Symptoms of COVID-19 in children.

The aim of this study was to review the symptomatic manifestations of COVID-19 in children in the scientific literature. An integrative review of studies published between December 2019 and September 5, 2021, from the Medical Literature Analysis and Retrieval System Online, Web of Science, Scopus, Literatura Latino-Americana em Ciência de Saúde, and Base de Dados de Enfermagem databases, was carried out to answer the following research question: What symptomatic manifestations does COVID-19 cause in children?". Twenty articles were included. The main symptoms described were fever, cough, diarrhea, vomiting, sore throat, dyspnea, headache, abdominal pain, malaise, and weakness or tiredness. The findings of this review can contribute to the diagnosis and clinical decision-making of the health team by providing information that facilitates the identification of COVID-19 in the target population, favoring early identification, better care, and consequently a better prognosis.

Investigating the transmission risk of infectious disease outbreaks through the Aotearoa Co-incidence Network (ACN): a population-based study.

BACKGROUND: The emergence and re-emergence of infectious diseases presents a significant challenge to public health and broader society. This study utilises novel nationwide data to calculate the transmission risk and potential inequity of infectious disease outbreaks through use of network analysis. METHODS: Nationwide employment and education microdata (∼4.7 million individuals in Aotearoa New Zealand) were used to develop the Aotearoa Co-incidence Network (ACN). The ACN considers connections generated when individuals are employed at the same workplaces or enrolled at the same schools. Through forms of network analysis, connections between geospatial areas can be established and provide proxy measures of infectious disease transmission risk. The ACN was also overlayed with nationwide population vulnerability data based on the number of older adults (>65 years) and individuals with long-term health conditions. FINDINGS: We identify areas that have both high potential transmission risk (i.e., highly connected) and high vulnerability to infectious diseases. Community detection identified geographic boundaries that can be relevant to the application of regional restrictions for limiting infectious disease transmission. INTERPRETATION: Integrating novel network science and geospatial analytics provides a simple way to study infectious disease transmission risk and population vulnerability to outbreaks. Our replicable method has utility for researchers globally with access to such data. It can help inform equitable preparation for, and responses to infectious disease outbreaks. FUNDING: This project was funded by the Health Research Council of New Zealand (20/1442) and from the NZ Government via Ministry for Business Innovation and Employment and Department of Prime Minister and Cabinet.

Symptoms of COVID-19 in children

The aim of this study was to review the symptomatic manifestations of COVID-19 in children in the scientific literature. An integrative review of studies published between December 2019 and September 5, 2021, from the Medical Literature Analysis and Retrieval System Online, Web of Science, Scopus, Literatura Latino-Americana em Ciência de Saúde, and Base de Dados de Enfermagem databases, was carried out to answer the following research question: What symptomatic manifestations does COVID-19 cause in children?". Twenty articles were included. The main symptoms described were fever, cough, diarrhea, vomiting, sore throat, dyspnea, headache, abdominal pain, malaise, and weakness or tiredness. The findings of this review can contribute to the diagnosis and clinical decision-making of the health team by providing information that facilitates the identification of COVID-19 in the target population, favoring early identification, better care, and consequently a better prognosis.

Management of infected pancreatic necrosis in the intensive care unit: a narrative review.

