Evaluation of Acute and Convalescent Antibody Concentration Against Pneumococcal Capsular Polysaccharides for the Diagnosis of Pneumococcal Infection in Children with Community-Acquired Pneumonia.

We evaluated whether the quantification of IgG to pneumococcal capsular polysaccharides is an accurate diagnostic test for pneumococcal infection in children with pneumonia in Nepal. Children with pneumococcal pneumonia did not have higher convalescent, or higher fold change, IgG to pneumococcal polysaccharides than children with other causes of pneumonia. Caution is needed in interpreting antibody responses in pneumococcal infections.

Immune responses to typhoid conjugate vaccine in a two dose schedule among Nepalese children <2 years of age.

BACKGROUND: Previously, the Vi-typhoid conjugate vaccine (Vi-TT) was found to be highly efficacious in Nepalese children under 16 years of age. We assessed the immunogenicity of Vi-TT at 9 and 12 months of age and response to a booster dose at 15 months of age. METHODS: Infants were recruited at Patan Hospital, Kathmandu and received an initial dose of Vi-TT at 9 or 12 months of age with a booster dose at 15 months of age. Blood was taken at four timepoints, and antibody titres were measured using a commercial ELISA kit. The primary study outcome was seroconversion (4-fold rise in antibody titre) of IgG one month after both the doses. FINDINGS: Fifty children were recruited to each study group.Some visits were disrupted by the COVID19 pandemic and occurred out of protocol windows.Both the study groups attained 100 % IgG seroconversion after the initial dose. IgG seroconversion in the 9-month group was significantly higher than in the 12-month group (68.42 % vs 25.8 %, p < 0.001). Among individuals who attended visits per protocol, IgG seroconversion after the first dose occurred in 100 % of individuals (n = 27/27 in 9-month and n = 32/32 in 12-month group). However, seroconversion rates after the second dose were 80 % in the 9-month and 0 % in the shorter dose-interval 12-month group (p < 0.001) (n = 16/20 and n = 0/8, respectively). INTERPRETATION: Vi-TT is highly immunogenic at both 9 and 12 months of age. Stronger response to a booster in the 9-month group is likely due to the longer interval between doses.

Optimising DTwP-containing vaccine infant immunisation schedules (OptImms) - a protocol for two parallel, open-label, randomised controlled trials.

BACKGROUND: Universal immunisation is the cornerstone of preventive medicine for children, The World Health Organisation (WHO) recommends diphtheria-tetanus-pertussis (DTP) vaccine administered at 6, 10 and 14 weeks of age as part of routine immunisation. However, globally, more than 17 unique DTP-containing vaccine schedules are in use. New vaccines for other diseases continue to be introduced into the infant immunisation schedule, resulting in an increasingly crowded schedule. The OptImms trial will assess whether antibody titres against pertussis and other antigens in childhood can be maintained whilst adjusting the current Expanded Programme on Immunisation (EPI) schedule to provide space for the introduction of new vaccines. METHODS: The OptImms studies are two randomised, five-arm, non-inferiority clinical trials in Nepal and Uganda. Infants aged 6 weeks will be randomised to one of five primary vaccination schedules based on age at first DTwP-vaccination (6 versus 8 weeks of age), number of doses in the DTwP priming series (two versus three), and spacing of priming series vaccinations (4 versus 8 weeks). Additionally, participants will be randomised to receive their DTwP booster at 9 or 12 months of age. A further sub-study will compare the co-administration of typhoid vaccine with other routine vaccines at one year of age. The primary outcome is anti-pertussis toxin IgG antibodies measured at the time of the booster dose. Secondary outcomes include antibodies against other vaccine antigens in the primary schedule and their safety. DISCUSSION: These data will provide key data to inform policy decisions on streamlining vaccination schedules in childhood. TRIAL REGISTRATIONS: ISRCTN12240140 (Nepa1, 7th January 2021) and ISRCTN6036654 (Uganda, 17th February 2021).

Assessing the implementation of COVID-19 structured reporting templates for chest radiography: a scoping review.

