Impact of the host immune response on the development of equine herpesvirus myeloencephalopathy in horses.

Herpesviruses establish a well-adapted balance with their host's immune system. Despite this co-evolutionary balance, infections can lead to severe disease including neurological disorders in their natural host. In horses, equine herpesvirus 1 (EHV-1) causes respiratory disease, abortions, neonatal foal death and myeloencephalopathy (EHM) in ~10 % of acute infections worldwide. Many aspects of EHM pathogenesis and protection from EHM are still poorly understood. However, it has been shown that the incidence of EHM increases to >70 % in female horses >20 years of age. In this study we used old mares as an experimental equine EHV-1 model of EHM to identify host-specific factors contributing to EHM. Following experimental infection with the neuropathogenic strain EHV-1 Ab4, old mares and yearling horses were studied for 21 days post-infection. Nasal viral shedding and cell-associated viremia were assessed by quantitative PCR. Cytokine/chemokine responses were evaluated in nasal secretions and cerebrospinal fluid (CSF) by Luminex assay and in whole blood by quantitative real-time PCR. EHV-1-specific IgG sub-isotype responses were measured by ELISA. All young horses developed respiratory disease and a bi-phasic fever post-infection, but only 1/9 horses exhibited ataxia. In contrast, respiratory disease was absent in old mares, but all old mares developed EHM that resulted in euthanasia in 6/9 old mares. Old mares also presented significantly decreased nasal viral shedding but higher viremia coinciding with a single fever peak at the onset of viremia. According to clinical disease manifestation, horses were sorted into an EHM group (nine old horses and one young horse) and a non-EHM group (eight young horses) for assessment of host immune responses. Non-EHM horses showed an early upregulation of IFN-α (nasal secretions), IRF7/IRF9, IL-1ß, CXCL10 and TBET (blood) in addition to an IFN-γ upregulation during viremia (blood). In contrast, IFN-α levels in nasal secretions of EHM horses were low and peak levels of IRF7, IRF9, CXCL10 and TGF-ß (blood) coincided with viremia. Moreover, EHM horses showed significantly higher IL-10 levels in nasal secretions, peripheral blood mononuclear cells and CSF and higher serum IgG3/5 antibody titres compared to non-EHM horses. These results suggest that protection from EHM depends on timely induction of type 1 IFN and upregulation cytokines and chemokines that are representative of cellular immunity. In contrast, induction of regulatory or TH-2 type immunity appeared to correlate with an increased risk for EHM. It is likely that future vaccine development for protection from EHM must target shifting this 'at-risk' immunophenotype.

Picosecond laser microwelding of AlSi-YAG for laser system assembly.

We report the successful picosecond laser welding of AlSi and YAG. This material combination is of significant interest to the field of laser design and construction. Parameter maps are presented that demonstrate the impact of pulse energy and focal position on the resultant weld. Weld performance relevant to industrial applications is measured, i.e., shear strength, process yield, and absolute thermal resistance are presented.

Mendelian susceptibility to mycobacterial disease in tuberculosis-hyperendemic South Africa.

BACKGROUND: Severe infections in the absence of secondary immunodeficiency can alert clinicians to single-gene inborn errors of immunity/primary immunodeficiency disorders (PIDDs). Mendelian susceptibility to mycobacterial disease (MSMD) is characterised by selective susceptibility to mycobacterial infections due to inborn errors in the interleukin 12-interferon gamma pathway. The South African (SA) burden of hyperendemic tuberculosis (TB) infection provides an interesting context for the study of MSMD. OBJECTIVES:  To evaluate whether severe, persistent, unusual or recurrent (SPUR) definitions of TB can be applied in the context of MSMD in SA. METHODS: This study is a retrospective review of an SA PIDD cohort. Patients aged 0 - 15 years with SPUR TB infections, assessed between 2013 and 2018, were identified using a proposed algorithm. HIV infection or other secondary causes for immunodeficiency were excluded. Basic investigations, then focused immunophenotyping and next-generation sequencing, were performed. RESULTS:  A total of 20 patients with a clinical diagnosis of MSMD were identified. A further two, forming part of a family cohort, had pathogenic variants but remain asymptomatic. Infection with Mycobacterium tuberculosis complex predominated (64%), while 27% had BCG infection or non-tuberculous mycobacteria (NTM) infection. Molecular analysis revealed pathogenic variants in 41% of patients with SPUR mycobacterial infection, mainly in those with BCG/NTM infection. CONCLUSIONS:  In the SA paediatric population, SPUR TB infections, particularly BCG/NTM, in the absence of secondary immunodeficiency, can alert to possible MSMD. The molecular diagnosis is pivotal, guiding disease classification and influencing clinical approach and management. The diagnosis is complex and requires a multidisciplinary approach with close collaboration between clinical immunologists, bioinformaticians, immunologists, clinical geneticists and genetic counsellors.