BACKGROUND: Severe acute pancreatitis is marked by organ failure and (peri)pancreatic necrosis with local complications such as infected necrosis. Infection of these necrotic collections together with organ failure remain the major causes of admission to an intensive care unit (ICU) in acute pancreatitis. Appropriate treatment of infected necrosis is essential to reduce morbidity and mortality. Overall knowledge of the treatment options within a multidisciplinary team-with special attention to the appropriate use of antimicrobial therapy and invasive treatment techniques for source control-is essential in the treatment of this complex disease. OBJECTIVES: To address the current state of microbiological diagnosis, antimicrobial treatment, and source control for infected pancreatic necrosis in the ICU. SOURCES: A literature search was performed using the Medline and Cochrane libraries for articles subsequent to 2003 using the keywords: infected necrosis, pancreatitis, intensive care medicine, treatment, diagnosis and antibiotic(s). CONTENT: This narrative review provides an overview of key elements of diagnosis and treatment of infected pancreatic necrosis in the ICU. IMPLICATIONS: In pancreatic necrosis it is essential to continuously (re)evaluate the indication for antimicrobial treatment and invasive source control. Invasive diagnostics (e.g. through fine-needle aspiration, FNA), preferably prior to the start of broad-spectrum antimicrobial therapy, is advocated. Antimicrobial stewardship principles apply: paying attention to altered pharmacokinetics in the critically ill, de-escalation of broad-spectrum therapy once cultures become available, and early withdrawal of antibiotics once source control has been established. This is important to prevent the development of antimicrobial resistance, especially in a group of patients who may require repeated courses of antibiotics during the prolonged course of their illness.

Antibodies against TFPI and protein C are associated with a severe thrombotic phenotype in patients with and without antiphospholipid syndrome.

BACKGROUND: Tissue factor pathway inhibitor (TFPI) antibodies, which have been reported in patients with antiphospholipid syndrome (APS), may impair TFPI activity and contribute to hypercoagulability, but their role in APS and in thrombosis remains undefined. OBJECTIVE/METHODS: We assessed the presence and avidity of TFPI IgG antibodies, associations with protein C IgG antibodies and associations with clinical disease severity, in 50 patients with thrombotic APS and 50 thrombotic control patients, on long term anticoagulation with warfarin. RESULTS: Thrombotic APS patients had a significantly higher prevalence of TFPI IgG antibodies (40%; 20/50) compared to thrombotic controls (18%; 9/50). TFPI antibodies were predominantly high avidity in APS (50%, 10/20 of positive patients) and strongly associated with a severe thrombotic phenotype (venous and arterial thromboembolism or recurrent thromboembolic episodes despite therapeutic anticoagulation) (odds ratio (OR): 12.0, 95%CI: 2.2-66.1, p = 0.004), while thrombotic control patients mainly showed low avidity antibodies (78%, 7/9 of positive patients). Coexistence of TFPI and protein C IgG antibodies, regardless of their avidity, was strongly associated with a more severe thrombotic phenotype in APS patients (OR: 20.2, 95%CI: 2.0-47.0, p < 0.0001) and also in thrombotic controls (OR: 75.0, 95%CI 1.2-195, p = 0.02). CONCLUSIONS: Coexistent TFPI and protein C IgG antibodies, irrespective of their avidity, may be a useful marker for a severe thrombotic phenotype in thrombotic patients. This suggests a possibly pathophysiological relationship between the two antibodies, predisposing to thrombosis with a possibly more general role in the development of thrombotic complications.

Release from PI: An analysis and a model.

Recall decreases across a series of subspan immediate-recall trials but rebounds if the semantic category of the words is changed, an example of release from proactive interference (RPI). The size of the rebound depends on the semantic categories used and ranges from 0% to 95%. We used a corpus of novels to create vectors representing the meaning of about 40,000 words using the BEAGLE algorithm. The distance between categories and spread within categories jointly predicted the size of the RPI. We used a holographic model for recall equipped with a lexicon of BEAGLE vectors representing the meaning of words. The model captured RPI using a hologram as an interface to bridge information from episodic and semantic memory; it is the first account of RPI to capture release at the level of individual words in categorized lists.

Should we abandon the APTT for monitoring unfractionated heparin?

