A comparison of chest radiographic findings in human immunodeficiency virus-positive and -negative children with pulmonary tuberculosis.

AIM: To compare chest radiography (CXR) findings in human immunodeficiency virus (HIV)-positive and HIV-negative children who had microbiologically confirmed pulmonary tuberculosis (PTB). MATERIALS AND METHODS: Retrospective analysis of CXRs from children with known HIV status and microbiologically confirmed PTB (culture or GeneXpert Xpert MTB/RIF positive), who were hospitalised or seen at a primary healthcare centre over a 5-year period. Radiological findings were compared according to HIV and nutritional status. RESULTS: CXRs of 130 children were analysed from 35 (27%) HIV- positive and 95 (73%) HIV-negative children with confirmed PTB, median age 45.7 months (interquartile range [IQR] 18-81.3 months). CXR changes consistent with PTB were reported in 21/35 (60%) of HIV-positive and 59/95 (62%) of HIV-negative patients, (p=0.81). Normal CXR was identified in 3/35 (8.6%) of HIV-positive and 5/95 (5.3%) of HIV-negative patients (p=0.81). Airway compression was present in 3/35 (8.6%) of HIV-positive and 7/95 (7.4%) of HIV-negative patients (p>0.99). Overall, lymphadenopathy was identified in 42/130 (32.3%) of patients, 11/35 (31.4 %) were HIV-positive compared with 31/95 (32.6%) HIV-negative patients. Airspace consolidation was present in 60% of both HIV-positive (21/35) and HIV-negative patients (57/95). Pleural effusion was present in 2/35 (5.7 %) of HIV-negative and 9/95 (9.5 %) of HIV-negative patients. There were no statistically significant radiological differences by HIV group. CONCLUSION: There were no significant differences in the CXR findings between the HIV-positive and HIV-negative children with confirmed PTB.

Primary cheilorhinoseptoplasty using the Talmant protocol in unilateral complete cleft lip: functional and aesthetic results on nasal correction and comparison with the Tennison-Malek protocol.

Many surgical procedures used to treat patients with unilateral complete cleft lip do not include a complete primary rhinoseptoplasty, which is delayed until the end of growth as part of secondary surgery. Primary cheilorhinoseptoplasty using the Talmant technique has been performed at Lapeyronie University Hospital, Montpellier for 15 years. This retrospective study evaluated and compared the functional and aesthetic results obtained in such patients at 4-6 years after surgery with those obtained without primary rhinoseptoplasty in patients undergoing the Tennison-Malek technique. This study included a cohort of 60 children who presented a unilateral complete cleft lip: 29 were operated on with the Tennison-Malek technique and 31 with the Talmant technique. Three functional and 14 aesthetic criteria were evaluated. All functional criteria showed better results in the Talmant group: nocturnal nasal breathing (P < 0.001), incidence of closed rhinolalia (P = 0.0019), and presence of asymmetric nasal breathing (P < 0.001). Concerning the aesthetic results, all criteria evaluated on the frontal and basal photographs of each patient showed significantly better results in the Talmant technique group. The rate of satisfactory results was> 75% for 12 of the 14 criteria in the Talmant group, compared with none of the 14 criteria in the Tennison-Malek group.

Diverse clinical and social circumstances: developing patient-centred care for DR-TB patients in South Africa.

OBJECTIVE: To describe the medical, socio-economic and geographical profiles of patients with rifampicin-resistant TB (RR-TB) and the implications for the provision of patient-centred care. SETTING: Thirteen districts across three South African provinces. DESIGN: This descriptive study examined laboratory and healthcare facility records of 194 patients diagnosed with RR-TB in the third quarter of 2016. RESULTS: The median age was 35 years; 120/194 (62%) of patients were male. Previous TB treatment was documented in 122/194 (63%) patients and 56/194 (29%) had a record of fluoroquinolone and/or second-line injectable resistance. Of 134 (69%) HIV-positive patients, viral loads were available for 68/134 (51%) (36/68 [53%] had viral loads of >1000 copies/ml) and CD4 counts were available for 92/134 (69%) (20/92 [22%] had CD4 <50 cells/mm3). Patients presented with varying other comorbidities, including hypertension (13/194, 7%) and mental health conditions (11/194, 6%). Of 194 patients, 44 (23%) were reported to be employed. Other socio-economic challenges included substance abuse (17/194, 9%) and ill family members (17/194, 9%). Respectively 13% and 42% of patients were estimated to travel more than 20 km to reach their diagnosing and treatment-initiating healthcare facility. CONCLUSIONS: RR-TB patients had diverse medical and social challenges highlighting the need for integrated, differentiated and patient-centred healthcare to better address specific needs and underlying vulnerabilities of individual patients.