Neurodevelopmental and behavioural outcomes of HIV-exposed uninfected and HIV-unexposed children at 2-3 years of age in Cape Town, South Africa.

Successful vertical HIV transmission prevention programmes (VTP) have resulted in an expanding population of HIV-exposed uninfected (HEU) infants whose growth, health and neurodevelopmental outcomes could have consequences for future resource allocation. We compared neurodevelopmental and behavioural outcomes in a prospective cohort of 2-3 year old HEU and HIV-unexposed uninfected (HU) children.Women living with and without HIV and their infants were enrolled within three days of birth from a low-risk midwife obstetric unit in Cape Town, South Africa during 2012 and 2013, under WHO Option A VTP guidelines. HIV-uninfected children aged 30-42 months were assessed using the Bayley scales of Infant Development-Third edition (BSID) and Strengths and Difficulties questionnaire (SDQ).Thirty-two HEU and 27 HU children (mean birth weight 3048g vs 3096g) were assessed. HEU children performed as well as HU children on BSID cognitive, language and motor domains. Mean scores fell within the low average range. Mothers of HEU children reported fewer conduct problems but stunting was associated with increased total difficulties on the SDQ.HEU and HU children's performance on the BSID was similar. In this low-risk cohort, HIV exposure did not confer additional risk. Stunting was associated with increased behavioural problems irrespective of HIV exposure.

Time-resolved thermally induced aberrations in a flash-lamp pumped Nd:Glass disk amplifier using a 2 × 2 position sensitive detector array.

A novel technique of measuring the prompt, thermally induced wave-front aberrations in a large aperture flash-lamp pumped Nd3+ glass disk amplifier is presented. Implementing a 2 × 2 lens array and a 2 × 2 position sensitive detector array as a diagnostic system, the wave-front profile was successfully reconstructed for the first five Zernike terms for a temporal window of 8.5 ms.

Pseudomonas aeruginosa PcrV and Psl, the Molecular Targets of Bispecific Antibody MEDI3902, Are Conserved Among Diverse Global Clinical Isolates.

Background: Bispecific antibody MEDI3902, targeting the Pseudomonas aeruginosa type 3 secretion system (PcrV) and Psl exopolysaccharide, is currently in phase 2b development for prevention of nosocomial pneumonia in patients undergoing mechanical ventilation. We surveyed a diverse collection of isolates to study MEDI3902 epitope conservation and protective activity. Methods: P. aeruginosa clinical isolates (n = 913) were collected from diverse patients and geographic locations during 2003-2014. We conducted whole-genome sequencing; performed PcrV and Psl expression analyses via immunoblotting and enzyme-linked immunosorbent assay, respectively; performed crystallography to determine the MEDI3902 PcrV epitope, using anti-PcrV Fab and PcrV components (resolved at 2.8 Å); and evaluated MEDI3902 protective activity against select isolates in vitro and in vivo. Results: Intact psl operon and pcrV genes were present in 94% and 99% of isolates, respectively, and 99.9% of isolates contained at least one of the genetic elements. Anti-Psl binding was confirmed in tested isolates harboring a complete Psl operon or lacking nonessential psl genes. We identified 46 PcrV variant sequences, and MEDI3902-PcrV contact residues were preserved. MEDI3902 maintained potent in vivo activity against various strains, including strains expressing only a single target. Conclusions: Psl and PcrV are highly prevalent in global clinical isolates, suggesting MEDI3902 can mediate broad coverage against P. aeruginosa.

Comparative study of high power Tm:YLF and Tm:LLF slab lasers in continuous wave regime.

We report on Tm:YLF and Tm:LLF slab lasers (1.5 x 11 x 20 mm3) end pumped from one end with a high-brightness 792 nm laser diode stack. These two lasers are compared under identical pump conditions in continuous-wave regime. A stronger negative thermal lens in Tm:LLF than in Tm:YLF is highlighted, making it more difficult to operate the Tm:LLF laser under stable lasing conditions. In a configuration where the high reflectivity cavity mirror has a radius of curvature of r = 150 mm, the Tm:YLF (Tm:LLF) laser produces a maximum output power of 150 W (143 W) for 428 W of incident pump power (respectively). For a second cavity configuration where the high reflectivity cavity mirror has a radius of curvature of r = 500 mm, the Tm:YLF laser produces a maximum output power of 164 W for 412 W of incident pump power and a 57% slope efficiency with respect to the absorbed pump power. The emitted wavelength of these two lasers are measured as a function of the output coupler reflectivity and it shows that Tm:LLF laser emits at a longer wavelength than Tm:YLF.

Towards industrial ultrafast laser microwelding: SiO2 and BK7 to aluminum alloy.

