Estimating global and regional morbidity from acute bacterial meningitis in children: assessment of the evidence

Aim

To estimate global morbidity from acute bacterial meningitis in children.

Methods

We conducted a systematic review of the PubMed and Scopus databases to identify both community-based and hospital registry-based studies that could be useful in estimation of the global morbidity from bacterial meningitis in children. We were primarily interested in the availability and quality of the information on incidence rates and case-fatality rates. We assessed the impact of the year of study, study design, study setting, the duration of study, and sample size on reported incidence values, and also any association between incidence and case-fatality rate. We also categorized the studies by 6 World Health Organization regions and analyzed the plausibility of estimates derived from the current evidence using median and inter-quartile range of the available reports in each region.

Results

We found 71 studies that met the inclusion criteria. The only two significant associations between the reported incidence and studied covariates were the negative correlation between the incidence and sample size (P < 0.001) and positive correlation between incidence and case-fatality rate (P < 0.001). The median incidence per 100 000 child-years was highest in the African region – 143.6 (interquartile range [IQR] 115.6-174.6), followed by Western Pacific region with 42.9 (12.4-83.4), the Eastern Mediterranean region with 34.3 (9.9-42.0), South East Asia with 26.8 (21.0-60.3), Europe with 20.8 (16.2-29.7), and American region with 16.6 (10.3-33.7). The median case-fatality rate was also highest in the African region (31.3%). Globally, the median incidence for all 71 studies was 34.0 (16.0-88.0) per 100 000 child-years, with a median case-fatality rate of 14.4% (5.3%-26.2%).

Conclusions

Our study showed that there was now sufficient evidence to generate improved and internally consistent estimates of the global burden of acute bacterial meningitis in children. Although some of our region-specific estimates are very uncertain due to scarcity of data from the corresponding regions, the estimates of morbidity and case-fatality from childhood bacterial meningitis derived from this study are consistent with mortality estimates derived from multi-cause mortality studies. Both lines of evidence imply that bacterial meningitis is a cause of 2% of all child deaths.Meningitis is an infectious disease affecting the brain membrane and spinal cord (1). Globally, bacterial meningitis is the most severe type of meningitis, mainly caused by a triad of species Neisseria meningitidis, Streptocccus pneumonia, and Haemophilus influenzae (2). While viral meningitis is usually a self-limiting disease with good prognosis, bacterial meningitis is potentially fatal, requiring urgent medical assistance and management with antibiotics treatment (3). Various estimates of the burden of bacterial meningitis have been proposed to date, but they have mainly focused on mortality (4), long-term sequels (5), or etiology-specific morbidity and mortality (6-8).Interestingly, there have been no comprehensive attempts to estimate the overall global burden of bacterial meningitis in children. This is not surprising, because such attempt would face almost insurmountable methodological challenges. First, there is a problem with case definition of “bacterial meningitis” (9). In low resource settings, where the problem is most common, many children may present with “purulent meningitis,” whose cause is highly likely bacterial, but laboratory capacity may not be sufficient to isolate the causal agent and confirm the diagnosis. This leads to a discrepancy between morbidity burden estimates based on “all purulent meningitis” and “laboratory confirmed meningitis” – the latter always being lower than the former, but to a different extent in different contexts (10). The second large methodological obstacle is the problem of “meningitis belt.” The meningitis belt is the band of countries extending from Senegal to Ethiopia, characterized by semi-arid climate, dry seasons, and dusty winds, with seasonal outbreaks of meningococcal meningitis being recorded since the beginning of the 20th century (11). The problem with these epidemics is that they can last for several years and dramatically change the importance of meningococcus in comparison to the other two bacterial agents (S. pneumoniae and H. influenzae) both regionally and globally (11). This makes it difficult to express the “burden of disease” for any given year, because it will be very different in intra-epidemic and inter-epidemic years. Moreover, the extent of vaccine coverage against N. meningitidis, S. pneumoniae and H. influenzae is changing the burden rapidly and rather dramatically in many places, rendering the scarce evidence from before the period of vaccination rather useless and indicates a need of revision (12). Finally, the emergence of HIV/AIDS pandemic led to a substantial number of infected children, whose resistance to other infections is impaired and they present a specific category of population in which the rates of incidence and case-fatality rates may be very different from those in other children (13).It is apparent that meningitis continues to contribute significantly to global mortality and morbidity, but the impact of the efforts to control it is difficult to estimate given that we do not have comprehensive estimates of global morbidity patterns. Understanding the global morbidity from bacterial meningitis would be useful because it would also help to validate the existing mortality estimates through application of appropriate case-fatality rates. The purpose of the present study is to provide a comprehensive assessment of the evidence that is available for estimating the global morbidity from acute bacterial meningitis in children globally. We will also propose initial, robust estimates of the burden, with suggestions on the possible ways to address the methodological challenges in future studies.     