OBJECTIF: Décrire les profils médicaux, socioéconomiques et géographiques des patients atteints de TB résistante à la rifampicine (RR-TB) et les implications en matière de soins centrés sur le patient. CONTEXTE: Treize districts de trois provinces d'Afrique du Sud. MÉTHODE: Cette étude descriptive a analysé les dossiers médicaux et de laboratoire de 194 patients ayant reçu un diagnostic de RR-TB au troisième trimestre de 2016. RÉSULTATS: L'âge médian était de 35 ans ; 120/194 (62%) patients étaient des hommes. Un traitement antituberculeux antérieur était documenté chez 122/194 (63%) patients, et 56/194 (29%) avaient une résistance à la fluoroquinolone et/ou à un agent injectable de deuxième ligne documentée. Sur 134 (69%) patients infectés par le VIH, les charges virales étaient disponibles pour 68/134 (51%) patients (36/68 [53%] avaient des charges virales >1 000 copies/ml) et les taux de CD4 étaient disponibles pour 92/134 (69%) patients (20/92 [22%] avaient un taux de CD4 <50 cellules/mm3). Les patients présentaient diverses autres comorbidités, dont hypertension (13/194, 7%) et troubles psychiques (11/194, 6%). Sur les 194 patients, 44 (23%) avaient un emploi. Les autres problèmes socioéconomiques comprenaient la toxicomanie (17/194, 9%) et le fait d'avoir un membre de sa famille malade (17/194, 9%). Respectivement 13% et 42% des patients parcouraient plus de 20 km pour se rendre à leur centre de diagnostic et au centre de soins responsable de l'instauration du traitement. CONCLUSIONS: Les patients atteints de RR-TB avaient divers problèmes médicaux et sociaux. Ces résultats soulignent le besoin de soins intégrés, différenciés et centrés sur le patient afin de mieux répondre aux besoins spécifiques et aux vulnérabilités sous-jacentes de chaque patient.

Markers of human endometrial hypoxia can be detected in vivo and ex vivo during physiological menstruation.

STUDY QUESTION: Can markers of human endometrial hypoxia be detected at menstruation in vivo? SUMMARY ANSWER: Our in vivo data support the presence of hypoxia in menstrual endometrium of women during physiological menstruation. WHAT IS KNOWN ALREADY: Current evidence from animal models and human in vitro studies suggests endometrial hypoxia is present at menstruation and drives endometrial repair post menses. However, detection of human endometrial hypoxia in vivo remains elusive. STUDY DESIGN, SIZE, DURATION: We performed a prospective case study of 16 women with normal menstrual bleeding. PARTICIPANTS/MATERIALS, SETTING, METHODS: Reproductively aged female participants with a regular menstrual cycle underwent objective measurement of their menstrual blood loss using the alkaline haematin method to confirm a loss of <80 ml per cycle. Exclusion criteria were exogenous hormone use, an intrauterine device, endometriosis or fibroids >3 cm. Participants attended for two MRI scans; during days 1-3 of menstruation and the early/mid-secretory phase of their cycle. The MRI protocol included dynamic contrast-enhanced MRI and T2* quantification. At each visit, an endometrial sample was also collected and hypoxia-regulated repair factor mRNA levels (ADM, VEGFA, CXCR4) were quantified by RT-qPCR. MAIN RESULTS AND THE ROLE OF CHANCE: Women had reduced T2* during menstrual scans versus non-menstrual scans (P = 0.005), consistent with menstrual hypoxia. Plasma flow (Fp) was increased at menstruation compared to the non-menstrual phase (P = 0.0005). Laboratory findings revealed increased ADM, VEGF-A and CXCR4 at menstruation on examination of paired endometrial biopsies from the menstrual and non-menstrual phase (P = 0.008; P = 0.03; P = 0.009). There was a significant correlation between T2* and these ex vivo hypoxic markers (P < 0.05). LIMITATIONS, REASONS FOR CAUTION: This study examined the in vivo detection of endometrial hypoxic markers at specific timepoints in the menstrual cycle in women with a menstrual blood loss <80 ml/cycle and without significant uterine structural abnormalities. Further research is required to determine the presence of endometrial hypoxia in those experiencing abnormal uterine bleeding with and without fibroids/adenomyosis. WIDER IMPLICATIONS OF THE FINDINGS: Heavy menstrual bleeding (HMB) is a common, debilitating condition. Understanding menstrual physiology may improve therapeutics. To our knowledge, this is the first in vivo data supporting the presence of menstrual hypoxia in the endometrium of women with normal menstrual bleeding. If aberrant in those with HMB, these non-invasive tests may aid diagnosis and facilitate personalized treatments for HMB. STUDY FUNDING/COMPETING INTEREST(S): This work was funded by Wellbeing of Women grant RG1820, Wellcome Trust Fellowship 209589/Z/17/Z and undertaken in the MRC Centre for Reproductive Health, funded by grants G1002033 and MR/N022556/1. H.O.D.C. has clinical research support for laboratory consumables and staff from Bayer AG and provides consultancy advice (but with no personal remuneration) for Bayer AG, PregLem SA, Gedeon Richter, Vifor Pharma UK Ltd, AbbVie Inc; Myovant Sciences GmbH. H.O.D.C. receives royalties from UpToDate for articles on abnormal uterine bleeding. TRIAL REGISTRATION NUMBER: N/A.

