Severe Sequelae Research Articles

Hemoglobin SD-Punjab with Stroke and Moyamoya Syndrome and Genotype-Phenotype Correlation: A Report of Two Siblings

Background: Hemoglobin (Hb) SD-Punjab is a rare Hb disorder which may present at any age ranging from infancy to adulthood with variable clinical severity. There are very few reports of HbSD-Punjab with stroke, leading to moyamoya syndrome. We report two siblings with HbSD-Punjab, their diagnosis, genotype–phenotype correlation, and management. Clinical Description: Two siblings, ages 6 and 4 years, presented together to the emergency for the first time with different manifestations. The elder child had fever and acute onset right-sided weakness with anemia and splenomegaly, whereas the younger sister presented with fever and decreased appetite with anemia and splenomegaly. Management and Outcome: Both siblings showed severe anemia with the second sibling showing low platelet counts also. Magnetic resonance imaging of the brain of the elder sister showed chronic infarcts in the left frontal region in addition to acute infarction in the left cerebral hemisphere with angiography suggestive of moyamoya disease. Both siblings had blood pictures suggestive of hemolytic anemia and Hb electrophoresis showed co-inheritance of HbSD-Punjab. Both siblings responded to supportive treatment and blood transfusions and were started on oral hydroxyurea. At the genotype level, a combination of factors was noted with normal α-gene copies known to increase severity and heterozygosity for Xmn1 polymorphism explaining the higher HbF levels which decrease severity. Conclusion: Knowledge of the varied clinical presentation of hemolytic disorders and early detection is key to prevent more severe sequelae in such disorders.

An integrated molecular risk score early in life for subsequent childhood asthma risk.

Numerous children present with early wheeze symptoms, yet solely a subgroup develops childhood asthma. Early identification of children at risk is key for clinical monitoring, timely patient-tailored treatment, and preventing chronic, severe sequelae. For early prediction of childhood asthma, we aimed to define an integrated risk score combining established risk factors with genome-wide molecular markers at birth, complemented by subsequent clinical symptoms/diagnoses (wheezing, atopic dermatitis, food allergy). Three longitudinal birth cohorts (PAULINA/PAULCHEN, n = 190 + 93 = 283, PASTURE, n = 1133) were used to predict childhood asthma (age 5-11) including epidemiological characteristics and molecular markers: genotype, DNA methylation and mRNA expression (RNASeq/NanoString). Apparent (ap) and optimism-corrected (oc) performance (AUC/R2) was assessed leveraging evidence from independent studies (Naïve-Bayes approach) combined with high-dimensional logistic regression models (LASSO). Asthma prediction with epidemiological characteristics at birth (maternal asthma, sex, farm environment) yielded an ocAUC = 0.65. Inclusion of molecular markers as predictors resulted in an improvement in apparent prediction performance, however, for optimism-corrected performance only a moderate increase was observed (upto ocAUC = 0.68). The greatest discriminate power was reached by adding the first symptoms/diagnosis (up to ocAUC = 0.76; increase of 0.08, p = .002). Longitudinal analysis of selected mRNA expression in PASTURE (cord blood, 1, 4.5, 6 years) showed that expression at age six had the strongest association with asthma and correlation of genes getting larger over time (r = .59, p < .001, 4.5-6 years). Applying epidemiological predictors alone showed moderate predictive abilities. Molecular markers from birth modestly improved prediction. Allergic symptoms/diagnoses enhanced the power of prediction, which is important for clinical practice and for the design of future studies with molecular markers.

Surveys on Baylisascaris procyonis in two of the three French wild raccoon populations

Human infection by Baylisascaris procyonis can result in larva migrans syndromes, which can cause severe neurological sequelae and fatal cases. The raccoon serves as the definitive host of the nematode, harboring adult worms in its intestine and excreting millions of eggs into the environment via its feces. Transmission to paratenic hosts (such as rodents, birds and rabbits) or to humans occurs by accidental ingestion of eggs. The occurrence of B. procyonis in wild raccoons has been reported in several Western European countries. In France, raccoons have currently established three separate and expanding populations as a result of at least three independent introductions. Until now the presence of B. procyonis in these French raccoon populations has not been investigated. Between 2011 and 2021, 300 raccoons were collected from both the south-western and north-eastern populations. The core parts of the south-western and north-eastern French raccoon populations were free of B. procyonis. However, three worms (molecularly confirmed) were detected in a young raccoon found at the edge of the north-eastern French raccoon population, close to the Belgian and Luxemburg borders. Population genetic structure analysis, genetic exclusion tests and factorial correspondence analysis all confirmed that the infected raccoon originated from the local genetic population, while the same three approaches showed that the worms were genetically distinct from the two nearest known populations in Germany and the Netherlands. The detection of an infected raccoon sampled east of the northeastern population raises strong questions about the routes of introduction of the roundworms. Further studies are required to test wild raccoons for the presence of B. procyonis in the area of the index case and further east towards the border with Germany.

