Community-acquired pneumonia in Malawian adults: Aetiology and predictors of mortality.

Background Community-acquired pneumonia (CAP) is one of the commonest causes of adult hospitalisation in sub-Saharan Africa, but recent data describing its epidemiology, microbial aetiology and outcome are limited. Focusing particularly on Malawi, the overall aim of this thesis was to describe the aetiology and outcome of CAP in sub-Saharan African to determine the key predictors of mortality. Methods Firstly, a systematic review of studies of CAP in adults in sub-Saharan Africa was performed to describe CAP aetiology, estimate the mortality rate and identify risk factors associated with death. Secondly, a prospective observational study of adults hospitalised with clinically diagnosed CAP to Queen Elizabeth Central Hospital, Blantyre, Malawi was completed to describe microbial aetiology using modern diagnostic modalities, determine outcome and identify prognostics factors. Thirdly, having identified in preliminary analyses of the prospective cohort that hypoxaemia was an independent risk factor for mortality, a study of the effectiveness of supplemental oxygen delivery by oxygen concentrator to correct hypoxaemia in adults with suspected CAP was performed. Results In both the systematic review and the prospective cohort the predominant burden of hospitalised CAP was in young (average age 38 and 35, respectively) and HIV-positive (52% and 78%) patients with limited chronic cardiovascular and pulmonary comorbidity. Streptococcus pneumoniae (27% and 21%) and Mycobacterium tuberculosis (19% and 23%) were the most commonly identified causes. The overall mortality rate for hospitalised patients in the systematic review was 9.5%, but data describing prognostic factors were limited. In the prospective cohort (n=459), death by day 30 occurred in 14.6% and was associated with: male sex (aOR 2.57); pre-presentation symptom duration (aOR 1.11 per day increase); inability to stand (aOR 4.28); heart rate (aOR 1.02 per beat/minute rise); oxygen saturations (aOR 0.95 per % rise); white cell count (aOR 0.91 per 109/L rise); haemoglobin (aOR 0.90 per g/dL rise). A newly derived four parameter mortality risk prediction tool based on male sex, oxygen saturations <90%, inability to stand and heart rate ≥125 /min predicted 30-day mortality with reasonable accuracy (area under the receiver-operating curve (AUROC) 0.79) whilst existing tools performed poorly (CURB65: AUROC 0.60; SMRT-CO: AUROC 0.66). Hypoxaemia was corrected in 86.4% (n=59) of adults with suspected CAP with supplemental oxygen at standard flow-rate of 5 litres/minute. Failure to attain normoxaemia was associated with a more than four-fold increase in the risk of death (RR 4.25). Conclusions The major burden of hospitalised CAP in low-resource, sub-Saharan African settings is seen in young and HIV-positive adults, many of whom have TB. Extrapolating CAP assessment and treatment algorithms from well-resourced settings where the epidemiology and aetiology of disease is very different is flawed. If validated, locally derived severity assessment tools may provide a rational basis on which to stratify CAP management. Strategies to increase early detection and treatment of TB and to improve supportive care, in particular the correction of hypoxaemia, hold considerable promise for improving CAP outcomes and should be evaluated in clinical trials

Extraordinary virtual multidisciplinary team meetings: a novel forum for coordinated care of patients with complex conditions within a secondary care setting

Multidisciplinary team (MDT) meetings are increasingly regarded as best practice for the successful management of chronic disease. However, for patients with undiagnosed illnesses, multiple interacting comorbidities or other complex needs that fall outside the remit of disease-specific MDTs or the scope of expertise of individual clinicians, there is often no suitable forum at which to discuss their care to develop a coordinated plan for management. We developed and piloted a new forum for interspecialty discussion and collaboration, an extraordinary virtual MDT, to enable clinicians to arrange an urgent meeting of all involved parties in response to challenging clinical scenarios. Here, we share our experience of implementing this innovation and suggest how this novel forum for coordinated care could be further developed to improve the integration, timeliness and quality of healthcare delivery for patients with complex needs

Suture Materials, 1980s: Properties, Uses, and Abuses

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66057/1/j.1365-4362.1982.tb03154.x.pd

Monotonicity of Fitness Landscapes and Mutation Rate Control

A common view in evolutionary biology is that mutation rates are minimised. However, studies in combinatorial optimisation and search have shown a clear advantage of using variable mutation rates as a control parameter to optimise the performance of evolutionary algorithms. Much biological theory in this area is based on Ronald Fisher's work, who used Euclidean geometry to study the relation between mutation size and expected fitness of the offspring in infinite phenotypic spaces. Here we reconsider this theory based on the alternative geometry of discrete and finite spaces of DNA sequences. First, we consider the geometric case of fitness being isomorphic to distance from an optimum, and show how problems of optimal mutation rate control can be solved exactly or approximately depending on additional constraints of the problem. Then we consider the general case of fitness communicating only partial information about the distance. We define weak monotonicity of fitness landscapes and prove that this property holds in all landscapes that are continuous and open at the optimum. This theoretical result motivates our hypothesis that optimal mutation rate functions in such landscapes will increase when fitness decreases in some neighbourhood of an optimum, resembling the control functions derived in the geometric case. We test this hypothesis experimentally by analysing approximately optimal mutation rate control functions in 115 complete landscapes of binding scores between DNA sequences and transcription factors. Our findings support the hypothesis and find that the increase of mutation rate is more rapid in landscapes that are less monotonic (more rugged). We discuss the relevance of these findings to living organisms

Performance deficits of NK1 receptor knockout mice in the 5 choice serial reaction time task: effects of d Amphetamine, stress and time of day.