INTRODUCTION: The activated partial thromboplastin time (APTT) is commonly used to monitor unfractionated heparin (UFH) but may not accurately measure the amount of heparin present. The anti-Xa assay is less susceptible to confounding factors and may be a better assay for this purpose. MATERIALS AND METHODS: The validity of the APTT for monitoring UFH was assessed by comparing with an anti-Xa assay on 3543 samples from 475 patients (infants [n=165], children 1-15years [n=60] and adults [n=250]) receiving treatment dose UFH. RESULTS: Overall concordance was poor. The highest concordance (66%; 168/254) was seen in children. Concordance (51.8%) or discordance (48.4%) was almost equal in adult patients. Among adult patients whose anti-Xa level was within 0.3-0.7IU/mL, only 38% had an APTT in the therapeutic range whilst 56% were below and 6% were above therapeutic range. Children and adult patients with anti-Xa of 0.3-0.7IU/mL but sub- therapeutic APTT had significantly higher fibrinogen levels compared to those with therapeutic or supra-therapeutic APTT. CONCLUSIONS: When the anti-Xa level was 0.3-0.7IU/mL, the majority of samples from infants demonstrated a supra-therapeutic APTT, whilst adults tended to have a sub-therapeutic APTT. This may lead to under anticoagulation in infants or over anticoagulation in adults with risk of bleeding if APTT is used to monitor UFH. These results further strengthen existing evidence of the limitation of APTT in monitoring UFH. Discordance of APTT and anti-Xa level in adults and children may be due to elevation of fibrinogen level.

Group intervention for individuals with primary progressive aphasia and their spouses: Who comes first?

Primary progressive aphasia (PPA) is a neurodegenerative dementia in which language impairment is the first and most dominant symptom. There is a considerable dearth of interventions for PPA although language rehabilitation has made headway in managing the disorder. Thus far, no comprehensive services have been proposed for PPA clients and/or their spouses. This paper describes the first structured group intervention program designated exclusively for people with PPA and their caregivers. This pilot project originates from a clinical service and presents supporting evidence for initiation of a larger study to establish an evidence-based intervention for PPA. A 10-week intervention program comprised working on language activities, learning communication strategies, counselling and education. Outcome measures administered to participants and their spouses before and after the intervention were compared showed improvements in quality of communication and coping skills in the PPA group compared to controls. Qualitative comments from all 10 participants in the active treatment group highlighted the necessity of intervention that is tailored specifically to the PPA population and addresses the needs of both individuals with PPA and their caregivers. All participants in the intervention group contributed to the study and are also co-authors of this paper.

Determinants of the Magnitude of Interaction Between Tacrolimus and Voriconazole/Posaconazole in Solid Organ Recipients.

Administration of azole antifungals to tacrolimus-treated solid organ recipients results in a major drug-drug interaction characterized by increased exposure to tacrolimus. The magnitude of this interaction is highly variable but cannot currently be predicted. We performed a retrospective analysis of 126 solid organ recipients (95 lung, 31 kidney) co-treated with tacrolimus and voriconazole (n = 100) or posaconazole (n = 26). Predictors of the change in tacrolimus dose-corrected trough concentrations (C/D) between baseline and tacrolimus-azole co-therapy were assessed using linear mixed modeling. Patients were genotyped for relevant polymorphisms in CYP3A4, CYP3A5, MDR1, CYP2C19, POR, and UGT1A4. Tacrolimus C/D increased by a factor 5.0 ± 2.7 (range 1.0-20.2) for voriconazole and 4.4 ± 2.6 (range 0.9-18.0) for posaconazole, suggesting that a 66% dose reduction is insufficient for the majority of patients. Change in C/D was blunted in CYP3A5 expressors (estimated effect: -43%, p = 0.017) and affected by hematocrit (+8% per %, p = 0.004), baseline C/D (-14% per 100% increase, p < 0.001), and age (+1%, p = 0.008). However, the final model explained only 22% of interindividual variability in C/D change. In conclusion, CYP3A5 genotype and several clinical variables were identified as modulators of the tacrolimus-azole interaction, but these did not permit accurate predictions in individual patients.

Effect of ABCB1 diplotype on tacrolimus disposition in renal recipients depends on CYP3A5 and CYP3A4 genotype.