We report systematic analysis and comparison of ps-laser microwelding of industry relevant Al6082 parts to SiO2 and BK7. Parameter mapping of pulse energy and focal depth on the weld strength is presented. The welding process was found to be strongly dependent on the focal plane but has a large tolerance to variation in pulse energy. Accelerated lifetime tests by thermal cycling from -50° to +90°C are presented. Welds in Al6082-BK7 parts survive over the full temperature range where the ratio of thermal expansion coefficients is 3.4:1. Welds in Al6082-SiO2 parts (ratio 47.1:1) survive only a limited temperature range.

Hemodynamic instability associated with increased risk of death or brain injury in neonates with hypoxic ischemic encephalopathy.

OBJECTIVE: To determine the association between hemodynamic instability requiring inotropes and brain injury or death in neonates with hypoxic ischemic encephalopathy (HIE). METHODS: Retrospective cohort study of 221 neonates with HIE. Brain injury was defined using four HIE patterns based on MRI diffusion or T1 changes. The primary outcome was death or brain injury. Secondary outcomes were abnormal MRI, death, and abnormal EEG. Logistic regression was used to examine the risk of death or brain injury with the use of inotropes while adjusting for confounding factors. RESULTS: Brain injury or death occurred more often in neonates who received inotropes (71.1%, 69/97) compared to those who did not (44.3%, 55/124). The use of inotropes was associated with increased risk of death or brain injury (OR 3.11; 95% CI 1.39-7.004) and abnormal MRI (OR 2.78; 95% CI 1.22-6.34) after adjusting for confounding factors. Mortality was significantly higher in neonates exposed to inotropes (21.6%, 21/97) compared with those who did not receive inotropes (4%, 5/124), P < 0.001. CONCLUSION: In infants with HIE, hemodynamic instability requiring inotropes in the first 72 hours of life was associated with increased risk of death or brain injury detected by MRI.

[Performance Indicators of Hospitals in One Region Between 2006/07 and 2013: a Trend Analysis]. / Trendanalyse der Qualitätsindikatoren der Krankenhäuser einer Region von 2006/07 bis 2013.

BACKGROUND: In spite of a nationwide implementation of performance indicators (PI) for monitoring inpatient medical care, a systematic evaluation of their development over time is still missing. METHODS: A trend analysis of annual rates of PI from 2006/07 to 2013 of Bavarian hospitals was conducted; 123 out of a total of 245 PI selected from 15 distinct clinical fields were available and comparable over the entire period and evaluated. Joinpoint regression was used to estimate annual percentage changes (APC) in regional averages. Individual hospital rates were inspected with box plots for selected indicators. RESULTS: 99 PI (80.5%) showed improvement over time, 67 (54.5% of all PI) were statistically significant. A change from positive to negative trend was found in 15 indicators (12.2%); the negative trend was significant only once. A continuous negative trend was observed in 9 cases (7.3%) (3 significant). Extreme values of hospital rates were present throughout the entire period of observation with results generally far below the national average. CONCLUSION: The majority of indicators improved continuously, which may be interpreted as indicating effectiveness of quality assurance programs, and could also give a strong impetus to further quality improvement measures.

Angio-oedema associated with colistin.

A 50-year-old woman known to have type 1 diabetes mellitus presented with a rare case of angio-oedema associated with colistin use. The angio-oedema was temporally associated with the use and discontinuation of colistin with the reasonable exclusion of important differential diagnoses. Pseudoallergy may be a probable underlying mechanism. However, we cannot exclude the possibility of hereditary angio-oedema type 2 or 3, or that her concomitant medications (particularly enalapril) and her renal impairment contributed to the risk and severity of her angio-oedema.

High average power Q-switched 1314-nm two-crystal Nd:YLF laser.

A 1314 nm two-crystal Nd:YLF laser was designed and operated in both CW and actively Q-switched modes. Maximum CW output of 26.5 W resulted from 125 W of combined incident pump power. Active Q-switching was obtained by inserting a Brewster-cut acousto optic modulator. This setup delivered an average power of 18.6 W, with a maximum of 5.6 mJ energy per pulse with a pulse duration of 36 ns at a pulse repetition frequency of 500 Hz.

The development of lasting impairments: a mild pediatric brain injury alters gene expression, dendritic morphology, and synaptic connectivity in the prefrontal cortex of rats.