Background The neurochemical status and hyperactivity of mice lacking functional substance P-preferring NK1 receptors (NK1R-/-) resemble abnormalities in Attention Deficit Hyperactivity Disorder (ADHD). Here we tested whether NK1R-/- mice express other core features of ADHD (impulsivity and inattentiveness) and, if so, whether they are diminished by d-amphetamine, as in ADHD. Prompted by evidence that circadian rhythms are disrupted in ADHD, we also compared the performance of mice that were trained and tested in the morning or afternoon. Methods and Results The 5-Choice Serial Reaction-Time Task (5-CSRTT) was used to evaluate the cognitive performance of NK1R-/- mice and their wildtypes. After training, animals were tested using a long (LITI) and a variable (VITI) inter-trial interval: these tests were carried out with, and without, d-amphetamine pretreatment (0.3 or 1 mg/kg i.p.). NK1R-/- mice expressed greater omissions (inattentiveness), perseveration and premature responses (impulsivity) in the 5-CSRTT. In NK1R-/- mice, perseveration in the LITI was increased by injection-stress but reduced by d-amphetamine. Omissions by NK1R-/- mice in the VITI were unaffected by d-amphetamine, but premature responses were exacerbated by this psychostimulant. Omissions in the VITI were higher, overall, in the morning than the afternoon but, in the LITI, premature responses of NK1R-/- mice were higher in the afternoon than the morning. Conclusion In addition to locomotor hyperactivity, NK1R-/- mice express inattentiveness, perseveration and impulsivity in the 5-CSRTT, thereby matching core criteria for a model of ADHD. Because d-amphetamine reduced perseveration in NK1R-/- mice, this action does not require functional NK1R. However, the lack of any improvement of omissions and premature responses in NK1R-/- mice given d-amphetamine suggests that beneficial effects of this psychostimulant in other rodent models, and ADHD patients, need functional NK1R. Finally, our results reveal experimental variables (stimulus parameters, stress and time of day) that could influence translational studies

Noradrenergic ‘Tone’ Determines Dichotomous Control of Cortical Spike-Timing-Dependent Plasticity

Norepinephrine (NE) is widely distributed throughout the brain. It modulates intrinsic currents, as well as amplitude and frequency of synaptic transmission affecting the ‘signal-to-noise ratio’ of sensory responses. In the visual cortex, α1- and β-adrenergic receptors (AR) gate opposing effects on long-term plasticity of excitatory transmission. Whether and how NE recruits these plastic mechanisms is not clear. Here, we show that NE modulates glutamatergic inputs with different efficacies for α1- and β-AR. As a consequence, the priming of synapses with different NE concentrations produces dose-dependent competing effects that determine the temporal window of spike-timing dependent plasticity (STDP). While a low NE concentration leads to long-term depression (LTD) over broad positive and negative delays, a high NE concentration results in bidirectional STDP restricted to very narrow intervals. These results indicate that the local availability of NE, released during emotional arousal, determines the compound modulatory effect and the output of STDP

Search for time-dependent B0s - B0s-bar oscillations using a vertex charge dipole technique

We report a search for B0s - B0s-bar oscillations using a sample of 400,000 hadronic Z0 decays collected by the SLD experiment. The analysis takes advantage of the electron beam polarization as well as information from the hemisphere opposite that of the reconstructed B decay to tag the B production flavor. The excellent resolution provided by the pixel CCD vertex detector is exploited to cleanly reconstruct both B and cascade D decay vertices, and tag the B decay flavor from the charge difference between them. We exclude the following values of the B0s - B0s-bar oscillation frequency: Delta m_s < 4.9 ps-1 and 7.9 < Delta m_s < 10.3 ps-1 at the 95% confidence level.Comment: 18 pages, 3 figures, replaced by version accepted for publication in Phys.Rev.D; results differ slightly from first versio

A search for the decay modes B+/- to h+/- tau l

We present a search for the lepton flavor violating decay modes B+/- to h+/- tau l (h= K,pi; l= e,mu) using the BaBar data sample, which corresponds to 472 million BBbar pairs. The search uses events where one B meson is fully reconstructed in one of several hadronic final states. Using the momenta of the reconstructed B, h, and l candidates, we are able to fully determine the tau four-momentum. The resulting tau candidate mass is our main discriminant against combinatorial background. We see no evidence for B+/- to h+/- tau l decays and set a 90% confidence level upper limit on each branching fraction at the level of a few times 10^-5.Comment: 15 pages, 7 figures, submitted to Phys. Rev.