Circulating exosome long non-coding RNAs are associated with atrial structural remodeling by increasing systemic inflammation in atrial fibrillation patients.

Atrial fibrillation (AF) is the most common cardiac arrhythmia with severe clinical sequelae, but its genetic characteristic implicated in pathogenesis has not been completely clarified. Accumulating evidence has indicated that circulating exosomes and their carried cargoes, such as long non-coding RNAs (lncRNAs), involve in the progress of multiple cardiovascular diseases. However, their potential role as clinical biomarkers in AF diagnosis and prognosis remains unknown. Herein, we conducted the sequence and bioinformatic analysis of circulating exosomes harvested from AF and sinus rhythm patients. A total of 53 differentially expressed lncRNAs were identified, and a total of 6 significantly changed lncRNAs (fold change > 2.0), including NR0046235, NR003045, NONHSAT167247.1, NONHSAT202361.1, NONHSAT205820.1 and NONHSAT200958.1, were verified by qRT-PCR in 215 participants. Moreover, these circulating exosome lncRNA levels were different between paroxysmal and persistent AF patients, which were dramatically associated with abnormal hemodynamics and atrial diameter. Furthermore, we observed that the area under ROC curve (AUC) of six lncRNAs combination for diagnosis of persistent AF was 80.34%. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment pathway analysis indicated these exosome lncRNAs mainly concerning response to chemokine-chemokine receptor interaction, which induced activated inflammation and structural remodeling. In addition, increased plasma levels of CXCR3 ligands, including CXCL4, CXCL9, CXCL10 and CXCL11, were accumulated in AF patient tissues. Our study provides the transcriptome profile revealing pattern of circulating exosome lncRNAs in atrial structural remodeling, which bring valuable insights into improving prognosis and therapeutic targets for AF.

Meta-analysis of evaluating neuron specific enolase as a serum biomarker for sepsis-associated encephalopathy

IntroductionBrain dysfunction in sepsis is known as Sepsis-associated encephalopathy (SAE), which often results in severe cognitive and neurological sequelae and increases the risk of death. Neuron specific enolase (NSE) may serve as an important neurocritical biomarker for detection and longitudinal monitoring in SAE patients. Our Meta-analysis aimed to explore the diagnostic and prognostic value of serum NSE in SAE patients. Currently, no systematic Review and Meta-analysis have been assessed that NSE as a biomarker of SAE. MethodsThe study protocol was registered in the PROSPERO database (CRD42023398736) and adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We conducted a systematic review and Meta-analysis to evaluate the serum NSE’s diagnostic accuracy for SAE and prognostic strength for probability of death of septic patients. We systematic searched electronic bibliographic databases from PubMed, MEDLINE, Web of Science, Embase, Cochrane databases, CNKI, CQVIP, and WFSD. QUADAS-2 assessment tool was used to evaluate quality and risk of bias of the selected studies. Subgroup analyses, funnel plots, sensitivity analyses were also carried out. Review Manager version 5.4 and Stata16.0. was used for statistical analysis. ResultsThis Meta-analysis included 22 studies with 1361 serum samples from SAE patients and 1580 serum samples from no-encephalopathy septic (NE) patients. The Meta-analysis showed that individuals with SAE had higher serum NSE level than NE controls (SMD 1.93 (95 % CI 1.51–2.35), P < 0.00001). In addition, there are 948 serum samples from survival septic patients and 446 serum samples from non-survival septic patients, septic patients with survival outcomes had lower serum NSE levels than those with death outcomes (SMD −1.87 (95 % CI −2.43 to −1.32), P < 0.00001). ConclusionOur Meta-analysis reveals a significant association between elevated NSE concentrations and the increased likelihood of concomitant SAE and mortality during septic patients. This comprehensive analysis will equip ICU physicians with up-to-date insights to accurately identify patients at risk of SAE and implement appropriate intervention strategies to mitigate morbidity and improve neurological outcomes. However, it is important to note that the presence of substantial heterogeneity among studies poses challenges in determining the most effective discrimination cutoff values and optimal sampling collection time.