Objective: One of the common modalities used in imaging COVID-19 positive patients is chest radiography (CXR), and serves as a valuable imaging method to diagnose and monitor a patients' condition. Structured reporting templates are regularly used for the assessment of COVID-19 CXRs and are supported by international radiological societies. This review has investigated the use of structured templates for reporting COVID-19 CXRs. Methods: A scoping review was conducted on literature published between 2020 and 2022 using Medline, Embase, Scopus, Web of Science, and manual searches. An essential criterion for the inclusion of the articles was the use of reporting methods employing either a structured quantitative or qualitative reporting method. Thematic analyses of both reporting designs were then undertaken to evaluate utility and implementation. Results: Fifty articles were found with the quantitative reporting method used in 47 articles whilst 3 articles were found employing a qualitative design. Two quantitative reporting tools (Brixia and RALE) were used in 33 studies, with other studies using variations of these methods. Brixia and RALE both use a posteroanterior or supine CXR divided into sections, Brixia with six and RALE with four sections. Each section is scaled numerically depending on the level of infection. The qualitative templates relied on selecting the best descriptor of the presence of COVID-19 radiological appearances. Grey literature from 10 international professional radiology societies were also included in this review. The majority of the radiology societies recommend a qualitative template for reporting COVID-19 CXRs. Conclusion: Most studies employed quantitative reporting methods which contrasted with the structured qualitative reporting template advocated by most radiological societies. The reasons for this are not entirely clear. There is also a lack of research literature on both the implementation of the templates or comparing both template types, indicating that the use of structured radiology reporting types may be an underdeveloped clinical strategy and research methodology. Advances in knowledge: This scoping review is unique in that it has undertaken an examination of the utility of the quantitative and qualitative structured reporting templates for COVID-19 CXRs. Moreover, through this review, the material examined has allowed a comparison of both instruments, clearly showing the favoured style of structured reporting by clinicians. At the time of the database interrogation, there were no studies found had undertaken such examinations of both reporting instruments. Moreover, due to the enduring influence of COVID-19 on global health, this scoping review is timely in examining the most innovative structured reporting tools that could be used in the reporting of COVID-19 CXRs. This report could assist clinicians in decision-making regarding templated COVID-19 reports.

COVID-19 vaccine effectiveness and variants in Nepal: study protocol for a test-negative case-control study with SARS-CoV-2 genetic sequencing.

INTRODUCTION: Inactivated, viral vector and mRNA vaccines have been used in the Nepali COVID-19 vaccination programme but there is little evidence on the effectiveness of these vaccines in this setting. The aim of this study is to describe COVID-19 vaccine effectiveness in Nepal and provide information on infections with SARS-CoV-2 variants. METHODS AND ANALYSIS: This is a hospital-based, prospective test-negative case-control study conducted at Patan Hospital, Kathmandu. All patients >18 years of age presenting to Patan Hospital with COVID-19-like symptoms who have received a COVID-19 antigen/PCR test are eligible for inclusion. The primary outcome is vaccine effectiveness of licensed COVID-19 vaccines against laboratory-confirmed COVID-19 disease.After enrolment, information will be collected on vaccine status, date of vaccination, type of vaccine, demographics and other medical comorbidities. The primary outcome of interest is laboratory-confirmed SARS-CoV-2 infection. Cases (positive for SARS-CoV-2) and controls (negative for SARS-CoV-2) will be enrolled in a 1:4 ratio. Vaccine effectiveness against COVID-19 disease will be analysed by comparing vaccination status with SARS-CoV-2 test results.Positive SARS-CoV-2 samples will be sequenced to identify circulating variants and estimate vaccine effectiveness against common variants.Measuring vaccine effectiveness and identifying SARS-CoV-2 variants in Nepal will help to inform public health efforts. Describing disease severity in relation to specific SARS-CoV-2 variants and vaccine status will also inform future prevention and care efforts. ETHICS AND DISSEMINATION: Ethical approval was obtained from the University of Oxford Tropical Ethics Committee (OxTREC) (ref: 561-21) and the Patan Academy of Health Sciences Institutional Review Board (ref: drs2111121578). The protocol and supporting study documents were approved for use by the Nepal Health Research Council (NHRC 550-2021). Results will be disseminated in peer-reviewed journals and to the public health authorities in Nepal.