Sex determination in skeletal remains from the medieval Eastern Adriatic coast – discriminant function analysis of humeri

Aim

To investigate the usefulness of humerus measurement for sex determination in a sample of medieval skeletons from the Eastern Adriatic Coast. Additional aim was to compare the results with contemporary female population.

Methods

Five humerus measurements (maximum length, epicondylar width, maximum vertical diameter of the head, maximum and minimum diameter of the humerus at midshaft) for 80 male and 35 female medieval and 19 female contemporary humeri were recorded. Only sufficiently preserved skeletons and those with no obvious pathological or traumatic changes that could affect the measurements were included. For ten samples, analysis of DNA was performed in order to determine sex using amelogenin.

Results

The initial comparison of men and women indicated significant differences in all five measures (P < 0.001). Discriminant function for sex determination indicated that as much as 85% of cases could be properly categorized, with better results in men (86%) than women (80%). Furthermore, the comparison of the medieval and contemporary women did not show significant difference in any of the measured features. Sex results obtained by anthropological and DNA analysis matched in all 10 cases.

Conclusion

The results indicate that humerus measurement in Croatian medieval population may be sufficient to determine the sex of the skeleton. Furthermore, it seems that secular changes have not substantially affected contemporary population, suggesting that the results of this study are transferable to contemporary population as well.Once the skeletal remains are uncovered, anthropologists initially aim to reconstruct the biological profile of the person, which includes sex, age, and height estimation. During the reconstruction process, numerous issues may arise, including bone fragmentation and poor preservation of skeletal remains, coupled with the complexity of human skeleton (1,2). Sex determination is one of the first and basic steps of assessing the biological profile. Although the analysis of DNA is the most reliable method for sex determination (3), it is also the most expensive and time consuming method, which can also be hindered by local conditions. This may especially be true in cases of poor preservation of the remains, inhibitors effects, or a small amount of extracted DNA from the sample.In absence of DNA results, skeletal remains can be used to infer subject’s sex via two methods, morphological and anthropometric. The morphological approach is based on the examination of the bones that show the strongest sexual dimorphism, principally the skull and the pelvis (4). However, this method is not always reliable, especially if the skull is fragmented or incomplete. Age can also affect the results, especially in elderly women, in which morphological characteristics of the skull tend to resemble those of men (5). Although morphological methods are very important for a preliminary sex assessment, they additionally rely on the experience of the examiner and are therefore rather subjective and unreliable.The second approach is based on anthropometric analysis, which relies on the bone measurements. The main analytic approach is based on discriminant function analysis, which attempts to classify subjects into each of the sexes, by using either one or more bones (6). This kind of analysis is a very important quantitative method (7) for sex determination as it reduces the subjectivity of the examiner (2,4,8). So far, only a few such studies have been published using Croatian bone samples. These include medieval and contemporary femurs and tibias (8-11) and medieval and contemporary mandibles and teeth (6,12). Such studies are important, since clear differences were observed in different populations (13-15), making this a locally-specific feature that requires the development of regional standards, applicable for local population (16).Besides already used femurs and tibias, humerus is another long bone from the body that is presumably informative for sex determination. This idea was initially derived from the empirical investigations of the skeletal remains, and further supported by the previously reported sexual dimorphism of humeri (7,17), even in cases of severe bone fragmentation (18). Furthermore, such location-specific results may be of interest in modern forensics as well, since observed changes in the skeleton marked predominantly by the increase in height (19), appear to be proportional, with no indication of sexual dimorphism in ancient and modern samples (20). Therefore, the aim of this study was to investigate the possibility to determine the sex of the subject based on anthropometric analysis of humeri measures.     

