Diagnostic test accuracy of procalcitonin and C-reactive protein for predicting invasive and serious bacterial infections in young febrile infants: a systematic review and meta-analysis.

BACKGROUND: Febrile infants presenting in the first 90 days of life are at higher risk of invasive and serious bacterial infections than older children. Modern clinical practice guidelines, mostly using procalcitonin as a diagnostic biomarker, can identify infants who are at low risk and therefore suitable for tailored management. C-reactive protein, by comparison, is widely available, but whether C-reactive protein and procalcitonin have similar diagnostic accuracy is unclear. We aimed to compare the test accuracy of procalcitonin and C-reactive protein in the prediction of invasive or serious bacterial infections in febrile infants. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, EMBASE, Web of Science, and The Cochrane Library for diagnostic test accuracy studies up to June 19, 2023, using MeSH terms "procalcitonin", and "bacterial infection" or "fever" and keywords "invasive bacterial infection*" and "serious bacterial infection*", without language or date restrictions. Studies were selected by independent authors against eligibility criteria. Eligible studies included participants aged 90 days or younger presenting to hospital with a fever (≥38°C) or history of fever within the preceding 48 h. The primary index test was procalcitonin, and the secondary index test was C-reactive protein. Test kits had to be commercially available, and test samples had to be collected upon presentation to hospital. Invasive bacterial infection was defined as the presence of a bacterial pathogen in blood or cerebrospinal fluid, as detected by culture or quantitative PCR; authors' definitions of serious bacterial infection were used. Data were extracted from selected studies, and the detection of invasive or serious bacterial infections was analysed with two models for each biomarker. Diagnostic accuracy was determined against internationally recognised cutoff values (0·5 ng/mL for procalcitonin, 20 mg/L for C-reactive protein) and pooled to calculate partial area under the curve (pAUC) values for each biomarker. Optimum cutoff values were identified for each biomarker. This study is registered with PROSPERO, CRD42022293284. FINDINGS: Of 734 studies derived from the literature search, 14 studies (n=7755) were included in the meta-analysis. For the detection of invasive bacterial infections, pAUC values were greater for procalcitonin (0·72, 95% CI 0·56-0·79) than C-reactive protein (0·28, 0·17-0·61; p=0·016). Optimal cutoffs for detecting invasive bacterial infections were 0·49 ng/mL for procalcitonin and 13·12 mg/L for C-reactive protein. For the detection of serious bacterial infections, procalcitonin and C-reactive protein had similar pAUC values (0·55, 0·44-0·69 vs 0·54, 0·40-0·61; p=0·92). For serious bacterial infections, the optimal cutoffs for procalcitonin and C-reactive protein were 0·17 ng/mL and 16·18 mg/L, respectively. Heterogeneity was low for studies investigating the test accuracy of procalcitonin in detecting invasive bacterial infection (I2=23·5%), high for studies investigating procalcitonin for serious bacterial infection (I2=75·5%), and moderate for studies investigating C-reactive protein for invasive bacterial infection (I2=49·5%) and serious bacterial infection (I2=28·3%). The absence of a single definition of serious bacterial infection across studies was the greatest source of interstudy variability and potential bias. INTERPRETATION: Within a large cohort of febrile infants, a procalcitonin cutoff of 0·5 ng/mL had a superior pAUC value to a C-reactive protein cutoff of 20 mg/L for identifying invasive bacterial infections. In settings without access to procalcitonin, C-reactive protein should therefore be used cautiously for the identification of invasive bacterial infections, and a cutoff value below 20 mg/L should be considered. C-reactive protein and procalcitonin showed similar test accuracy for the identification of serious bacterial infection with internationally recognised cutoff values. This might reflect the challenges involved in confirming serious bacterial infection and the absence of a universally accepted definition of serious bacterial infection. FUNDING: None.