Congenital Toxoplasmosis and Long-term Outcomes.

Congenital toxoplasmosis (CT) can have severe early and late sequelae in children. In this study, we aimed to evaluate the demographic, clinical, treatment characteristics of patients diagnosed with congenital Toxoplasma infection and to highlight the long-term complications of the patients. Patients with CT were included in this study who were followed between 2010 and 2022 in Cukurova University Medical Faculty Hospital. Demographic, clinical and treatment characteristics were searched retrospectively. In the diagnosis of maternal and CT, Toxoplasma IgM, IgG, IgG avidity, T. gondii polymerase chain reaction tests were used along with clinical and symptoms. Eighteen children (two twins) with CT and their mothers (n=16) were included in the study. Median age was 1 month. Ten (55.5%) of the children were male. CT diagnosis was made during pregnancy in 7 mothers (resulting in 8 babies) and postnatally in 9 mothers (resulting in 10 babies). The mothers of 5 (31.1%) babies with CT received spiramycin treatment during pregnancy. Three (60%) of 5 pregnant women who received spiramycin were diagnosed in the first trimester, 4 (80%) of the babies did not have any sequale and only 1 (20%) had microphthalmia. Ocular involvement was the most common presentation of the disease occured in 10 patients (55.5%), hydrocephalus and intracranial calcification developed in five patients (27.7%). Hearing loss developed in 2 (11.1%) patients. During the follow-up period, seizures developed in 3 patients (16.6%), microcephaly in 2 patients (11.1%), and neurodevolopmental retardation in 7 patients (38.8%), two of the patients had severe mental retardation. One (5.5%) patient with hydrocephalus died at 36 months of age due to complications after ventriculoperitoneal shunt application. In our study, we observed severe sequelae in vision, hearing, and neurodevelopmental aspects in children diagnosed with CT at birth and during follow-ups. Early diagnosis and treatment of infants, along with the detection of Toxoplasma infection during pregnancy, are essential in preventing severe sequelae that may arise due to CT.

Respiratory adenovirus infections in children: a focus on Africa.

Lower respiratory tract infections (LRTIs) are an important cause of child morbidity and mortality globally, especially in children under the age of 5 years in Africa. Respiratory viruses, including human adenoviruses (HAdVs), are common causes of LRTIs in children. This review aims to shed light on the epidemiology, clinical manifestations, sequelae, and treatment options specific to adenovirus respiratory infections in African children. Recent evidence has challenged the perception that adenovirus is a negligible cause of LRTIs. Studies show HAdV emerging as the third most common viral pathogen in fatal pneumonias among under-5 children in low-income and middle-income African countries, contributing to 5.5% of all pneumonia deaths and ranking second in hospital-associated viral pneumonia deaths. Predominant HAdV serotypes associated with disease differ by country and region, and have changed over time. Risk factors for increased disease severity and long-term respiratory sequelae in previously healthy African children with HAdV LRTIs are not well established. Although respiratory viruses, including HAdV, are recognized contributors to LRTIs, the prevalence and impact of adenovirus infections have been under-recognized and understated. Available data suggests that African children, particularly those under 5 years old, are at risk of severe sequelae from respiratory HAdV infections. Long-term sequelae, including bronchiectasis and postinfectious bronchiolitis obliterans, further underscore the significant impact of HAdV infections. However, the scarcity of comprehensive data hampers our understanding of the extent of the impact of HAdV infections on child lung health in Africa. We recommend scaled-up HAdV surveillance, ensuring its consistent inclusion in population-level LRTI assessments, and expanded and equitable access to diagnostics for early recognition of African children at risk of developing chronic sequelae and death. Enhanced understanding of adenovirus epidemiology and clinical outcomes and the availability of therapeutic options are essential for informed public health strategies and clinical care.