Clinical Implications of Landing Distance on Landing Error Scoring System Scores

ContextThe Landing Error Scoring System (LESS) screens for risk of noncontact anterior cruciate ligament injury. The LESS requires individuals to jump forward from a 30-cm box to a distance of 50% of their body height. However, different landing distances have been cited in the scientific literature.ObjectiveTo examine whether landing distance influences LESS outcomes.DesignCross-sectional study.SettingLaboratory.Participants or Other ParticipantsSeventy young active individuals (34 males, 36 females).Intervention(s)Participants performed 3 × 30-cm jump-landing tasks under 2 landing conditions in randomized order: (1) 50% of body height (d_50%), (2) self-selected distance (d_ss).Main Outcome Measure(s)Mean LESS scores, proportions of individuals categorized at high (LESS: ≥ 5 errors) and low (LESS: < 5 errors) injury risk, and landing distances were compared between conditions using generalized estimating equations. Consistency of risk categorization was examined using odds ratios (ORs) and McNemar tests. McNemar and Wilcoxon signed rank tests were used to compare the occurrence of specific LESS errors.ResultsParticipants landed closer to the box under the d_ss condition (difference = −23.28 [95% CI = −20.73, −25.81]%, P < .001). Group mean LESS scores (difference = −0.01 [95% CI = −0.59, 0.57] error, P = .969) and risk categorization (OR = 0.94 [95% CI = 0.47, 1.88], P = .859) were similar between conditions. However, individual-level risk categorization was inconsistent in 33% of participants, as was the occurrence of specific errors.ConclusionsUsing d_ss during the LESS might lead to different LESS errors and risk categorizations at an individual level than using d_50%. Given that individual LESS scores are of primary interest in clinical and sport settings and the injury-risk threshold has not been validated for d_ss, we recommend use of the original LESS protocol. When only group mean LESS scores or proportions of at-risk individuals are of interest, using d_ss is feasible to facilitate the testing of large cohorts.     

Serological testing for SARS-CoV-2 in Bosnia and Herzegovina: first report

IntroductionSerological detection of SARS-CoV-2-specific immunoglobulins G (IgG) and M (IgM) antibodies is becoming increasingly important in the management of the COVID-19 pandemic.MethodsWe report the first results of COVID-19 serological testing in Bosnia and Herzegovina on 2841 samples collected and analysed in 2 medical institutions in Sarajevo. Antibody detection was performed using commercially available kits.ResultsIn the first cohort, 43 IgM-positive/IgG-negative and 16 IgM-positive/IgG-positive individuals were detected, corresponding to 3.41% of participants having developed antibodies. In the second cohort, 4.28% participants were found to be IgM-negative/IgG-positive.ConclusionsOur results suggest the need for population-wide serological surveying in Bosnia and Herzegovina.     

Combined NGS Approaches Identify Mutations in the Intraflagellar Transport Gene IFT140 in Skeletal Ciliopathies with Early Progressive Kidney Disease

Ciliopathies are genetically heterogeneous disorders characterized by variable expressivity and overlaps between different disease entities. This is exemplified by the short rib‐polydactyly syndromes, Jeune, Sensenbrenner, and Mainzer‐Saldino chondrodysplasia syndromes. These three syndromes are frequently caused by mutations in intraflagellar transport (IFT) genes affecting the primary cilia, which play a crucial role in skeletal and chondral development. Here, we identified mutations in IFT140, an IFT complex A gene, in five Jeune asphyxiating thoracic dystrophy (JATD) and two Mainzer‐Saldino syndrome (MSS) families, by screening a cohort of 66 JATD/MSS patients using whole exome sequencing and targeted resequencing of a customized ciliopathy gene panel. We also found an enrichment of rare IFT140 alleles in JATD compared with nonciliopathy diseases, implying putative modifier effects for certain alleles. IFT140 patients presented with mild chest narrowing, but all had end‐stage renal failure under 13 years of age and retinal dystrophy when examined for ocular dysfunction. This is consistent with the severe cystic phenotype of Ift140 conditional knockout mice, and the higher level of Ift140 expression in kidney and retina compared with the skeleton at E15.5 in the mouse. IFT140 is therefore a major cause of cono‐renal syndromes (JATD and MSS). The present study strengthens the rationale for IFT140 screening in skeletal ciliopathy spectrum patients that have kidney disease and/or retinal dystrophy.     

