Rob Miller

Treatment of tuberculosis in HIV-infected persons in the era of highly active antiretroviral therapy

Objective To assess the risks and benefits of administering highly active antiretroviral therapy (HAART) during the treatment of tuberculosis (TB) in HIV-infected patients. Design and methods HIV-1 patients presenting to 12 HIV centres in Greater London and south-east England with culture-proven TB were identified from January 1996 to June 1999. Case-notes were reviewed retrospectively. Results Patients (n = 188) were severely immunocompromised with a median CD4 cell count at TB diagnosis of 90 × 106 cells/l (IQR: 30–180). At presentation, 85% (n = 159) were not taking antiretrovirals. A total of 45% commenced HAART during TB treatment, which was associated with significant reductions in viral load, AIDS-defining illness (ADI) [3.5 versus 24.5%; relative risk (RR) = 0.14] and mortality. Only nine of 91 (10%) patients with a CD4 count > 100 × 106 cells/l at TB diagnosis experienced a further ADI, whereas 18 of 92 (20%) patients with a CD4 count < 100 × 106 cells/l developed this complication. Adverse events (AE) occurred in 99 (54%) of 183 patients, one-third of whom changed or interrupted HIV and/or TB medication. The majority of AE occurred within the first 2 months, with peripheral neuropathy (21%), rash (17%) and gastrointestinal upset (10%) occurring most commonly. Conclusions Many physicians delay HAART in patients presenting with TB because of pill burden, drug/drug interactions and toxicity. Although the use of HAART led to significant reductions in viral load, ADI and mortality, co-infected patients commonly experienced AE leading to interruptions in TB/HIV therapy. We therefore recommend starting HAART early for patients with advanced HIV disease (CD4 < 100 × 106 cells/l) and deferring HAART until the continuation phase of TB therapy (i.e. after 2 months) for patients who are clinically stable (CD4 > 100 × 106 cells/l).

HIV-associated respiratory diseases

The lungs of individuals infected with HIV are often affected by opportunistic infections and tumours; over two-thirds of patients have at least one respiratory episode during the course of their disease. Despite the availability of effective prophylaxis, infection with the fungus Pneumocystis carinii remains a common cause of respiratory disease. Bacterial infections, which occur more frequently in HIV-infected persons than in the general population, and tuberculosis are increasing causes of morbidity and mortality. Kaposis sarcoma, the commonest HIV-associated malignancy, may affect the lungs in addition to the skin. Pulmonary involvement by non-Hodgkin lymphoma is common in those with disseminated disease.

Narratives in the Situation Calculus

A narrative is a course of real events about which we might have incomplete information. Formalisms for reasoning about action may be broadly divided into those which are narrative-based, such as the Event Calculus of Kowalski and Sergot, and those which reason on the level of hypothetical sequences of actions, in particular the Situation Calculus. This paper bridges the gap between these types of formalism by supplying a technique for linking incomplete narrative descriptions to Situation Calculus domain formulae written in the usual style using a Result function. Particular attention is given to actions with duration and overlapping actions. By illuminating the relationship between these two diierent styles of representation, the paper moves us one step closer to a full understanding of the space of all possible formalisms for reasoning about action.

A simple declarative language for describing narratives with actions

Abstract We describe a simple declarative languageEfor describing the effects of a series of action occurrences within a narrative.Eis analogous to Gelfond and Lifschitzs LanguageAand its extensions, but is based on a different ontology. The semantics ofEis based on a simple characterisation of persistence which facilitates a modular approach to extending the expressivity of the language. Domain descriptions inAcan be translated to equivalent theories inE. We show how, in the context of reasoning about actions,Es narrative-based ontology may be exploited in order to characterise and synthesise two complementary notions of explanation. According to the first notion, explanation may be partly modelled as the process of suitably extending an apparently inconsistent theory written inEso as to establish consistency, thus providing a natural method, in many cases, to account for conflicting sets of information about the domain. According to the second notion, observations made at later times can sometimes be explained in terms of what is true at earlier times. This enables domains to be given an alternative characterisation in which knowledge arising from observations is appropriately separated from other aspects of the domain. We also describe howEdomains may be implemented as Event Calculus style logic programs, which facilitate automated reasoning both backwards and forwards in time, and which behave correctly even when the knowledge entailed by the domain description is incomplete.