Lower urinary tract injury in transvaginal reconstructive pelvic surgery

Objective: To explore the characteristics, prevention and treatment strategies of lower urinary tract injury in transvaginal reconstructive pelvic surgery (vRPS). Methods: A retrospective analysis was conducted on 24 patients who suffered lower urinary tract injuries occuring in vRPS from January 2005 to June 2021, among which 4 cases were referred to our hospital from other hospitals. Results: (1) In our hospital, 1 952 patients underwent vRPS for anterior and (or) middle pelvic organ prolapse during that study period, with a 1.0% (20/1 952) incidence of lower urinary tract injuries occurring in 20 cases. (2) Ureteral injuries were observed in 14 cases who underwent transvaginal high uterosacral ligament suspension (1.4%, 14/966). The symptoms were relieved after the removal of sutures. (3) Bladder injuries occurred in 6 cases in our hospital, with 4 cases (0.7%, 4/576) in anterior transvaginal mesh surgery (aTVM), one (0.4%, 1/260) in colpocleisis, and one (0.7%, 1/150) in apical suspension for fornix prolapse. An additional 4 cases of bladder injury were referred to our hospital after aTVM. Among the 8 cases of bladder injury during aTVM, 2 cases were intraoperative incidents. Cystoscopy confirmed that the superficial branch or puncture rod of anterior vaginal mesh had penetrated into the bladder. Re-puncturing and placement of the mesh were successfully performed. No abnormalities were observed during a follow-up period of 4-5 years. Postoperative bladder injuries were identified in 6 cases, characterized by mesh erosion into the bladder and formation of calculi. These injuries were confirmed between 6 months to 2 years after vRPS. The exposed mesh and calculi in the bladder were removed through laparotomy or cystoscopy, followed up for 2-12 years. One case experienced slight re-erosion of mesh to the bladder. Conclusions: Lower urinary tract injuries are difficult to avoid in vRPS, particularly in transvaginal high uterosacral ligament suspension and aTVM. However, the incidence is low. Lower urinary tract injuries during vRPS could be easily detected and managed intraoperatively because of the use of cystoscopy. As long-term postoperative complications, erosion of transvaginal mesh to lower urinary tract postoperatively could be treated correctly, seldom with severe sequelae.

Mycoplasma pneumoniae-Associated Encephalitis: Favorable Aggressive Immunosuppression in a Patient

AbstractMeningoencephalitis is the most important extrapulmonary manifestation of Mycoplasma pneumoniae infection. It is complicated by seizures in at least 40% of cases, and in half of them, status epilepticus can occur during the acute phase, often leading to severe neurological sequelae. Brain imaging ranges from normal to diffuse edema, focal changes, and abnormal signals in the white matter, basal ganglia, and hippocampi. Here, we describe a boy who presented with an acute onset of transient alteration of behavior, meningeal irritation, fever, vomiting, and leg pain. Meningoencephalitis due to M. pneumoniae infection was confirmed by focal pneumonia, positive immunological tests, and increased protein content in cerebrospinal fluid. Magnetic resonance imaging of the brain showed bilateral focal abnormalities in the temporoinsular cortex, and electroencephalographic recordings showed slow waves in the same regions. After early infusion of acyclovir on the first day, aggressive combination therapy with oral erythromycin, and intravenous methylprednisolone and immunoglobulin was promptly initiated once a complete diagnosis was obtained on the second day, and the boy recovered within a few days. Two weeks later, brain imaging findings had resolved completely. The rapid clinical and neuroradiological recovery after immunosuppressive therapy suggests an immune-mediated pathogenetic mechanism. He developed immune-mediated myositis 2 years later demonstrating the instability of his immunological status.

Bone morphogenic protein-4 availability in the cardiac microenvironment controls inflammation and fibrosis in autoimmune myocarditis

Myocarditis is an inflammatory heart disease that leads to loss of cardiomyocytes and frequently precipitates fibrotic remodeling of the myocardium, culminating in heart failure. However, the molecular mechanisms underlying immune cell control and maintenance of tissue integrity in the inflamed cardiac microenvironment remain elusive. In this study, we found that bone morphogenic protein-4 (BMP4) gradients maintain cardiac tissue homeostasis by single-cell transcriptomics analyses of inflamed murine and human myocardial tissues. Cardiac BMP pathway dysregulation was reflected by reduced BMP4 serum concentration in patients with myocarditis. Restoration of BMP signaling by antibody-mediated neutralization of the BMP inhibitors gremlin-1 and gremlin-2 ameliorated T cell-induced myocardial inflammation in mice. Moreover, progression to inflammatory cardiomyopathy was blocked through the reduction of fibrotic remodeling and preservation of cardiomyocyte integrity. These results unveil the BMP4–gremlin axis as a druggable pathway for the treatment of myocardial inflammation, limiting the severe sequelae of cardiac fibrosis and heart failure.