Developmental, Morphological and Physiological Traits in Plants Exposed for Five Generations to Chronic Low-Level Ionising Radiation.

The effects of ionising radiation (IR) on plants are important for environmental protection but also in agriculture, horticulture, space science, and plant stress biology. Much current understanding of the effects of IR on plants derives from acute high-dose studies but exposure to IR in the environment frequently occurs at chronic low dose rates. Chronic low dose-rate studies have primarily been field based and examined genetic or cytogenetic endpoints. Here we report research that investigated developmental, morphological and physiological effects of IR on Arabidopsis thaliana grown over 7 generations and exposed for five generations to chronic low doses of either 137Cs (at a dose rate of c. 40 µGy/h from ß/γ emissions) or 10 µM CdCl2. In some generations there were significant differences between treatments in the timing of key developmental phases and in leaf area or symmetry but there were, on the basis of the chosen endpoints, no long-term effects of the different treatments. Occasional measurements also detected no effects on root growth, seed germination rates or redox poise but in the generation in which it was measured exposure to IR did decrease DNA-methylation significantly. The results are consistent with the suggestion that chronic exposure to c. 40 µGy/h can have some effects on some traits but that this does not affect function across multiple generations at the population level. This is explained by the redundancy and/or degeneracy between biological levels of organization in plants that produces a relatively loose association between genotype and phenotype. The importance of this explanation to understanding plant responses to stressors such as IR is discussed. We suggest that the data reported here provide increased confidence in the Derived Consideration Reference Levels (DCRLs) recommended by the International Commission for Radiological Protection (ICRP) by providing data from controlled conditions and helping to contextualize effects reported from field studies. The differing sensitivity of plants to IR is not well understood and further investigation of it would likely improve the use of DCRLs for radiological protection.

Drug-resistant tuberculosis patient care journeys in South Africa: a pilot study using routine laboratory data.

SETTING: Thirteen districts in Eastern Cape (EC), KwaZulu-Natal (KZN) and Western Cape (WC) Provinces, South Africa.OBJECTIVE: To pilot a methodology for describing and visualising healthcare journeys among drug-resistant tuberculosis (DR-TB) patients using routine laboratory records.DESIGN: Laboratory records were obtained for 195 patients with laboratory-detected rifampicin-resistant TB (RR-TB) during July-September 2016. Health facility visits identified from these data were plotted to visualise patient healthcare journeys. Data were verified by facility visits.RESULTS: In the 9 months after the index RR-TB sample was collected, patients visited a mean of 2.3 health facilities (95% CI 2.1-2.6), with 9% visiting ≥4 facilities. The median distance travelled by patients from rural areas (116 km, interquartile range [IQR] 50-290) was greater than for urban patients (51 km, IQR 9-140). A median of 21% of patient's time was spent under the care of primary healthcare facilities: this was respectively 6%, 37% and 39% in KZN, EC and WC. Journey patterns were generally similar within districts. Some reflected a semi-centralised model of care where patients were referred to regional hospitals; other journeys showed greater involvement of primary care.CONCLUSION: Routine laboratory data can be used to explore DR-TB patient healthcare journeys and show how the use of healthcare services for DR-TB varies in different settings.