Effect of the of 10-valent pneumococcal conjugate vaccine in Nepal 4 years after introduction: an observational cohort study.

BACKGROUND: In Nepal, Streptococcus pneumoniae (pneumococcus) is a common cause of bacterial pneumonia in children, and is a major health concern. There are few data on the effect of vaccination on the disease or colonisation with pneumococci in the nasopharynx of children in this setting. The 10-valent pneumococcal conjugate vaccine (PCV10) was introduced into the routine infant immunisation schedule in Nepal in 2015. We aimed to investigate the effect of the introduction of PCV10 on pneumococcal carriage and disease in children in Nepal. METHODS: We did an observational cohort study in children in Nepal. The hospital surveillance study took place in Patan Hospital, Kathmandu, and community studies in healthy children took place in Kathmandu and Okhaldhunga district. For the surveillance study, all children admitted to Patan Hospital between March 20, 2014, and Dec 31, 2019, aged between 2 months and 14 years with clinician-suspected pneumonia, were eligible for enrolment. For the community study, healthy children aged 0-8 weeks, 6-23 months, and 24-59 months were recruited from Kathmandu, and healthy children aged 6-23 months were recruited from Okhaldhunga. We assessed the programmatic effect of PCV10 introduction using surveillance for nasopharyngeal colonisation, pneumonia, and invasive bacterial disease from 1·5 years before vaccine introduction and 4·5 years after vaccine introduction. For the surveillance study, nasopharyngeal swabs, blood cultures, and chest radiographs were obtained from children admitted to Patan Hospital with suspected pneumonia or invasive bacterial disease. For the community study, nasopharyngeal swabs were obtained from healthy children in the urban and rural settings. Pneumonia outcomes were analysed using log-binomial models and adjusted prevalence ratios (aPR) comparing each calendar year after the introduction of the vaccine into the national programme with the pre-vaccine period (2014-15), adjusted for calendar month, age, and sex. FINDINGS: Between March 20, 2014, and Dec 31, 2019, we enrolled 2051 children with suspected pneumonia, and 11 354 healthy children (8483 children aged 6-23 months, 761 aged 24-59 months, and 2110 aged 0-8 weeks) to assess nasopharyngeal colonisation. Among clinical pneumonia cases younger than 2 years, vaccine serotype carriage declined 82% (aPR 0·18 [95% CI 0·07-0·50]) by 2019. There was no decrease in vaccine serotype carriage in cases among older unvaccinated age groups. Carriage of the additional serotypes in PCV13 was 2·2 times higher by 2019 (aPR 2·17 [95% CI 1·16-4·05]), due to increases in serotypes 19A and 3. Vaccine serotype carriage in healthy children declined by 75% in those aged 6-23 months (aPR 0·25 [95% CI 0·19-0·33]) but not in those aged 24-59 months (aPR 0·59 [0·29-1·19]). A decrease in overall vaccine serotype carriage of 61% by 2019 (aPR 0·39 [95% CI 0·18-0·85]) was also observed in children younger than 8 weeks who were not yet immunised. Carriage of the additional PCV13 serotypes in children aged 6-23 months increased after PCV10 introduction for serotype 3 and 19A, but not for serotype 6A. The proportion of clinical pneumonia cases with endpoint consolidation on chest radiographs declined from 41% in the pre-vaccine period to 25% by 2018, but rose again in 2019 to 36%. INTERPRETATION: The introduction of the PCV10 vaccine into the routine immunisation programme in Nepal has reduced vaccine serotype carriage in both healthy children and children younger than 2 years with pneumonia. Increases in serotypes 19A and 3 highlight the importance of continued surveillance to monitor the effect of vaccine programmes. This analysis demonstrates a robust approach to assessing vaccine effect in situations in which pneumococcal disease endpoint effectiveness studies are not possible. FUNDING: Gavi, the Vaccine Alliance and the World Health Organization.

COVID-19 and its enduring influence on medical imaging.