Applying clinical decision aids for the assessment and management of febrile infants presenting to emergency care in the UK and Ireland: Febrile Infant Diagnostic Assessment and Outcome (FIDO) Study protocol.

INTRODUCTION: Febrile infants 90 days and younger are at risk of invasive bacterial infections (bacteraemia and meningitis) and urinary tract infections. Together this is previously termed serious bacterial infection with an incidence of approximately 10-20%. The National Institute for Health and Care Excellence guidance advocates a cautious approach with most infants requiring septic screening, parenteral broad-spectrum antibiotics and hospital admission. Internationally, variations exist in the approach to febrile infants, with European and North American guidance advocating a tailored approach based on clinical features and biomarker testing. None of the available international clinical decision aids (CDAs) has been validated in the UK and Irish cohorts. The aim of the Febrile Infant Diagnostic Assessment and Outcome (FIDO) Study is to prospectively validate a range of CDAs in a UK and Irish population including CDAs that use procalcitonin testing. METHODS AND ANALYSIS: The FIDO Study is a prospective multicentre mixed-methods cohort study conducted in UK and Irish hospitals. All infants aged 90 days and younger presenting with fever or history of fever (≥38°C) are eligible for inclusion. Infants will receive standard emergency clinical care without delay. Clinical data and blood samples will be collected, and consent will be obtained at the earliest appropriate opportunity using research without prior consent methodology. The performance and cost-effectiveness of CDAs will be assessed. An embedded qualitative study will explore clinician and caregiver views on different approaches to care and perceptions of risk. ETHICS AND DISSEMINATION: This study was reviewed and approved by the Office for Research Ethics Committees Northern Ireland-Health and Social Care Research Ethics Committee B, Public Benefit and Privacy Panel for Health and Social Care Scotland, and Children's Health Ireland Research and Ethics Committee Ireland. The results of this study will be presented at academic conferences and in peer-reviewed publications. TRIAL REGISTRATION NUMBER: NCT05259683.

American Football Play and Parkinson Disease Among Men.

Importance: Parkinsonism and Parkinson disease (PD) are known to result from repetitive head impacts from boxing. Repetitive head impacts from American football may also be associated with increased risk of neurodegenerative pathologies that cause parkinsonism, yet in vivo research on the association between football play and PD is scarce and limited by small samples and equivocal findings. Objective: To evaluate the association between football participation and self-reported parkinsonism or PD diagnosis. Design, Setting, and Participants: This cross-sectional study leveraged data from the online Fox Insight study. Participants completed online questionnaires and self-reported whether they currently had a diagnosis of Parkinson disease or parkinsonism by a physician or other health care professional. In November 2020, the Boston University Head Impact Exposure Assessment was launched for data collection on repetitive head impacts. Data used for this manuscript were obtained from the Fox Insight database on June 9, 2022. A total of 1875 men who endorsed playing any organized sport were included. Former athletes were divided into those who participated in football (n = 729 [38.9%]) and those who participated in other sports (reference group). Exposures: Self-reported participation in football, duration and level of football play, age at first exposure. Main Outcomes and Measures: Logistic regression tested associations between PD status and history of football play, duration of football play, highest level played, and age at first exposure, controlling for age, education, history of diabetes or heart disease, body mass index, history of traumatic brain injury with loss of consciousness, and family history of PD. Results: In this sample of 1875 men (mean [SD] age, 67.69 [9.84] years) enriched for parkinsonism or PD (n = 1602 [85.4%]), 729 (38.9%) played football (mean [SD] duration, 4.35 [2.91] years). History of playing football was associated with higher odds of having a parkinsonism or PD diagnosis (odds ratio [OR], 1.61; 95% CI, 1.19-2.17). Among the entire sample, longer duration of play was associated with higher odds of having a parkinsonism or PD diagnosis (OR, 1.12; 95% CI, 1.06-1.19). Among football players, longer duration of football play (OR, 1.12; 95% CI, 1.02-1.23) and higher level of play (OR, 2.93; 95% CI, 1.28-6.73) were associated with higher odds of having parkinsonism or PD. Conclusions and Relevance: In this cross-sectional study of participants enriched for PD, participation in football was associated with higher odds of having a reported parkinsonism or PD diagnosis.

