolved.

Immune checkpoint inhibitor-mediated myasthenia gravis with focal subclinical myocarditis progressing to symptomatic cardiac disease.

The advent of immune checkpoint inhibitors (ICIs) for cancer therapy has heralded increasing frequency of immune-related adverse events including endocrinopathies, hepatitis, colitis and rarely myocarditis and myasthenia gravis (MG). The heterogeneity in clinical presentations regardless of organ-specific involvement can lead to delayed recognition and management of these events and adverse health outcomes. We describe a case of ICI-induced subclinical focal myocarditis that was recognised and treated in the broader context of MG. It is essential that patients with ICI-induced MG should be screened and monitored for myocarditis, a potentially fatal complication.

Malignant teratoma of the thyroid: A difficult diagnosis by fine-needle aspiration.

Primary thyroid teratomas are rare, usually benign, and typically occur in children. We report the unusual occurrence of a malignant thyroid teratoma in a young man. Initial ultrasound and CT studies revealed an 8.5 heterogeneous mass involving the entire right thyroid lobe causing tracheal compression and deviation. Fine-needle aspiration (FNA) revealed malignant cells with possible neuroendocrine features. Similar findings have been previously reported, with an occasional interpretation as possible medullary thyroid carcinoma. In no report, as with our case, has the correct diagnosis been suggested with FNA. The surgical specimen contained abundant primitive neuroepithelium with a very minor component of mature ectodermal tissue in one area. Like this case, an abundance of immature neuroepithelium has been reported in essentially all previous reports of primary malignant thyroid teratoma, sometimes creating a challenge to find another type of germ cell tissue. Array comparative genomic hybridization studies in this case revealed a markedly complex karyotype including gain of chromosome 12 and loss of 17p. Amplification of MYCN, EWSR1 rearrangement and isochromosome 12p were not identified, providing no evidence for neuroblastoma or Ewing sarcoma/peripheral neuroectodermal tumor, both of which have also rarely been reported as primary thyroid tumors. With the use of cisplatinum-based chemotherapy combined with radiation, survival times have increased dramatically. Our patient is now disease free and back to his normal activities after relatively short follow-up. Although rare, it is important to be aware that teratomas may present as a thyroid nodule. Recognition by FNA is challenging, and requires multiple modalities for full identification.

Hyperbolic metamaterials for dispersion-assisted directional light emission.

A novel method is presented to outcouple high spatial frequency (large-k) waves from hyperbolic metamaterials (HMMs) without the use of a grating. This approach relies exclusively on dispersion engineering, and enables preferential power extraction from the top or from the side of a HMM. Multilayer (ML) HMMs are shown to be better suited for lateral outcoupling, while nanowire HMMs are the most convenient choice for top outcoupling. A 6-fold increase in laterally extracted power is predicted for a dipole-HMM system with a Ag/Si ML operating at λ = 530 nm, when metallic filling ratio is changed from an unoptimized to the optimized one. This new design concept supports the cost-effective mass production of high-speed HMM optical transmitters.

Patients with computed tomography-proven acute diverticulitis require follow-up to exclude colorectal cancer.

BACKGROUND/AIMS: Traditionally, patients with acute diverticulitis undergo follow-up endoscopy to exclude colorectal cancer (CRC). However, its usefulness has been debated in this era of high-resolution computed tomography (CT) diagnosis. We assessed the frequency and outcome of endoscopic follow-up for patients with CT-proven acute diverticulitis, according to the confidence in the CT diagnosis. METHODS: Records of patients with CT-proven acute diverticulitis between October 2007 and March 2014 at Sandwell & West Birmingham Hospitals NHS Trust were retrieved. The National Cancer Registry confirmed the cases of CRC. Endoscopy quality indicators were compared between these patients and other patients undergoing the same endoscopic examination over the same period. RESULTS: We identified 235 patients with CT-proven acute diverticulitis, of which, 187 were managed conservatively. The CT report was confident of the diagnosis of acute diverticulitis in 75% cases. Five of the 235 patients were subsequently diagnosed with CRC (2.1%). Three cases of CRC were detected in the 187 patients managed conservatively (1.6%). Forty-eight percent of the conservatively managed patients underwent follow-up endoscopy; one case of CRC was identified. Endoscopies were often incomplete and caused more discomfort for patients with diverticulitis compared with controls. CONCLUSIONS: CRC was diagnosed in patients with CT-proven diverticulitis at a higher rate than in screened asymptomatic populations, necessitating follow-up. CT reports contained statements regarding diagnostic uncertainty in 25% cases, associated with an increased risk of CRC. Follow-up endoscopy in patients with CT-proven diverticulitis is associated with increased discomfort and high rates of incompletion. The use of other follow-up modalities should be considered.

Conversion of colonoscopy to flexible sigmoidoscopy: an unintended consequence of quality measurement in endoscopy.

OBJECTIVE: To quantify the proportion of requests for colonoscopy that are performed as flexible sigmoidoscopy and documented reasons for this in ordinary UK hospital practice. To determine the effect these requests have on colonoscopy completion rate if they are included in the denominator of the calculated rate by individual endoscopist. DESIGN: Retrospective study of 22 months flexible sigmoidoscopy practice at a major UK teaching hospital. All flexible sigmoidoscopies performed had their associated request form examined. SETTING: UK NHS University Hospital. PATIENTS: All patients receiving outpatient flexible sigmoidoscopy from January 2013 to October 2014 with no exclusions. INTERVENTION: Conversion of colonoscopy to flexible sigmoidoscopy. MAIN OUTCOME MEASURES: Conversion of colonoscopy to flexible sigmoidoscopy, reason for conversion and adjusted colonoscopy completion rate. RESULTS: 71 of the 3526 flexible sigmoidoscopies performed (2.0%), representing 71 of 5905 colonoscopy requests (1.2%). Conversion reason was noted only in 26 (37%) of converted cases. Adjustment of colonoscopy completion rate to include conversions pushed four of our unit's 22 endoscopists below the UK national 90% standard. CONCLUSIONS: Conversion to flexible sigmoidoscopy occurs in 1.2% of patients originally booked for colonoscopy. The reason for this conversion is often unqualified and may be inappropriate. Conversion can affect the colonoscopy completion rate, and therefore, should be included in endoscopists' overall performance statistics.