Our article comments on the enduring impact of COVID-19 in medical imaging. The emotional impact on COVID-19 is well reported in articles published at JMRS. This editorial covers the qualitative and quantitative structured templates now used for the reporting of chest x-rays on COVID-19.

Efficacy of typhoid conjugate vaccine in Nepal: final results of a phase 3, randomised, controlled trial.

BACKGROUND: Typhoid fever is a major public health problem in low-resource settings. Vaccination can help curb the disease and might reduce transmission. We have previously reported an interim analysis of the efficacy of typhoid conjugate vaccine (TCV) in Nepali children. Here we report the final results after 2 years of follow-up. METHODS: We did a participant-masked and observer-masked individually randomised trial in Lalitpur, Nepal, in which 20 019 children aged 9 months to younger than 16 years were randomly assigned in a 1:1 ratio to receive a single dose of TCV (Typbar TCV, Bharat Biotech International, India) or capsular group A meningococcal conjugate vaccine (MenA). Participants were followed up until April 9, 2020. The primary outcome was blood culture-confirmed typhoid fever. Cases were captured via passive surveillance and active telephone surveillance followed by medical record review. The trial is registered at ISRCTN registry, ISRCTN43385161 and is ongoing. FINDINGS: From Nov 20, 2017, to April 9, 2018, of 20 119 children screened, 20 019 participants were randomly assigned to receive TCV or MenA vaccine. There were 75 cases of blood culture-confirmed typhoid fever included in the analysis (13 in the TCV group and 62 in the MenA group) over the 2-year period. The protective efficacy of TCV against blood culture-confirmed typhoid fever at 2 years was 79·0% (95% CI 61·9-88·5; p<0·0001). The incidence of typhoid fever was 72 (95% CI 38-123) cases per 100 000 person-years in the TCV group and 342 (95% CI 262-438) cases per 100 000 person-years in the MenA group. Adverse events occurring within the first 7 days post-vaccination were reported previously. INTERPRETATION: The final results of this randomised, controlled trial are in keeping with the results of our published interim analysis. There is no evidence of waning protection over a 2-year period. These findings add further support for the WHO recommendations on control of enteric fever. FUNDING: Bill & Melinda Gates Foundation.

Protection by vaccination of children against typhoid fever with a Vi-tetanus toxoid conjugate vaccine in urban Bangladesh: a cluster-randomised trial.

BACKGROUND: Typhoid fever remains a major cause of morbidity and mortality in low-income and middle-income countries. Vi-tetanus toxoid conjugate vaccine (Vi-TT) is recommended by WHO for implementation in high-burden countries, but there is little evidence about its ability to protect against clinical typhoid in such settings. METHODS: We did a participant-masked and observer-masked cluster-randomised trial preceded by a safety pilot phase in an urban endemic setting in Dhaka, Bangladesh. 150 clusters, each with approximately 1350 residents, were randomly assigned (1:1) to either Vi-TT or SA 14-14-2 Japanese encephalitis (JE) vaccine. Children aged 9 months to less than 16 years were invited via parent or guardian to receive a single, parenteral dose of vaccine according to their cluster of residence. The study population was followed for an average of 17·1 months. Total and overall protection by Vi-TT against blood culture-confirmed typhoid were the primary endpoints assessed in the intention-to-treat population of vaccinees or all residents in the clusters. A subset of approximately 4800 participants was assessed with active surveillance for adverse events. The trial is registered at www.isrctn.com, ISRCTN11643110. FINDINGS: 41 344 children were vaccinated in April-May, 2018, with another 20 412 children vaccinated at catch-up vaccination campaigns between September and December, 2018, and April and May, 2019. The incidence of typhoid fever (cases per 100 000 person-years) was 635 in JE vaccinees and 96 in Vi-TT vaccinees (total Vi-TT protection 85%; 97·5% CI 76 to 91, p<0·0001). Total vaccine protection was consistent in different age groups, including children vaccinated at ages under 2 years (81%; 95% CI 39 to 94, p=0·0052). The incidence was 213 among all residents in the JE clusters and 93 in the Vi-TT clusters (overall Vi-TT protection 57%; 97·5% CI 43 to 68, p<0·0001). We did not observe significant indirect vaccine protection by Vi-TT (19%; 95% CI -12 to 41, p=0·20). The vaccines were well tolerated, and no serious adverse events judged to be vaccine-related were observed. INTERPRETATION: Vi-TT provided protection against typhoid fever to children vaccinated between 9 months and less than 16 years. Longer-term follow-up will be needed to assess the duration of protection and the need for booster doses. FUNDING: The study was funded by the Bill & Melinda Gates Foundation.