TGFβ1-induced hedgehog signaling suppresses the immune response of brain microvascular endothelial cells elicited by meningitic Escherichia coli

BackgroundMeningitic Escherichia coli (E. coli) is the major etiological agent of bacterial meningitis, a life-threatening infectious disease with severe neurological sequelae and high mortality. The major cause of central nervous system (CNS) damage and sequelae is the bacterial-induced inflammatory storm, where the immune response of the blood-brain barrier (BBB) is crucial.MethodsWestern blot, real-time PCR, enzyme-linked immunosorbent assay, immunofluorescence, and dual-luciferase reporter assay were used to investigate the suppressor role of transforming growth factor beta 1 (TGFβ1) in the immune response of brain microvascular endothelial cells elicited by meningitic E. coli.ResultIn this work, we showed that exogenous TGFβ1 and induced noncanonical Hedgehog (HH) signaling suppressed the endothelial immune response to meningitic E. coli infection via upregulation of intracellular miR-155. Consequently, the increased miR-155 suppressed ERK1/2 activation by negatively regulating KRAS, thereby decreasing IL-6, MIP-2, and E-selectin expression. In addition, the exogenous HH signaling agonist SAG demonstrated promising protection against meningitic E. coli-induced neuroinflammation.ConclusionOur work revealed the effect of TGFβ1 antagonism on E. coli-induced BBB immune response and suggested that activation of HH signaling may be a potential protective strategy for future bacterial meningitis therapy.BxeG5o_KFymqkvc8v8uqghVideo

Particulars of sinogenic orbital complications in children

Sinogenic orbital complications in children are relatively rare but critical conditions that require accurate diagnosis and timely appropriate treatment to prevent severe sequelae. This article concentrates on clinical, diagnostic, and therapeutic specifics of sinogenic orbital complications in children. The work is based on aliterature review (PubMed, Google Scholar) and own experience as well as data from the authors' own pediatric population. In children, sinogenic orbital complications are usually secondary due to acute bacterial sinusitis. Correct distinction between pre- and postseptal cellulitis is of utmost importance for correct diagnostic and therapeutic management in order to prevent long-term sequelae. Preseptal cellulitis can be treated conservatively. If there are signs of postseptal involvement, prompt cross sectional imaging will be required. Depending on the severity of the postseptal involvement, surgical treatment may be necessary. Recent literature debates three main issues: 1)developing models for different combinations of symptoms that reliably distinguish between pre- and postseptal cellulitis; 2)selection of appropriate cross-sectional imaging (MRI vs. CT); and 3)indications for surgery. All three issues will be discussed in detail in this article.

Clinical Picture and Risk Factors for Poor Outcome in Streptococcus pneumoniae Meningitis of Childhood on Three Continents.

Streptococcus pneumoniae meningitis (SpM) remains a major health burden worldwide, particularly in low- and middle-income countries. Identifying the patients at highest risk for mortality and disabling sequelae may reveal potentially avoidable predisposing factors and identify patients most in need of intensive care. We searched for factors that do not require laboratory facilities. This study was a secondary analysis of prospectively collected data from 5 clinical trials of childhood bacterial meningitis on 3 continents between 1984 and 2017. SpM cases were analyzed by study site and predictors for poor outcome (death or severe sequelae) were identified from the whole series, Latin America and Angola. Among a total of 1575 children (age range: 2 months to 15 years), 505 cases were due to pneumococci. Compared to other etiologies, SpM doubled the death rate (33% vs. 17%) and tripled poor outcome (15% vs. 6%). In SpM, Glasgow Coma Score <13 [odds ratio (OR): 4.73] and previous antibiotics in Angola (OR: 1.70) were independent predictors for death. Predictors for poor outcome were age <1 year (OR: 2.41) and Glasgow Coma Score <13 (OR: 6.39) in the whole series, seizures in Latin America (OR: 3.98) and previous antibiotics in Angola (OR: 1.91). Angolan children had a 17-fold increased risk for poor outcome when compared with Finnish children ( P = 0.011). Our study proved the severity of SpM when compared with other etiologies. The outcome was especially poor in Angola. Most patients at risk for poor outcome are easily identified by clinical factors on admission.

The blood routine test holds screening values for influenza A in 2023: a retrospective study.