Diagnosis and management of community-acquired pneumonia in children: South African Thoracic Society guidelines.

BACKGROUND: Pneumonia remains a major cause of morbidity and mortality amongst South African children. More comprehensive immunisation regimens, strengthening of HIV programmes, improvement in socioeconomic conditions and new preventive strategies have impacted on the epidemiology of pneumonia. Furthermore, sensitive diagnostic tests and better sampling methods in young children improve aetiological diagnosis. OBJECTIVES: To produce revised guidelines for pneumonia in South African children under 5 years of age. METHODS: The Paediatric Assembly of the South African Thoracic Society and the National Institute for Communicable Diseases established seven expert subgroups to revise existing South African guidelines focusing on: (i) epidemiology; (ii) aetiology; (iii) diagnosis; (iv) antibiotic management and supportive therapy; (v) management in intensive care; (vi) prevention; and (vii) considerations in HIV-infected or HIVexposed, uninfected (HEU) children. Each subgroup reviewed the published evidence in their area; in the absence of evidence, expert opinion was accepted. Evidence was graded using the British Thoracic Society (BTS) grading system. Sections were synthesized into an overall guideline which underwent peer review and revision. RECOMMENDATIONS: Recommendations include a diagnostic approach, investigations, management and preventive strategies. Specific recommendations for HIV infected and HEU children are provided. VALIDATION: The guideline is based on available published evidence supplemented by the consensus opinion of SA paediatric experts. Recommendations are consistent with those in published international guidelines.

What causes symptoms suggestive of tuberculosis in HIV-positive people with negative initial investigations?

OBJECTIVE: To identify the causes of symptoms suggestive of tuberculosis (TB) among people living with the human immunodeficiency virus (PLHIV) in South Africa. METHODS: A consecutive sample of HIV clinic attendees with symptoms suggestive of TB (1 of cough, weight loss, fever or night sweats) at enrolment and at 3 months, and negative initial TB investigations, were systematically evaluated with standard protocols and diagnoses assigned using standard criteria. TB was 'confirmed' if Mycobacterium tuberculosis was identified within 6 months of enrolment, and 'clinical' if treatment started without microbiological confirmation. RESULTS: Among 103 participants, 50/103 were pre-antiretroviral therapy (ART) and 53/103 were on ART; respectively 68% vs. 79% were female; the median age was 35 vs. 45 years; the median CD4 count was 311 vs. 508 cells/mm³. Seventy-two (70%) had 5% measured weight loss and 50 (49%) had cough. The most common final diagnoses were weight loss due to severe food insecurity (n = 20, 19%), TB (n = 14, 14%: confirmed n = 7; clinical n = 7), other respiratory tract infection (n = 14, 14%) and post-TB lung disease (n = 9, 9%). The basis for TB diagnosis was imaging (n = 7), bacteriological confirmation from sputum (n = 4), histology, lumbar puncture and other (n = 1 each). CONCLUSION: PLHIV with persistent TB symptoms require further evaluation for TB using all available modalities, and for food insecurity in those with weight loss.

Blood and virus detection on barber clippers.