Persistence of Immunity Following 2-Dose Priming with a 10-Valent Pneumococcal Conjugate Vaccine at 6 and 10 Weeks or 6 and 14 Weeks of Age in Nepalese Toddlers.

BACKGROUND: The pneumococcal conjugate vaccine has had a substantial impact on invasive pneumococcal disease. Previously, we compared immunity following vaccination with the 10-valent pneumococcal conjugate vaccine (PCV10) administered at 2 slightly different schedules: at 6 and 10 weeks of age, and at 6 and 14 weeks of age, both followed by a 9-month booster. In this study, we followed up those participants to evaluate the medium-term persistence of serotype-specific pneumococcal immunity at 2-3 years of age. METHOD: Children from the previous studies were contacted and after taking informed consent from their parents, blood samples and nasopharyngeal swabs were collected. Serotype-specific IgG antibody concentrations were determined by enzyme-linked immunosorbent assay, for the 10 vaccine serotypes, at a WHO pneumococcal serology reference laboratory. FINDINGS: Two hundred twenty of the 287 children who completed the primary study returned at 2-3 years of age to provide a blood sample and nasopharyngeal swab. The nasopharyngeal carriage rate of PCV10 serotypes in the 6 + 14 group was higher than the 6 + 10 group (13.4% vs. 1.9%). Nevertheless, the proportion of toddlers with serum pneumococcal serotype-specific IgG greater than or equal to 0.35 µg/mL was comparable for all PCV10 serotypes between the 6 + 10 week and 6 + 14 week groups. Similarly, the geometric mean concentrations of serum pneumococcal serotype-specific IgG levels were similar in the 2 groups for all serotypes, except for serotype 19F which was 32% lower in the 6 + 10 group than the 6 + 14 group. CONCLUSION: Immunization with PCV10 at 6 + 10 weeks or 6 + 14 weeks, with a booster at 9 months in each case, results in similar persistence of serotype-specific antibody at 2-3 years of age. Thus, protection from pneumococcal disease is expected to be similar when either schedule is used.

Progress in the overall understanding of typhoid fever: implications for vaccine development.

INTRODUCTION: Typhoid fever continues to have a substantial impact on human health, especially in Asia and sub-Saharan Africa. Access to safe water, and adequate sanitation and hygiene remain the cornerstone of prevention, but these are not widely available in many impoverished settings. The emergence of antibiotic resistance affects typhoid treatment and adds urgency to typhoid control efforts. Vaccines provide opportunities to prevent and control typhoid fever in endemic settings. AREAS COVERED: Literature search was performed looking for evidence concerning the global burden of typhoid and strategies for the prevention and treatment of typhoid fever. Cost of illness, available typhoid and paratyphoid vaccines and cost-effectiveness were also reviewed. The objective was to provide a critical overview of typhoid fever, in order to assess the current understanding and potential future directions for typhoid treatment and control. EXPERT COMMENTARY: Our understanding of typhoid burden and methods of prevention has grown over recent years. However, typhoid fever still has a significant impact on health in low and middle-income countries. Introduction of typhoid conjugate vaccines to the immunization schedule is expected to make a major contribution to control of typhoid fever in endemic countries, although vaccination alone is unlikely to eliminate the disease.

Do preterm bones still break? Incidence of rib fracture and osteopenia of prematurity in very low birth weight infants.