Influenza A is the most common viral pathogen isolated from pediatric clinics during influenza seasons. Some young patients with influenza manifest rapid progression with high fever and severe sequelae, such as pneumonia and meningitis. Therefore, early diagnosis and prompt treatment are highly important. Specific diagnostic tests currently include antigen detection, antibody detection, nucleic acid test and virus isolation. Rapid antigen testing is the most commonly adopted method in the outpatient setting, but false negative results are frequently observed, which causes delayed treatment and severe outcome. Routine blood test is the most commonly used detection for the outpatients. Incorporating specific blood cell counts into rapid antigen test may overcome some technical issues and enable accurate early diagnosis. We enrolled 537 children with influenza-like symptoms like fever or respiratory symptoms from pediatric outpatients and 110 children without infectious diseases for control. Routine blood tests detected by a routine analyzer and influenza A virus antigen detection were performed in the patients. Significant blood routine parameters between groups were examined by statistical tests. Parameters in routine blood test were assessed by the receiver operating characteristic curve to find the screening indicators of influenza A. Multivariate logistic regression were used to establish the optimal combinations of blood routine parameters in our screening model. Two subgroups were set according to age: ≤6 years old group and >6 years old group. In each group, patients were further divided into three subgroups: the influenza A-positive-result group (A+ group) (n=259), influenza A-negative-result group (A- group) (n=277) and healthy control group (H group) (n=110). Most routine blood parameters showed significant differences among the three subgroups in each age group. Notably, lymphocyte (LYM) number, platelet (PLT) number, lymphocyte-to-monocyte ratio (LMR) and LYM multiplied by PLT (LYM*PLT) exhibited extremely significant differences. Using A- group as a reference based on the area under the curve (AUC), both age groups had a similar trend. For A- group, the optimal cutoff value of LYM*PLT was 221.6, the AUC, the sensitivity and specificity were 0.6830, 55.71% and 76.92% in the ≤6 years old group. Meanwhile, the cutoff value of LYM*PLT was 196.7, and the AUC, the sensitivity and specificity were 0.6448, 53.97% and 70.81%, respectively in the >6 years old group. Screening model based on multivariate logistic regression model revealed that LYM*PLT was the optimal parameter combinations in ≤6 years old group (AUC =0.7202), while LYM and PLT were the optimal parameter combinations in >6 years old group (AUC =0.6760). Several blood routine parameters in children with influenza A demonstrate differential levels in both age subgroups. The LYM*PLT exhibits the potential screening value of influenza infection.

Early detection of active Human CytomegaloVirus (hCMV) infection in pregnant women using data generated for noninvasive fetal aneuploidy testing

Prenatal hCMV infections can lead to severe embryopathy and neurological sequelae in neonates. Screening during pregnancy is not recommended by global societies, as there is no effective therapy. Recently, several groups showed that maternal-fetal hCMV transmission can be strongly reduced by administering anti-viral agents early in pregnancy. This calls for a screening method to identify at risk pregnancies at an appropriate gestational age, with the possibility for large-scale enrolment. Non-Invasive Prenatal Testing (NIPT) for fetal aneuploidy screening early in pregnancy is already implemented in many countries and performed on a large-scale basis. We investigated the use of whole genome cell-free DNA (cfDNA) sequencing data, generated for the purpose of NIPT, as (pre-)screening tool to identify women with active hCMV-infections, eligible for therapy. Coded raw sequencing NIPT data from 204,818 pregnant women from three testing laboratories were analyzed for the presence of hCMV-cfDNA. Samples were stratified by cfDNA-hCMV load. For validation and interpretation, diagnostic hCMV-qPCR and serology testing were performed on a subset of cfDNA-hCMV-positive (n=112) and -negative (n=127) samples. In 1930 samples (0.94%) hCMV fragments were detected. Validation by hCMV-qPCR showed that samples with high cfDNA-hCMV load tested positive and cfDNA-hCMV-negative samples tested negative. In 32/112 cfDNA-hCMV-positive samples (28.6%) the serological profile suggested a recent primary infection: this was more likely in samples with high cfDNA-hCMV load (78.6%) than in samples with low cfDNA-hCMV load (11.0%). In none of the cfDNA-hCMV-negative samples serology was indicative of a recent primary infection. Our study shows that large-scale (pre-)screening for both genetic fetal aberrations and active maternal hCMV infections during pregnancy can be combined in one cfDNA sequencing test, performed on a single blood sample, drawn in the first trimester of pregnancy. This work was partly funded by the Prenatal Screening Foundation Nijmegen, the Netherlands.

Management of alcohol withdrawal syndrome in patients with alcohol-associated liver disease.