The relevance of most genetic polymorphisms beyond CYP3A5*1 on tacrolimus disposition remains unclear. We constructed a predictive mixed model for tacrolimus dose-corrected trough concentration (C0/dose) at months 3, 12 and 24 after transplantation in a retrospective cohort of 766 predominantly Causasian adult renal recipients (n=2042 trough concentrations). All patients were genotyped for 32 single-nucleotide polymorphisms with a proven or possible relevance to tacrolimus disposition based on the previous studies. Of these, ABCB1, ABCC2, OATP1B1, COMT, FMO, PPARA and APOA5 were analyzed as (functional) diplotype groups. Predictors of C0/dose were CYP3A5*1, hematocrit, age, CYP3A4*22, use of concomitant CYP3A4 inhibitor or inducer, ALT, estimated glomerular filtration rate, tacrolimus formulation (once vs twice daily), ABCB1 diplotype and time after transplantation. The effect of ABCB1 diplotype was small but strongly accentuated in CYP3A4*22 carriers and non-existent in CYP3A5 expressors. ABCC2 diplotype had a limited effect on C0/dose that was only statistically significant in CYP3A5 non-expressors.

Rivaroxaban limits complement activation compared with warfarin in antiphospholipid syndrome patients with venous thromboembolism.

Essentials Complement activation has a pathogenic role in thrombotic antiphospholipid syndrome (APS). Coagulation proteases such as factor Xa can activate complement proteins. Complement activation markers were elevated in anticoagulated thrombotic APS patients. Complement activation decreased in APS patients switching from warfarin to rivaroxaban. SUMMARY: Background Complement activation may play a major role in the pathogenesis of thrombotic antiphospholipid syndrome (APS). Coagulation proteases such as factor Xa can activate complement proteins. Aims To establish whether rivaroxaban, a direct factor Xa inhibitor, limits complement activation compared with warfarin in APS patients with previous venous thromboembolism (VTE). Methods A total of 111 APS patients with previous VTE, on warfarin target INR 2.5, had blood samples taken at baseline and at day 42 after randomization in the RAPS (Rivaroxaban in Antiphospholipid Syndrome) trial. Fifty-six patients remained on warfarin and 55 switched to rivaroxaban. Fifty-five normal controls (NC) were also studied. Markers of complement activation (C3a, C5a, terminal complement complex [SC5b-9] and Bb fragment) were assessed. Results APS patients had significantly higher complement activation markers compared with NC at both time-points irrespective of the anticoagulant. There were no differences between the two patient groups at baseline, or patients remaining on warfarin at day 42. In 55 patients randomized to rivaroxaban, C3a, C5a and SC5b-9 were lower at day 42 (median (ng mL-1 ) [confidence interval] 64 [29-125] vs. 83 [35-147], 9 [2-15] vs. 12 [4-18] and 171 [56-245] vs. 201 [66-350], respectively) but levels of Bb fragment were unchanged. There were no correlations between rivaroxaban levels and complement activation markers. Conclusions APS patients with previous VTE on warfarin exhibit increased complement activation, which is likely to occur via the classical pathway and is decreased by rivaroxaban administration. Rivaroxaban may therefore potentially provide an additional benefit to its anticoagulant effect in this patient group by limiting complement activation.

Clinicopathologic Correlation of Lens Epithelial Metaplasia and Late Intraocular Lens Dislocation After Repair of Retinal Detachment.

IMPORTANCE: In-the-bag intraocular lens dislocation is an uncommon but serious complication of cataract surgery in patients with previous repair of retinal detachment. The causative mechanism is currently unknown. We report histologic findings from a retrospective case series from 1993 to 2010 and suggest a possible mechanism to explain this association. OBSERVATIONS: Clinical characteristics of 8 patients presenting with in-the-bag intraocular lens dislocation after repair of retinal detachment were evaluated. Explanted capsular bags from 3 of these patients were compared with pathologic changes of crystalline lenses associated with retinal detachment. Histologic examination of the explanted capsular bags revealed a paucicellular membrane that covered the concertina-like folded surface of the lens capsule. The lens capsule was devoid of epithelial cell nuclei and showed excessive thickening with the presence of spindle-shaped cells, such as fibroblasts. Collagen fibers were noted in the extracellular matrix. CONCLUSIONS AND RELEVANCE: Previous studies of crystalline lens pathologic findings associated with retinal detachment have shown changes in the epithelium with migration and subsequent metaplasia of epithelial cells, resulting in excessive thickening of the anterior capsule with a layer of fibrous tissue. In this retrospective series, similar histologic findings were seen, suggesting that zonular dehiscence and lens dislocation may result from progressive capsular contraction secondary to retinal detachment-induced lens epithelial metaplasia.