Psychographic segmentation to identify higher-risk teen peer crowds for health communications: Validation of Virginia's Mindset Lens Survey.

Audience segmentation is necessary in health communications to ensure equitable resource distribution. Peer crowds, which are macro-level teen subcultures, are effective psychographic segments for health communications because each crowd has unique mindsets, values, norms, and health behavior profiles. These mindsets affect behaviors, and can be used to develop targeted health communication campaigns to reach those in greatest need. Though peer crowd research is plentiful, no existing peer crowd measurement tool has been formally validated. As such, we developed and validated Virginia's Mindset Lens Survey (V-MLS), a mindset-based teen peer crowd segmentation survey to support health communication efforts. Using an online convenience sample of teens (N = 1,113), we assessed convergent and discriminant validity by comparing the V-MLS against an existing, widely-used peer crowd survey (I-Base Survey®) utilizing a multi-trait multi-method matrix. We also examined the V-MLS's predictive ability through a series of regressions using peer crowd scores to predict behaviors, experiences, and traits relevant to health communication campaign planning. The V-MLS demonstrated reliability and convergent and discriminant validity. Additionally, the V-MLS effectively distinguished teen peer crowds with unique health behaviors, experiences, and personal traits. When combined with appropriate information processing and campaign development frameworks, this new tool can complement existing instruments to inform message framing, tone, and style for campaigns that target at-risk teens to increase campaign equity and reach.

Systematic review and meta-analysis assessing the diagnostic test accuracy of procalcitonin in the diagnosis of invasive bacterial infections in febrile infants: a study protocol.

INTRODUCTION: Young febrile infants are at higher risk of invasive bacterial infections (IBIs) compared with older children. The clinical features of IBI are subtle in this cohort mandating that clinicians take a cautious approach to their initial assessment and management. This includes the measurement of blood biomarkers of infection such as C reactive protein (CRP) and procalcitonin (PCT). In the UK, PCT is not widely available and not recommended for routine use in hospital. This is in contrast to Europe and the USA where PCT is regularly used to assist clinical decision-making. The objective of this review and meta-analysis is to report the diagnostic test accuracy of PCT in detecting IBI in febrile infants less than 91 days old, compare its accuracy with CRP and define optimal PCT cut-off values in this cohort. METHODS AND ANALYSIS: A search strategy will include MEDLINE, EMBASE, Web of Science, The Cochrane Library and grey literature. There will be no language or date limitations. Diagnostic accuracy studies compliant with STARD criteria will be considered against eligibility criteria. Abstracts, then full texts, of potentially eligible studies will be independently screened for selection. Data extraction and quality assessment, using the QUADAS-2 tool, will be completed by two independent authors and a third author used for any inconsistencies. True positives, false positives, true negatives and false negatives will be pooled to collate specificity and sensitivity with 95% CIs. Results will be portrayed in forest plots, alongside their quality assessments. ETHICS AND DISSEMINATION: This review does not require ethical clearance. This review will be published in peer-reviewed journals and key messages will be disseminated through presentations at local and international conferences related to this field. The authors aim for this review to be completed and published in 2023.

Hemostasis, coagulation and thrombin in venoarterial and venovenous extracorporeal membrane oxygenation: the HECTIC study.