Alcohol-associated liver disease is a common and severe sequela of excessive alcohol use; effective treatment requires attention to both liver disease and underlying alcohol use disorder (AUD). Alcohol withdrawal syndrome (AWS) can be dangerous, is a common barrier to AUD recovery, and may complicate inpatient admissions for liver-related complications. Hepatologists can address these comorbid conditions by learning to accurately stage alcohol-associated liver disease, identify AUD using standardized screening tools (eg, Alcohol Use Disorder Identification Test), and assess risk for and symptoms of AWS. Depending on the severity, alcohol withdrawal often merits admission to a monitored setting, where symptom-triggered administration of benzodiazepines based on standardized scoring protocols is often the most effective approach to management. For patients with severe liver disease, selection of benzodiazepines with less dependence on hepatic metabolism (eg, lorazepam) is advisable. Severe alcohol withdrawal often requires a "front-loaded" approach with higher dosing, as well as intensive monitoring. Distinguishing between alcohol withdrawal delirium and HE is important, though it can be difficult, and can be guided by differentiating clinical characteristics, including time to onset and activity level. There is little data on the use of adjuvant medications, including anticonvulsants, dexmedetomidine, or propofol, in this patient population. Beyond the treatment of AWS, inpatient admission and outpatient hepatology visits offer opportunities to engage in planning for ongoing management of AUD, including initiation of medications for AUD and referral to additional recovery supports. Hepatologists trained to identify AUD, alcohol-associated liver disease, and risk for AWS can proactively address these issues, ensuring that patients' AWS is managed safely and effectively and supporting planning for long-term recovery.

Gene polymorphisms of IL-17A and bacterial meningitis in Angolan children

Interleukin (IL)-17 A plays a crucial role in protecting hosts from invading bacterial pathogens. In this study, we investigated if single nucleotide polymorphisms (SNPs) in IL-17A are associated with susceptibility and outcome of bacterial meningitis (BM) in Angolan children. The study sample comprised 241 confirmed BM patients and 265 controls, which were matched for age and ethnicity. Three IL-17A SNPs – rs2275913 (−197G > A), rs8193036 (-737C > T) and rs4711998 (−877 A > G) – were determined by high-resolution melting analysis (HRMA). The frequency of variant genotype rs4711998 was significantly higher in patients with BM caused by Haemophilus influenzae (odds ratio [OR] 3.5; 95% confidence interval [CI] 1.49–8.23; P = 0.0025) than in controls. Also, patients with BM caused by Gram-negative bacteria and who carried the variant genotype rs2275913 had a lower glucose level (P = 0.0051) in cerebrospinal fluid (CSF). Patients with BM caused by Streptococcus pneumoniae who carried the variant type rs8193036 had a reduced risk for severe neurological sequelae (OR: 0.14; 95% CI: 0.029–0.68; P = 0.0079), blindness (OR: 0.012; 95% CI: 0.012–0.87; P = 0.017) and ataxia (OR: 0.28; 95% CI: 0.091–0.83; P = 0.023). This study suggests an association of IL-17A genetic variations with susceptibility and outcome of bacterial meningitis in Angolan children.

Purpura fulminans – meningococcal infection or postsplenectomy sepsis

The article presents two clinical cases with description of peculiarities of septic infection occurred after splenectomy and due to congenital splenic hypoplasia.Decreased immune defense resulted from splenectomy leads to severe infections with a high risk of death. The most severe sequela is overwhelming postsplenectomy infection (OPSI-syndrome) which is characterized by high mortality rate (50-70%) within 12-24 hours from the onset of the first symptoms. The main risk factors of postsplenectomy sepsis are a condition which became an indication for splenectomy, the immune status of the patient, age and the time period after splenectomyStreptococcus pneumoniae, Haemophilus infuenzae type b, Neisseria meningitidis are commonly identified etiological factors of OPSI-syndrome. The diagnosis could be delayed due to nonspecific flu-like prodromal symptoms of the OPSI-syndrome. Delay in the diagnosis and treatment of sepsis may increase the risk of death.One of the syndromes associated with post-splenectomy sepsis is fulminant purpura (purpura fulminans), which requires differential diagnosis with meningococcal infection. However, half of the cases of fulminant pneumococcal purpura occur in patients with asplenia or hyposplenia. In the first clinical case, a preliminary diagnosis of generalized meningococcal infection was made on admission, but the diagnosis of pneumococcal infection could not be excluded in asplenic patient and was subsequently confirmed by laboratory tests.Given the high risk of fulminant postsplenectomy sepsis, and the difficulties of timely diagnosis, the preventive strategy of infections after splenectomy falls into three major categories- vaccination, antibiotic prophylaxis, and patient (patient’s parents) education.Improving healthcare workers’ knowledge is required to ensure prompt diagnosis of hyposplenism, adequate risk assessment of postplenectomy infection and prevention of OPSI-syndrome.