AIM: Extremely premature babies are at risk of osteopenia of prematurity (OOP) as bone mineralisation in utero increases exponentially after 24 weeks gestation. Our aim was to assess the bone health of very low birth weight (VLBW) infants. We wanted to establish the incidences of OOP and rib fracture. We also looked at which biochemical markers best predicted OOP. Bone health in this vulnerable population is an important aspect of management which should not be overlooked. METHODS: This was an observational study which included all VLBW infants, born in a national maternity hospital, over a 5-year period. All X-rays performed on these infants were reviewed. Data were also collected on biochemical markers associated with bone health. The medical records of infants with rib fractures were reviewed looking for causes of bone fragility. RESULTS: Of the 609 VLBW infants included in the study, only two cases of definitive rib fractures were found. This represents a rib fracture incidence of 3 per 1000. Thirty-nine percent of VLBW babies showed radiological evidence suggestive of OOP. CONCLUSION: Our findings show a lower rate of rib fracture in preterm infants compared to previous evidence. We also showed that these fractures were not evident on the final X-ray prior to discharge. This implies that when an ex-preterm infant presents to the emergency department with a rib fracture there should be an even higher suspicion for non-accidental injury than previously thought.

Psychological morbidity among forcibly displaced children-a literature review.

In 2018, nearly 75 million people were displaced from their place of origin of which 20.4 million are considered as refugees. Children constitute over half of this population. A review of the currently available literature regarding the psychological impact of forced displacement on children was performed with the concept examined under three stages of flight: pre-migration, intra-migration and post-migration. The resilience of children despite adversities is explored. Post-traumatic stress disorder (PTSD), depression and anxiety are the most commonly studied effects of forced migration on children. Rates range from 20 to 52.7%, 23 to 44.1% and 38.3 to 69% respectively. PTSD is associated with pre-migration disturbances such as witnessing death or torture of relatives, assaults and separation from family. Intra-migration difficulties relate to the hazardous journey, length of detention, type of facility and failed asylum application. Post-migration difficulties highlighted are insecure asylum status, housing worries, multiple relocations and poor acculturation technique and are more related to depression and anxiety. Despite these challenges and the tremendous horror witnessed, the majority of children report good functionality in their host countries in the long-term. The purpose of this report is to provide an overview of the factors contributing to the manifestation of mental health issues in child refugees as well as to examine mechanisms which enhance successful resettling in the host society. Health and social care providers must understand the complex interplay between the damaging effects of displacement, and the innate protective factors that persecuted children possess. Management should involve a holistic approach that considers children, families and native communities.

Profiling emergency department presentations of 14-15-year-olds in modern Ireland.

BACKGROUND: Mid-adolescence, that twilight era when the human child transitions to adulthood, is an often overlooked developmental age yet harbours a subpopulation of patients with their own myriad of medical problems somewhat unique to their age group. AIMS: Our study is aimed at reviewing the typical presentations to a paediatric emergency department of modern Irish teenagers in mid-adolescence, the profile of which has changed significantly over the past 10 years. METHODS: Hospital electronic databases were used to conduct a retrospective review of the paediatric emergency department presentations of patients aged 14-15 years during the year of 2017. We collated data on the presenting complaint, background history, admission rate and medical specialities involved in each patient's care while in our Emergency Department. RESULTS: A total of 1485 presentations were made, with 1363 being eligible for inclusion in this study. The results highlight the varied and challenging presentations (Table 1) and the high number of specialities required within emergency medicine to care for this unique population (Table 2). CONCLUSION: The results highlight the most common presentations of this subgroup of patients, with trauma, in keeping with recent international data, being the most common presentation. The noted high frequency in the number of mental health/intoxication/self-harm presentations among the Irish teenagers in our region is consistent with trends reported in world literature and serves to emphasise one of the main challenges facing those working in paediatrics in Ireland over the next 10 years.

Clinical, biochemical, and genetic features of four patients with short-chain enoyl-CoA hydratase (ECHS1) deficiency.