High Intrapatient Variability of Tacrolimus Concentrations Predicts Accelerated Progression of Chronic Histologic Lesions in Renal Recipients.

High intrapatient variability (IPV) of tacrolimus concentrations is increasingly recognized as a predictor of poor outcome in solid organ recipients. How it relates to evolution of histology has not been explored. We analyzed tacrolimus IPV using the coefficient of variability (CV) from months 6-12 after transplantation in a cohort of 220 renal recipients for whom paired protocol biopsies at 3 mo and 2 years were available. Recipients in the highest CV tertile had an increased risk of moderate to severe fibrosis and tubular atrophy by 2 years compared with the low-IPV tertile (odds ratio [OR] 2.47, 95% confidence interval [CI] 1.09-5.60, p = 0.031; and OR 2.40, 95% CI 1.03-5.60, p = 0.043, respectively). Other predictors were donor age, severity of chronic lesions at 3 mo, and presence of borderline or subclinical rejection at 3 mo. Chronicity score increased significantly more in the high CV tertile group than in the middle and low tertiles (mean increase 1.97 ± 2.03 vs. 1.18 ± 2.44 and 1.12 ± 1.80, respectively; p < 0.05). CV did not predict evolution of renal function, which did not deteriorate within the 2-year follow-up period. These results indicate that high IPV is related to accelerated progression of chronic histologic lesions before any evidence of renal dysfunction.

Choosing and using non-steroidal anti-inflammatory drugs in haemophilia.

The management of pain and inflammation in haemophilic arthropathy is challenging due to the lack of anti-inflammatory analgesic agents perfectly suitable for this population. Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in the management of arthritis due to their analgesic and anti-inflammatory effects. Their use in persons with haemophilia (PWH), however, is limited due to increased risk of bleeding mainly from the upper gastrointestinal (UGI) tract. Cyclooxygenase-2 (COX-2) selective NSAIDs which have comparable analgesic effect to traditional NSAIDs (tNSAIDs) but with less UGI bleeding have been considered to be a suitable option for treatment of haemophilic arthropathy. COX-2 inhibitors, however, have an increased in the risk of cardiovascular (CV) disease. Although the atherosclerotic burden in PWH is similar to that in the general population, the risk of CV-related deaths is lower. PWH have a higher risk of GI bleeding and lower risk of thrombotic disease compared to general population. Therefore, when PWH require anti-inflammatory/analgesic agents, it seems reasonable to use lowest dose of COX-2 inhibitors for the shortest period together with a proton pump inhibitor. Helicobacter pylori infection should be tested for and eradicated prior to starting NSAID treatment in PWH. Furthermore, regular blood pressure and renal function test monitoring is required during COX-2 inhibitor treatment.

A Tool to Quickly Detect Short Hamstring Syndrome in Boys who Play Soccer.

UNLABELLED: There is a lack of studies of alternative techniques differing from the straight leg raise test (SLR) and the passive knee extension test (PKE) to diagnose short hamstring syndrome (SHS). We built a predictive model with simple parameters to diagnose SHS and implemented it in a mobile app. This cross-sectional study analyzed 85 Spanish boys aged 10-16 years who played soccer in 2012. OUTCOMES: SHS (SLR<70° and/or PKE>15°), and grade II SHS (SLR<60° and/or PKE≥35°). Secondary variables: toe-touch test (TT), body mass index (BMI), age, laterality and number of years registered as part of a federation. A risk table implemented in a mobile app was built to estimate the probability of SHS and grade II SHS according to secondary variables. The area under the ROC curve (AUC) was calculated and we constructed risk groups. Scoring factors for SHS: low TT, younger age and lower BMI. AUC: 0.89 (95% CI: 0.82-0.96, p<0.001). Scoring factors for grade II SHS: younger age, higher BMI, left footed and lower TT. AUC: 0.78 (95% CI: 0.68-0.88, p<0.001). We provide a tool with minimum material but with a high discriminatory power to quickly calculate whether a boy who plays soccer has SHS. The models need validation studies.