Central nervous system tumours in neonates: what should the neonatologist know?

Central nervous system (CNS) tumours in neonates are relatively rare and present differently when compared with those occurring later in childhood in terms of aetiology, clinical features, location, histology and prognosis. The clinical presentation is extremely variable. Even if the most frequent clinical sign is a macrocephaly, there are many other non-specific symptoms associated. The prognosis is usually poor with overall survival of less than 30%. Surgery continues to be the primary treatment for neonatal CNS tumours, aiming for a gross total resection, directly correlated with prognosis and the overall outcome. The chemotherapy is the only adjuvant therapy whereas the radiotherapy is avoided under three years of age because of the severe sequelae. Hence the importance of molecular characterization of these neoplasms in order to improve the accuracy of the diagnosis and identify new therapeutic targets. The aim of this review is to describe the main characteristics of these tumours and the recent advances in their treatment in order to recognize these pathologies in the prenatal period and create a multidisciplinary team providing the best possible treatment while minimising the risk of long-term complications. Neonatologists play a key role in the early detection, diagnostic evaluation, management and supportive care of these neonates. Conclusion: The aim of this review is to describe the main characteristics of these tumours and the recent advances in their treatment in order to ensure the essential knowledge that will help the neonatologist identify them and create a multidisciplinary team providing the best possible treatment while minimising the risk of long-term complications. What is Known: • Neonatal CNS tumours are relatively rare and their early identification is important to identify the best diagnostic-therapeutic management. • Surgery is the main treatment of neonatal CNS tumours. The extent of surgical resection directly correlates with prognosis and outcome. What is New: • Predisposing conditions such as Cancer Predisposition Syndromes must be considered. • Targeted drugs and other therapeutic strategies can be identified through molecular characterization.

Immunofluorescence study of cytoskeleton in endothelial cells induced with malaria sera

BackgroundEndothelial cells (ECs) play a major role in malaria pathogenesis, as a point of direct contact of parasitized red blood cells to the blood vessel wall. The study of cytoskeleton structures of ECs, whose main functions are to maintain shape and provide strength to the EC membrane is important in determining the severe sequelae of Plasmodium falciparum malaria. The work investigated the cytoskeletal changes (microfilaments-actin, microtubules-tubulin and intermediate filaments-vimentin) in ECs induced by malaria sera (Plasmodium vivax, uncomplicated P. falciparum and complicated P. falciparum), in relation to the levels of pro-inflammatory cytokines.MethodsMorphology and fluorescence intensity of EC cytoskeleton stimulated with malaria sera were evaluated using immunofluorescence technique. Levels of tumour necrosis factor (TNF) and interferon (IFN)-gamma (γ) were determined using enzyme-linked immunosorbent assay (ELISA). Control experimental groups included ECs incubated with media alone and non-malaria patient sera. Experimental groups consisted of ECs incubated with malaria sera from P. vivax, uncomplicated P. falciparum and complicated P. falciparum. Morphological scores of cytoskeletal alterations and fluorescence intensity were compared across each experiment group, and correlated with TNF and IFN-γ.ResultsThe four morphological changes of cytoskeleton included (1) shrinkage of cytoskeleton and ECs with cortical condensation, (2) appearance of eccentric nuclei, (3) presence of “spiking pattern” of cytoskeleton and EC membrane, and (4) fragmentation and discontinuity of cytoskeleton and ECs. Significant damages were noted in actin filaments compared to tubulin and vimentin filaments in ECs stimulated with sera from complicated P. falciparum malaria. Morphological damages to cytoskeleton was positively correlated with fluorescence intensity and the levels of TNF and IFN-γ.ConclusionsECs stimulated with sera from complicated P. falciparum malaria showed cytoskeletal alterations and increased in fluorescence intensity, which was associated with high levels of TNF and IFN-γ. Cytoskeletal changes of ECs incubated with complicated P. falciparum malaria sera can lead to EC junctional alteration and permeability changes, which is mediated through apoptotic pathway. The findings can serve as a basis to explore measures to strengthen EC cytoskeleton and alleviate severe malaria complications such as pulmonary oedema and cerebral malaria. In addition, immunofluorescence intensity of cytoskeleton could be investigated as potential prognostic indicator for malaria severity.