Short-chain enoyl-CoA hydratase (SCEH or ECHS1) deficiency is a rare inborn error of metabolism caused by biallelic mutations in the gene ECHS1 (OMIM 602292). Clinical presentation includes infantile-onset severe developmental delay, regression, seizures, elevated lactate, and brain MRI abnormalities consistent with Leigh syndrome (LS). Characteristic abnormal biochemical findings are secondary to dysfunction of valine metabolism. We describe four patients from two consanguineous families (one Pakistani and one Irish Traveler), who presented in infancy with LS. Urine organic acid analysis by GC/MS showed increased levels of erythro-2,3-dihydroxy-2-methylbutyrate and 3-methylglutaconate (3-MGC). Increased urine excretion of methacrylyl-CoA and acryloyl-CoA related metabolites analyzed by LC-MS/MS, were suggestive of SCEH deficiency; this was confirmed in patient fibroblasts. Both families were shown to harbor homozygous pathogenic variants in the ECHS1 gene; a c.476A > G (p.Gln159Arg) ECHS1variant in the Pakistani family and a c.538A > G, p.(Thr180Ala) ECHS1 variant in the Irish Traveler family. The c.538A > G, p.(Thr180Ala) ECHS1 variant was postulated to represent a Canadian founder mutation, but we present SNP genotyping data to support Irish ancestry of this variant with a haplotype common to the previously reported Canadian patients and our Irish Traveler family. The presence of detectable erythro-2,3-dihydroxy-2-methylbutyrate is a nonspecific marker on urine organic acid analysis but this finding, together with increased excretion of 3-MGC, elevated plasma lactate, and normal acylcarnitine profile in patients with a Leigh-like presentation should prompt consideration of a diagnosis of SCEH deficiency and genetic analysis of ECHS1. ECHS1 deficiency can be added to the list of conditions with 3-MGA.

The fracture toughness of eggshell.

UNLABELLED: The shells of avian eggs are very brittle, but how brittle? Fracture toughness, Kc is a standard measure used widely to characterise engineering materials. We devised a novel way to measure Kc and applied it to commercial hens' eggs, obtaining a value of 0.3MPa√m. This value is much lower than previous published values, which we argue are incorrect and misleading. We discuss how this exceptionally low toughness value (in comparison to that of other natural materials made from calcium carbonate) has been achieved by prevention of toughening mechanisms. Eggshell has an unusual combination of mechanical properties (low fracture toughness combined with high Young's modulus), making it ideally suited as a container for the developing chick, which must be stiff and rigid but also brittle enough to be broken when required. Further testing and analysis using the Theory of Critical Distances and Weibull probability theory allowed us to describe the effects of defects of various types: cracks, holes and notches, on the strength of whole eggs. These results are of commercial importance because many eggs break prematurely as a result of microscopic defects. STATEMENT OF SIGNIFICANCE: This paper presents the first accurate measurements of the fracture toughness of eggshell. These results are important because eggshell is a brittle material which fails from microscopic defects, so knowledge of the fracture toughness is essential to understand its mechanical performance. The toughness value obtained is discussed in the context of other mechanical properties, of eggshell and other natural materials. This is useful for understanding how eggshell's stiffness and toughness make it ideally suited to its purpose, and the mechanisms by which toughness is achieved. The paper also contains analysis of the effect of defect type, including cracks, notches and holes, to provide a fuller picture of defect tolerance which will be useful in the egg producing industry.

Evaluation of New Bone Formation and Osseointegration Around Subperiosteal Titanium Implants with Histometry and Nanoindentation.

PURPOSE: To assess the quality and quantity of newly formed bone around rough-surfaced titanium subperiosteal implants stabilized with two different fixation techniques and to investigate nanoindentation as a method for measuring the elastic properties of the bone around these implants. MATERIALS AND METHODS: Ten 6-month-old white rabbits were used in this study. One femur received a subperiosteal implant fixed to the bone with screws. The other femur received a subperiosteal implant stabilized with a trough (bed) in the bone area, plus fixation screws. After a 3-month healing period, the animals were sacrificed and each titanium plate was resected along with the surrounding bone. Histometric measurements of osseointegration were performed on 16 titanium plates, and 16 titanium plates were evaluated qualitatively (hardness and modulus of elasticity) with nanoindentation. A regression model was used to analyze the data. RESULTS: Subperiosteal implants placed into a trough performed significantly better than those placed on top of the cortical bone in terms of percentage of bone in direct contact with the titanium plate, length of new bone, and percentage of area of new bone. The mechanical properties (modulus of elasticity, hardness) of the newly formed bone above the plate measured at the microstructural level were significantly inferior to those of the mature cortical bone below the plate. CONCLUSION: Subperiosteal implants placed into a trough performed better than those placed on top of the cortical bone, but it seems that 3 months of healing is not enough to achieve optimal integration and bone maturation around them. Nanoindentation can offer valuable insight into the elastic properties of the microstructural component of the bone.