BACKGROUND: Bleeding from the popular clean-shave 'chiskop' haircut was recently reported as prevalent in South Africa (SA), a country with 6.9 million HIV-infected people. OBJECTIVES: To investigate the prevalence of barber hair clipper contamination with blood and HIV and hepatitis B viruses. METHODS: Fifty barbers from three townships in Cape Town, SA, were invited to participate. One clipper from each barber was collected immediately after it had been used for a clean-shave haircut. Each clipper was rinsed with phosphate-buffered saline and then submerged in viral medium. The polymerase chain reaction (PCR) was used to identify the blood-specific RNA marker haemoglobin beta (HBB), hepatitis B virus (HBV) and HIV. RESULTS: The clean-shave haircut was the most common haircut requested by clients (78%). Of the clippers collected, 42% were positive for HBB, confirming detection of blood, none were positive for HIV, and 4 (8%) were positive for HBV. Two clippers (clippers 16 and 20) were positive on qualitative HBV PCR. HBV DNA from clipper 16 clustered with genotype A sequences from SA, India, Brazil and Martinique, while clipper 20 clustered with SA genotype D sequences. The clipper 20 sequence was identical to a subtype D sequence (GenBank accession AY233291) from Gauteng, SA. CONCLUSIONS: This study confirms that there is significant contamination of barber hair clippers with blood and blood-borne viruses. Hepatitis B was detected with enough DNA copies to pose a risk of transmitting infection. Although HIV was not detected in this small study, the risk of transmission should be quantified. Further studies to investigate barber clipper sterilisation practices and whether the clean-shave hairstyle is an independent risk factor for HIV, HBV and hepatitis C virus infections are warranted. Public education on individual clipper ownership (as is the case with a toothbrush) should be advocated for clean-shave and blade-fade haircuts.

Hypermetabolism is a deleterious prognostic factor in patients with amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: The aim of this study was to investigate patients with amyotrophic lateral sclerosis in order to determine their nutritional, neurological and respiratory parameters, and survival according to metabolic level. METHODS: Nutritional assessment included resting energy expenditure (REE) measured by indirect calorimetry [hypermetabolism if REE variation (ΔREE) > 10%] and fat mass (FM) using impedancemetry. Neurological assessment included the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised score. Survival analysis used the Kaplan-Meier method and multivariate Cox model. RESULTS: A total of 315 patients were analysed. Median age at diagnosis was 65.9 years and 55.2% of patients were hypermetabolic. With regard to the metabolic level (ΔREE: < 10%, 10-20% and >20%), patients with ΔREE > 20% initially had a lower FM(29.7% vs. 32.1% in those with ΔREE ≤10%; P = 0.0054). During follow-up, the median slope of Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised tended to worsen more in patients with ΔREE > 20% (-1.4 vs. -1.0 points/month in those with ΔREE ≤10%; P = 0.07). Overall median survival since diagnosis was 18.4 months. ΔREE > 20% tended to increase the risk of dying compared with ΔREE ≤10% (hazard ratio, 1.33; P = 0.055). In multivariate analysis, an increased REE:FM ratio was independently associated with death (hazard ratio, 1.005; P = 0.001). CONCLUSIONS: Hypermetabolism is present in more than half of patients with amyotrophic lateral sclerosis. It modifies the body composition at diagnosis, and patients with hypermetabolism >20% have a worse prognosis than those without hypermetabolism.

Fluctuating asymmetry of the normal facial skeleton.

The purpose of this study was to produce reliable estimations of fluctuating facial asymmetry in a normal population. Fifty-four computed tomography (CT) facial models of average-looking and symmetrical Chinese subjects with a class I occlusion were used in this study. Eleven midline landmarks and 12 pairs of bilateral landmarks were digitized. The repeatability of the landmark digitization was first evaluated. A Procrustes analysis was then used to measure the fluctuating asymmetry of each CT model, after all of the models had been scaled to the average face size of the study sample. A principal component analysis was finally used to establish the direction of the fluctuating asymmetries. The results showed that there was excellent absolute agreement among the three repeated measurements. The mean fluctuating asymmetry of the average-size face varied at each anthropometric landmark site, ranging from 1.0mm to 2.8mm. At the 95% upper limit, the asymmetries ranged from 2.2mm to 5.7mm. Most of the asymmetry of the midline structures was mediolateral, while the asymmetry of the bilateral landmarks was more equally distributed. These values are for the average face. People with larger faces will have higher values, while subjects with smaller faces will have lower values.