Differences in the management of hypertension, diabetes mellitus and dyslipidemia between obesity classes.

We did not find any paper that assessed clinical inertia in obese patients. Therefore, no paper has compared the clinical inertia rates between morbidly and nonmorbidly obese patients. A cross-sectional observational study was carried out. We analysed 8687 obese patients ⩾40 years of age who attended their health-care center for a checkup as part of a preventive program. The outcome was morbid obesity. Secondary variables were as follows: failure in the management of high blood pressure (HBP), high blood cholesterol (HBC) and high fasting blood glucose (HFBG); gender; personal history of hypertension, dyslipidemia, diabetes, smoking and cardiovascular disease; and age (years). We analysed the association between failures and morbid obesity by calculating the adjusted odds ratio (OR). Of 8687 obese patients, 421 had morbid obesity (4.8%, 95% confidence interval (CI): 4.4-5.3%). The prevalence rates for failures were as follows: HBP, 34.7%; HBC, 35.2%; and HFBG, 12.4%. Associated factors with morbid obesity related with failures were as follows: failure in the management of HBP (OR=1.42, 95% CI: 1.15-1.74, P=0.001); failure in the management of HBC (OR=0.73, 95% CI: 0.58-0.91, P=0.004); and failure in the management of HFBG (OR=2.24, 95% CI: 1.66-3.03, P<0.001). Morbidly obese patients faced worse management for HBP and HFBG, and better management for HBC. It would be interesting to integrate alarm systems to avoid this problem.

Parapatric distribution and sexual competition between two tick species, Amblyomma variegatum and A. hebraeum (Acari, Ixodidae), in Mozambique.

BACKGROUND: Amblyomma variegatum and A. hebraeum are two ticks of veterinary and human health importance in south-east Africa. In Zimbabwe they occupy parapatric (marginally overlapping and juxtaposed) distributions. Understanding the mechanisms behind this parapatry is essential for predicting the spatio-temporal dynamics of Amblyomma spp. and the impacts of associated diseases. It has been hypothesized that exclusive competition between these species results from competition at the levels of male signal reception (attraction-aggregation-attachment pheromones) or sexual competition for mates. This hypothesis predicts that the parapatry described in Zimbabwe could also be present in other countries in the region. METHODS: To explore this competitive exclusion hypothesis we conducted field surveys at the two species' range limits in Mozambique to identify areas of sympatry (overlapping areas) and to study potential interactions (communicative and reproductive interference effects) in those areas. At sympatric sites, hetero-specific mating pairs were collected and inter-specific attractiveness/repellent effects acting at long and short distances were assessed by analyzing species co-occurrences on co-infested herds and co-infested hosts. RESULTS: Co-occurrences of both species at sampling sites were infrequent and localized in areas where both tick and host densities were low. At sympatric sites, high percentages of individuals of both species shared attachment sites on hosts and inter-specific mating rates were high. Although cross-mating rates were not significantly different for A. variegatum and A. hebraeum females, attraction towards hetero-specific males was greater for A. hebraeum females than for A. variegatum females and we observed small asymmetrical repellent effects between males at attachment sites. CONCLUSIONS: Our observations suggest near-symmetrical reproductive interference between A. variegatum and A. hebraeum, despite between-species differences in the strength of reproductive isolation barriers acting at the aggregation, fixation and partner contact levels. Theoretical models predict that sexual competition coupled with hybrid inviability, greatly reduces the probability of one species becoming established in an otherwise suitable location when the other species is already established. This mechanism can explain why the parapatric boundary in Mozambique has formed within an area of low tick densities and relatively infrequent host-mediated dispersal events.