High-resolution ultrasound findings in the symptomatic residual limbs of amputees.

INTRODUCTION: Amputations are increasingly prevalent because of medical complications associated with diabetes, meningitis, peripheral vascular disease, and neoplasms as well as road traffic accidents and war. The use of ultrasound (U/S) to diagnose the cause of pain in the residual limb of amputees is presented together with a review of the literature. PATIENTS AND METHODS: 133 civilian patients with one or more amputations were included in the study. They were seen over a 2-year period, at the Douglas Bader Unit, Queen Mary's Hospital, Roehampton, Surrey, United Kingdom, in an outpatient setting. Patients were scanned using a Philips ATL/HDI 5000 U/S scanner. RESULTS: There were 89 male and 44 female patients, age range 14 to 91 years, with a total of 136 amputated sites. 80% of amputations involved the lower limb. Neuromas were the most frequently found lesions, followed by inflammatory edema, soft-tissue calcifications, bony spurs, soft-tissue infection, overuse injuries, bursae, and skin lesions. Scar tissue, bony erosion, bone infection, aneurysm formation, venous thrombosis, and myodesis failure were less frequently seen. CONCLUSIONS: There is a wide spectrum of lesions in the amputated limb, which can be visualized by high-resolution U/S. Neuromas were the most frequent lesions seen.

Management of extensive subcutaneous emphysema with a subcutaneous drain.

We present a case of a gentleman in his 70s with extensive subcutaneous emphysema. Usually self-limiting, subcutaneous emphysema around the thoracic inlet can rarely lead to airway and cardiovascular compromise by compression of structures in the neck. This patient presented with a large pneumothorax on a background of chronic obstructive pulmonary disease (COPD). This was initially treated with an intrapleural chest drain. However, after removal of this drain, the patient developed subcutaneous emphysema and later signs of tension pneumothorax. Further intrapleural chest drains were required. One of these chest drains produced a broncho-subcutaneous fistula, which contributed to extensive subcutaneous emphysema. He developed symptoms of dysphonia and dysphagia. A subcutaneous drain was inserted for palliation of his symptoms and to improve his quality of life. His symptoms improved significantly after insertion of this subcutaneous drain. There are only a handful of case reports published on interventions to relieve subcutaneous emphysema.

The mechanical effect of the existing cement mantle on the in-cement femoral revision.

BACKGROUND: Cement-in-cement revision hip arthroplasty is an increasingly popular technique to replace a loose femoral stem which retains much of the original cement mantle. However, some concern exists regarding the retention of the existing fatigued and aged cement in such cement-in-cement revisions. This study investigates whether leaving an existing fatigued and aged cement mantle degrades the mechanical performance of a cement-in-cement revision construct. METHODS: Primary cement mantles were formed by cementing a polished stem into sections of tubular steel. If in the test group, the mantle underwent conditioning in saline to simulate ageing and was subject to a fatigue of 1 million cycles. If in the control group no such conditioning or fatigue was carried out. The cement-in-cement procedure was then undertaken. Both groups underwent a fatigue of 1 million cycles subsequent to the revision procedure. FINDINGS: Application of a Mann-Whitney test on the recorded subsidence (means: 0.51, 0.46, n=10+10, P=0.496) and inducible displacement (means: 0.38, 0.36, P=0.96) revealed that there was no statistical difference between the groups. INTERPRETATION: This study represents further biomechanical investigation of the mechanical behaviour of cement-in-cement revision constructs. Results suggest that pre-revision fatigue and ageing of the cement may not be deleterious to the mechanical performance of the revision construct. Thus, this study provides biomechanical evidence to back-up recent successes with this useful revision technique.