Extracorporeal membrane oxygenation (ECMO) support has a high incidence of both bleeding and thrombotic complications. Despite clear differences in patient characteristics and pathologies between veno-venous (VV) and veno-arterial (VA) ECMO support, anticoagulation practices are often the same across modalities. Moreover, there is very little data on their respective coagulation profiles and comparisons of thrombin generation in these patients. This study compares the coagulation profile and thrombin generation between patients supported with either VV and VA ECMO. A prospective cohort study of patients undergoing VA and VV ECMO at an Intensive care department of a university hospital and ECMO referral centre. In addition to routine coagulation testing and heparin monitoring per unit protocol, thromboelastography (TEG), multiplate aggregometry (MEA), calibrated automated thrombinography (CAT) and von-Willebrand's activity (antigen and activity ratio) were sampled second-daily for 1 week, then weekly thereafter. VA patients had significantly lower platelets counts, fibrinogen, anti-thrombin and clot strength with higher d-dimer levels than VV patients, consistent with a more pronounced consumptive coagulopathy. Thrombin generation was higher in VA than VV patients, and the heparin dose required to suppress thrombin generation was lower in VA patients. There were no significant differences in total bleeding or thrombotic event rates between VV and VA patients when adjusted for days on extracorporeal support. VA patients received a lower median daily heparin dose 8500 IU [IQR 2500-24000] versus VV 28,800 IU [IQR 17,300-40,800.00]; < 0.001. Twenty-eight patients (72%) survived to hospital discharge; comprising 53% of VA patients and 77% of VV patients. Significant differences between the coagulation profiles of VA and VV patients exist, and anticoagulation strategies for patients of these modalities should be different. Further research into the development of tailored anticoagulation strategies that include the mode of ECMO support need to be completed.

Improving GP websites - the perspective of teenagers.

Teenagers struggle to engage with healthcare providers. This article explores teenagers' perspectives of accessing healthcare needs and provides some suggestions for what practices could be doing to improve engagement with this group.

The Diverged Trypanosome MICOS Complex as a Hub for Mitochondrial Cristae Shaping and Protein Import.

The mitochondrial contact site and cristae organization system (MICOS) is a multiprotein complex responsible for cristae formation. Even though cristae are found in all mitochondria capable of oxidative phosphorylation, only Mic10 and Mic60 appear to be conserved throughout eukaryotes. The remaining 4 or 5 known MICOS subunits are specific to the supergroup Opisthokonta, which includes yeast and mammals that are the only organisms in which this complex has been analyzed experimentally. We have isolated the MICOS from Trypanosoma brucei, a member of the supergroup Excavata that is profoundly diverged from opisthokonts. We show that it is required for the maintenance of the unique discoidal cristae that typify excavates, such as euglenids and kinetoplastids, the latter of which include trypanosomes. The trypanosome MICOS consists of 9 subunits, most of which are essential for normal growth. Unlike in opisthokonts, it contains two distinct Mic10 orthologs and an unconventional putative Mic60 that lacks a mitofilin domain. Interestingly, one of the essential trypanosomatid-specific MICOS subunits called TbMic20 is a thioredoxin-like protein that appears to be involved in import of intermembrane space proteins, including respiratory chain complex assembly factors. This result points to trypanosome MICOS coordinating cristae shaping and population of its membrane with proteins involved in respiration, the latter via the catalytic activity of TbMic20. Thus, trypanosome MICOS allows us to define which of its features are conserved in all eukaryotes and decipher those that represent lineage-specific adaptations.

Not so mass effect? Finding of a remarkable 'incidentaloma' in a teenager with neurofibromatosis.

A 13-year-old boy with neurofibromatosis type 1 presented to the emergency department twice in a fortnight with moderate intermittent abdominal pain, radiating to the back and associated with nausea and vomiting. He examined as a well child with a soft abdomen and minimal tenderness. A history of constipation was identified but he failed to respond to a trial of laxatives. Subsequent ultrasound abdomen demonstrated a large mass surrounding the porta hepatis. MRI further characterised a focal, non-aggressive lesion extending from his liver, encapsulating his pancreas, portal vessels and laterally displacing his spleen and left kidney. Biopsy performed at a specialist cancer treatment hospital of our reference later confirmed this to be a benign neurofibroma of a size not previously reported in the literature. He will be managed conservatively with surveillance imaging and the potential for chemotherapy should the lesion continue to grow.