Apart from therapeutic discovery, the study of mild traumatic brain injury (mTBI) has been focused on two challenges: why do a majority of individuals recover with little concern, while a considerable proportion suffer with persistent and often debilitating symptomology; and, how do mild injuries significantly increase risk for an early-onset neurodegeneration? Owing to a lack of observable damage following mTBI, this study was designed to determine if there were changes in neuronal morphology, synaptic connectivity, and epigenetic patterning that could contribute to the manifestation of persistent neurological dysfunction. Prefrontal cortex tissue from male and female rats was used for Golgi-Cox analysis along with the profiling of changes in gene expression (BDNF, DNMT1, FGF2, IGF1, Nogo-A, OXYR, and TERT) and telomere length (TL), following a single mTBI or sham injury in the juvenile period. Golgi-Cox analysis of dendritic branch order, dendritic length, and spine density demonstrate that an early mTBI increases complexity of pyramidal neurons in the mPFC. Furthermore, there are also substantial changes in the expression levels of the seven genes of interest and TL following a single mild injury in this brain region. The results from the neuroanatomical measures and changes in gene expression indicate that the mTBI disrupts normal pruning processes that are typically underway at this point in development. In addition, there are significant interactions between the social environment and epigenetic processes that work in concert to perpetuate neurological dysfunction.

Optically pumped tunable HBr laser in the mid-infrared region.

An optically pumped tunable HBr laser has been demonstrated for the first time. The pump source was a single-frequency Ho:YLF laser and amplifier system, which was locked to the 2064 nm absorption line of HBr. Laser oscillation was demonstrated on 19 molecular transition lines, which included both the R-branch (3870-4015 nm) and the P-branch (4070-4453 nm), by the use of an intra-cavity diffraction grating. The highest output energy was 2.4 mJ at 4133 nm.

Mean girls: sex differences in the effects of mild traumatic brain injury on the social dynamics of juvenile rat play behaviour.

Clinical studies indicate that children who experience a traumatic brain injury (TBI) are often the victim of peer rejection, have very few mutual friends, and are at risk for long-term behavioural and social impairments. Owing to the fact that peer play is critical for healthy development, it is possible that the long-term impairments are associated not only with the TBI, but also altered play during this critical period of brain development. This study was designed to determine if social dynamics and juvenile play are altered in rats that experience a mild TBI (mTBI) early in life. Play-fighting behaviours were recorded and analyzed for young male and female Sprague Dawley rats that were given either an mTBI or a sham injury. The study found that the presence of an mTBI altered the play fighting relationship, and the nature of the alterations were dependent upon the sex of the pairing and the injury status of their peers. Sham rats were significantly less likely to initiate play with an mTBI rat, and were more likely to respond to a play initiation from an mTBI rat with an avoidant strategy. This effect was significantly more pronounced in female rats, whereby it appeared that female rats with an mTBI were particularly rejected and most often excluded from play experiences. Male rats with an mTBI learned normal play strategies from their sham peers (when housed in mixed cages), whereas female rats with an mTBI show heightened impairment in these conditions. Play therapy may need to be incorporated into treatment strategies for children with TBI.

Investigation and management of primary immunodeficiency in South African children.

The primary immunodeficiency diseases (PIDs) are inherited, non-communicable diseases that cause immunological dysfunction. PIDs are seldom reported in South Africa (SA). Based on a mid-2013 population estimate of 52.98 million and assuming that the prevalence of PIDs is similar to that in well-resourced settings, the total number of individuals with PIDs in our country should range between2 850 and 45 723. However, fewer than 500 cases of PID have been reported in SA. Between five and 15 new, fully characterised PIDs are reported annually. Our understanding of the physiology of the immune system has been substantially enhanced by these discoveries, and consequently the international classification of PIDs has been updated.

The imaging and classification of severe pelvic ring fractures: Experiences from two level 1 trauma centres.

We describe the routine imaging practices of Level 1 trauma centres for patients with severe pelvic ring fractures, and the interobserver reliability of the classification systems of these fractures using plain radiographs and three-dimensional (3D) CT reconstructions. Clinical and imaging data for 187 adult patients (139 men and 48 women, mean age 43 years (15 to 101)) with a severe pelvic ring fracture managed at two Level 1 trauma centres between July 2007 and June 2010 were extracted. Three experienced orthopaedic surgeons classified the plain radiographs and 3D CT reconstruction images of 100 patients using the Tile/AO and Young-Burgess systems. Reliability was compared using kappa statistics. A total of 115 patients (62%) had plain radiographs as well as two-dimensional (2D) CT and 3D CT reconstructions, 52 patients (28%) had plain films only, 12 (6.4%) had 2D and 3D CT reconstructions images only, and eight patients (4.3%) had no available images. The plain radiograph was limited to an anteroposterior pelvic view. Patients without imaging, or only plain films, were more severely injured. A total of 72 patients (39%) were imaged with a pelvic binder in situ. Interobserver reliability for the Tile/AO (Kappa 0.10 to 0.17) and Young-Burgess (Kappa 0.09 to 0.21) was low, and insufficient for clinical and research purposes. Severe pelvic ring fractures are difficult to classify due to their complexity, the increasing use of early treatment such as with pelvic binders, and the absence of imaging altogether in important patient sub-groups, such as those who die early of their injuries.