Synonymous Mutations in RNASEH2A Create Cryptic Splice Sites Impairing RNase H2 Enzyme Function in Aicardi–Goutières Syndrome

Aicardi–Goutières syndrome is an inflammatory disorder resulting from mutations in TREX1, RNASEH2A/2B/2C, SAMHD1, or ADAR1. Here, we provide molecular, biochemical, and cellular evidence for the pathogenicity of two synonymous variants in RNASEH2A. Firstly, the c.69G>A (p.Val23Val) mutation causes the formation of a splice donor site within exon 1, resulting in an out of frame deletion at the end of exon 1, leading to reduced RNase H2 protein levels. The second mutation, c.75C>T (p.Arg25Arg), also introduces a splice donor site within exon 1, and the internal deletion of 18 amino acids. The truncated protein still forms a heterotrimeric RNase H2 complex, but lacks catalytic activity. However, as a likely result of leaky splicing, a small amount of full‐length active protein is apparently produced in an individual homozygous for this mutation. Recognition of the disease causing status of these variants allows for diagnostic testing in relevant families.     

Treatment after inadequate immediate replantation of accidentally extracted immature mandibular premolar during primary molar extraction

During extraction of the primary mandibular right second molar in an 11‐year‐old girl, the unerupted second premolar was accidentally extracted. Clinical and radiographic examination showed that the immediately replanted immature premolar was not oriented and positioned correctly. Four hours later, treatment consisted of manual extrusion of the permanent tooth bud, rotation, and gentle repositioning into its original position. Adequate replantation was confirmed by a post‐operative radiograph. After 2 years and 4 months, clinical examination revealed normal, healthy appearance of the replanted tooth, no sensitivity to percussion, no tenderness to palpation, and a slight response to a cold pulp sensibility test. A radiograph showed completely developed root with closed apical foramen, slightly irregular root morphology and shorter root length, complete obliteration of the pulp, and no signs of periapical pathosis.     

Categorias de Aptidão Física Baseadas no VO2max em População Brasileira com Suposto Alto Nível Socioeconômico e sem Cardiopatia Estrutural

Background The most widely used data for cardiorespiratory fitness (CRF) referrals are from the Cooper Clinic, which uses calculated maximal oxygen uptake (VO₂max) values.Objective To develop CRF values from cardiopulmonary exercise testing (CPX) in a Brazilian population with high socioeconomic level and free of structural heart disease. VO₂max testing results were compared with the Cooper Clinic and FRIEND Registry data.Methods CPX data from consecutive individuals between January 1,2000, and May 31,2016 were used in this study. Inclusion criteria were: VO₂max by a pre-specified definition. We built a CRF chart according to VO₂max percentiles: very poor (≤20%), poor (20-40%), fair (40-60%), good (60-80%), excellent (80-90%), and superior (≥90%). Kappa correlation was used to analyze our data in comparison with that of the other two databases. Statistical tests with p<0.005 were considered significant.Results Final cohort included 18,186 tests: 12,552 men, 5,634 women (7–84 years). The most recurrent response was “good” (20.2%). There was a mean difference in weight, height, body mass index (BMI), and age in the CRF chart. An inverse correlation existed between VO₂max and age, weight, and BMI. Using a linear regression and these variables, a predictive equation was developed for VO₂max. Our findings differed from that of the other databases.Conclusion We developed a classification for CRF and found higher values in all classification ranges of functional capacity in contrast to the Cooper Clinic and FRIEND Registry. Our findings offer a more accurate interpretation of ACR in this large Brazilian population sample when compared to previous standards based on the estimated VO2max. (Arq Bras Cardiol. 2020; 115(3):468-477)