Loss of AZGP1 as a Superior Predictor of Relapse in Margin-Positive Localized Prostate Cancer.

BACKGROUND: Positive surgical margins (PSMs) in localized prostate cancer (PC) confer a two- to three-fold increased risk of biochemical relapse (BR). Absent/weak AZGP1 expression and Gleason grade ≥4 at the margin are each independent predictors of BR in patients with PSMs. Our study aimed to determine whether the biomarkers AZGP1 expression and Gleason grade at the site of a PSM are significant independent markers of biochemical and clinical relapse (CR) when modeled together and whether one of these biomarkers may be superior in its capacity to predict outcome. METHODS: A cohort of 275 consecutive patients with margin-positive localized PC following surgery were assessed for Gleason grade and AZGP1 expression at the PSM. BR-free survival was the primary end-point, while CR-free survival and PC-specific death were secondary endpoints. Kaplan-Meier Analysis and Cox Proportional Hazards Modeling were performed. RESULTS: Absent AZGP1 expression was significantly associated with increased risk of BR (P = 0.001) and PC-specific death (P = 0.02). Gleason grade ≥4 at PSM was associated with BR (P = 0.02), CR (P = 0.003), and PC-specific death (P = 0.004). On multivariable analysis, absent AZGP1 expression remained an independent predictor of BR (HR 2.4, 95%CI 1.5-3.9, P < 0.001) when modeled with Gleason grade at margin (HR 1.3, 95%CI 0.9-1.9, P = 0.16), preoperative PSA (P = 0.002), seminal vesicle involvement (P = 0.002), extraprostatic extension (P = 0.001), Gleason score (P = 0.01), adjuvant treatment (P = 0.75), linear length of the involved margin (P = 0.001) and margin number (P = 0.09). CONCLUSION: Absent AZGP1 expression is an independent predictor of BR in margin-positive localized PC and is associated with increased PC-specific mortality in a Phase II study. Absent AZGP1 expression was superior to Gleason grade at PSM in predicting relapse and should be incorporated into subsequent clinical trials of post-operative radiotherapy in men with margin-positive PC. Prostate 76:1491-1500, 2016. © 2016 Wiley Periodicals, Inc.

Development of a Rheumatology-specific Patient Concerns Inventory and Its Use in the Rheumatology Outpatient Clinic Setting.

OBJECTIVE: Successful management of rheumatic conditions involves increasing complexity of care. Delivering this in a holistic way is a growing challenge. The aim of our study was to develop a Patient Concerns Inventory (PCI) and assess it in the rheumatology clinic setting. METHODS: This observational exploratory study occurred with 2 phases. In phase I, the PCI was developed after a systematic literature search, expert opinion, and 3 patient focus group discussions. In phase II, the PCI was piloted in a general rheumatology clinic. RESULTS: Fifty-four patients were assessed in the pre-PCI group and 51 in the post-PCI group. Median (IQR) duration of consultation was 8 min (5-14) without PCI and 15 min (10-20) with PCI. The pre-PCI group raised 335 concerns from 50 patients, median (IQR) of 5 (3-10) per patient, rising post-PCI to 521 concerns, median (IQR) of 9 (5-16) from 51 patients, p = 0.002. Additional concerns predominantly arose from "physical and functional well-being" and "social care and well-being" domains. Most patients rated their experience with their doctor in the consultation as excellent or outstanding across all 11 questions in the questionnaire, both before and after the introduction of the PCI to the clinic setting. CONCLUSION: The PCI is a useful holistic needs assessment tool for rheumatology clinics. Although its use may initially prolong the consultation slightly, patients can raise a significantly higher number of concerns, which does not occur at the expense of patient satisfaction. This may help in identifying areas of unmet needs that previously went unnoticed.