Blood and virus detection on barber clippers

Background. Bleeding from the popular clean-shave 'chiskop' haircut was recently reported as prevalent in South Africa (SA), a country with 6.9 million HIV-infected people.Objectives. To investigate the prevalence of barber hair clipper contamination with blood and HIV and hepatitis B viruses.Methods. Fifty barbers from three townships in Cape Town, SA, were invited to participate. One clipper from each barber was collected immediately after it had been used for a clean-shave haircut. Each clipper was rinsed with phosphate-buffered saline and then submerged in viral medium. The polymerase chain reaction (PCR) was used to identify the blood-specific RNA marker haemoglobin beta (HBB), hepatitis B virus (HBV) and HIV.Results. The clean-shave haircut was the most common haircut requested by clients (78%). Of the clippers collected, 42% were positive for HBB, confirming detection of blood, none were positive for HIV, and 4 (8%) were positive for HBV. Two clippers (clippers 16 and 20) were positive on qualitative HBV PCR. HBV DNA from clipper 16 clustered with genotype A sequences from SA, India, Brazil and Martinique, while clipper 20 clustered with SA genotype D sequences. The clipper 20 sequence was identical to a subtype D sequence (GenBank accession AY233291) from Gauteng, SA.Conclusions. This study confirms that there is significant contamination of barber hair clippers with blood and blood-borne viruses. Hepatitis B was detected with enough DNA copies to pose a risk of transmitting infection. Although HIV was not detected in this small study, the risk of transmission should be quantified. Further studies to investigate barber clipper sterilisation practices and whether the clean-shave hairstyle is an independent risk factor for HIV, HBV and hepatitis C virus infections are warranted. Public education on individual clipper ownership (as is the case with a toothbrush) should be advocated for clean-shave and blade-fade haircuts

Carriage of extended-spectrum beta-lactamase-producing Enterobacteriaceae in HIV-infected children in Zimbabwe.

BACKGROUND: Antimicrobial resistance is an emerging global health issue. Data on the epidemiology of multidrug-resistant organisms are scarce for Africa, especially in HIV-infected individuals who often have frequent contact with healthcare. We investigated the prevalence of extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-E) carriage in stool among HIV-infected children attending an HIV outpatient department in Harare, Zimbabwe. METHODS: We recruited children who were stable on antiretroviral therapy (ART) attending a HIV clinic from August 2014 to June 2015. Information was collected on antibiotic use and hospitalization. Stool was tested for ESBL-E through combination disc diffusion. API20E identification and antimicrobial susceptibility was performed on the positive samples followed by whole genome sequencing. RESULTS: Stool was collected from 175/202 (86.6 %) children. Median age was 11 [inter-quartile range (IQR) 9-12] years. Median time on ART was 4.6 years (IQR 2.4-6.4). ESBL-Es were found in 24/175 samples (13.7 %); 50 % of all ESBL-Es were resistant to amoxicillin-clavulanate, 100 % to co-trimoxazole, 45.8 % to chloramphenicol, 91.6 % to ceftriaxone, 20.8 % to gentamicin and 62.5 % to ciprofloxacin. ESBL-Es variously encoded CTX-M, OXA, TEM and SHV enzymes. The odds of ESBL-E carriage were 8.5 times (95 % CI 2.2-32.3) higher in those on ART for less than one year (versus longer) and 8.5 times (95 % CI 1.1-32.3) higher in those recently hospitalized for a chest infection. CONCLUSION: We found a 13.7 % prevalence of ESBL-E carriage in a population where ESBL-E carriage has not been described previously. Antimicrobial resistance (AMR) in Africa merits further study, particularly given the high HIV prevalence and limited diagnostic and therapeutic options available.

ALS and frontotemporal dementia belong to a common disease spectrum.

ALS is now understood to be a complex multisystem neurodegenerative disease because areas other than the motor cortices of the brain undergo degeneration. Frontotemporal dementia (FTD) may be associated with motor neuron disease, and the transactive response DNA-binding protein 43 (TDP-43) is a major pathological substrate underlying both diseases. The recent discovery of a gene that can cause both FTD, ALS and FTD-ALS, C9ORF72, has modified the way for considering these two pathologies. These findings would allow the development of potential biomarkers and therapeutic targets for these devastating diseases. This review summarizes the key points leading up to our current understanding of the genetic, clinical and neuropathological overlap between FTD and ALS.

Epidemiology of amyotrophic lateral sclerosis: A review of literature.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of motor neurons, resulting in worsening weakness of voluntary muscles until death occurs from respiratory failure. The incidence of ALS in European populations is two to three people per year per 100,000 of the general population. In Europe, crude prevalences range from 1.1/100,000 population in Yugoslavia to 8.2/100,000 in the Faroe Islands. Major advances have been made in our understanding of the genetic causes of ALS, whereas the contribution of environmental factors has been more difficult to assess and large-scale studies have not yet revealed a replicable, definitive environmental risk factor. The only established risk factors to date are older age, male gender and a family history of ALS. Median survival time from onset to death is usually 3 years from the first appearance of symptoms. Older age and bulbar onset are consistently reported to have poorer outcomes. However, there are conflicting data regarding gender, diagnostic delay and El Escorial criteria. The rate of symptom progression has been revealed to be an independent prognostic factor. Psychosocial factors and impaired cognitive function are negatively related to ALS outcome, while nutritional status and respiratory function are also related to ALS prognosis. The effect of enteral nutrition on survival is still unclear, although noninvasive positive pressure ventilation (NIPPV) has been found to improve survival. These findings have relevant implications for the design of future trials.

The primal sagittal plane of the head: a new concept.

To assess facial form, one has to determine the size, position, orientation, shape, and symmetry of the different facial units. Many of these assessments require a frame of reference. The customary coordinate system used for these assessments is the 'standard anatomical frame of reference', a three-dimensional Cartesian system made by three planes: the sagittal, the axial, and the coronal. Constructing the sagittal plane seems simple, but because of universal facial asymmetry, it is complicated. Depending on the method one selects, one can build hundreds of different planes, never knowing which one is correct. This conundrum can be solved by estimating the sagittal plane a patient would have had if his or her face had developed symmetrically. We call this the 'primal sagittal plane'. To estimate this plane we have developed a mathematical algorithm called LAGER (Landmark Geometric Routine). In this paper, we explain the concept of the primal sagittal plane and present the structure of the LAGER algorithm.

Algorithm for planning a double-jaw orthognathic surgery using a computer-aided surgical simulation (CASS) protocol. Part 2: three-dimensional cephalometry.

Three-dimensional (3D) cephalometry is not as simple as just adding a 'third' dimension to a traditional two-dimensional cephalometric analysis. There are more complex issues in 3D analysis. These include how reference frames are created, how size, position, orientation and shape are measured, and how symmetry is assessed. The main purpose of this article is to present the geometric principles of 3D cephalometry. In addition, the Gateno-Xia cephalometric analysis is presented; this is the first 3D cephalometric analysis to observe these principles.

Investigating the early-life determinants of illness in Africa: the Drakenstein Child Health Study.

Respiratory disease is the predominant cause of illness in children globally. We describe a unique multidisciplinary South African birth cohort, the Drakenstein Child Health Study (DCHS), to investigate the incidence, risk factors, aetiology and long-term impact of early lower respiratory tract infection (LRTI) on child health. Pregnant women from a poor, peri-urban community with high exposure to infectious diseases and environmental risk factors are enrolled with 1000 mother-child pairs followed for at least 5 years. Biomedical, environmental, psychosocial and demographic risk factors are longitudinally measured. Environmental exposures are measured using monitors placed at home visits. Lung function is measured in children at 6 weeks, annually and during LRTI episodes. Microbiological investigations including microbiome and multiplex PCR measures are done longitudinally and at LRTI episodes. The DCHS is a unique African birth cohort study that uses sophisticated measures to comprehensively investigate the early-life determinants of child health in an impoverished area of the world.

How can mathematical models advance tuberculosis control in high HIV prevalence settings?

Existing approaches to tuberculosis (TB) control have been no more than partially successful in areas with high human immunodeficiency virus (HIV) prevalence. In the context of increasingly constrained resources, mathematical modelling can augment understanding and support policy for implementing those strategies that are most likely to bring public health and economic benefits. In this paper, we present an overview of past and recent contributions of TB modelling in this key area, and suggest a way forward through a modelling research agenda that supports a more effective response to the TB-HIV epidemic, based on expert discussions at a meeting convened by the TB Modelling and Analysis Consortium. The research agenda identified high-priority areas for future modelling efforts, including 1) the difficult diagnosis and high mortality of TB-HIV; 2) the high risk of disease progression; 3) TB health systems in high HIV prevalence settings; 4) uncertainty in the natural progression of TB-HIV; and 5) combined interventions for TB-HIV. Efficient and rapid progress towards completion of this modelling agenda will require co-ordination between the modelling community and key stakeholders, including advocates, health policy makers, donors and national or regional finance officials. A continuing dialogue will ensure that new results are effectively communicated and new policy-relevant questions are addressed swiftly.