Human immunodeficiency virus associated thrombotic thrombocytopenic purpura – favourable outcome with plasma exchange and prompt initiation of highly active antiretroviral therapy

Thrombotic thrombocytopenic purpura (TTP) is an acute prothrombotic disorder. Human immunodeficiency virus (HIV) is an identified precipitant. This study reviewed 30 episodes of HIV‐associated TTP in 24 patients from the South‐East England Apheresis units, over the last 10 years. All patients were heterosexual Black Africans. First presentation of TTP revealed a new diagnosis of HIV in eight patients. TTP relapse occurred on six occasions (in four patients) as a result of non‐adherence to highly active antiretroviral therapy (HAART). Prompt initiation/re‐initiation of HAART in parallel with plasma exchange (PEX) ± steroid led to prompt remission. Adjunct immunomodulatory agents (e.g. Rituximab) were required in 10% of cases. Once‐daily HAART regimens are recommended, being compatible with PEX requirement, maximizing drug exposure between PEX. High viral loads (>500 000 copies/ml) require more PEX to remission. ADAMTS13 activity was reduced (<5%) as detected by collagen‐binding assay and anti‐ADAMTS13 immunoglobulin G antibodies were raised in 80%. Continued HAART‐adherence ensured a durable TTP remission with associated viral control resulting in no evidence of relapse. PEX and HAART are associated with replenishment of ADAMTS13 and viral suppression. More PEX is required in cases with higher viral loads. Continued HAART maintains remission. In a small proportion of cases, further immunomodulatory therapy may be required.

Preoperative CA 19-9 level is an important prognostic factor in patients with pancreatic adenocarcinoma treated with surgical resection and adjuvant concurrent chemoradiotherapy.

ObjectivesTo evaluate preoperative CA 19-9 level as a prognostic factor in patients with resected adenocarcinoma of the pancreas. MethodsWe retrospectively reviewed the cases of consecutive patients with pancreatic adenocarcinoma who had CA 19-9 measured preoperatively and underwent potentially curative resection at Mayo Clinic from September 1995 to January 2005. Patients who died within 30 days of resection were excluded. ResultsSearch of our database identified 226 consecutive patients who met all the inclusion criteria. Adjuvant therapy was concurrent chemoradiotherapy (CCRT) in 122 patients, CCRT followed by chemotherapy in 23 patients, chemotherapy alone in 6 patients, and none in 69 patients. Median follow-up for surviving patients was 2.1 years. Median survival in all patients was 1.6 years. Patients with a high preoperative CA 19-9 level (defined as ≥180 U/mL) had a greater chance of having pathologic T3-T4 disease (P=0.03), positive lymph nodes (P=0.01), and histologic grade 3 or 4 (P=0.02). In multivariate analysis, a high preoperative CA 19-9 level (P=0.006) and R1-R2 margin status (P=0.03) were associated with decreased survival. Overall survival was increased for patients who received adjuvant CCRT (vs. those who did not; P=0.002) and for patients with high preoperative CA 19-9 level who received adjuvant CCRT (vs. those who did not; P<0.001). ConclusionsIn patients with resected adenocarcinoma of the pancreas, high preoperative CA 19-9 level was associated with adverse pathologic features and poorer survival. Adjuvant CCRT was associated with a significant survival benefit in patients with high preoperative CA 19-9 but not in those with low CA 19-9.

SAGE: A Logical Agent-Based Environment Monitoring and Control System

We propose SAGE, an agent-based environment monitoring and control system based on computation logic. SAGE uses forward chaining deductive inference to map low level sensor data to high level events, multi-agent abductive reasoning to provide possible explanations for these events, and teleo-reactive programming to react to these explanations, e.g. to gather extra information to check abduced hypotheses. The system is embedded in a publish/subscribe architecture.

HIV associated tuberculosis.

People who are infected with HIV are at an increased risk of contracting tuberculosis. The WHO estimates that just over 20 million people are currently infected with HIV and of these 6 million are co-infected with Mycobacterium tuberculosis . Worldwide there has been a resurgence of tuberculosis, mainly in developing countries but also in the United States and Europe. Between 1987 and 1993 tuberculosis rates increased by 35.5% in London (with the increase most notable in inner London) compared with 15% in England and Wales as a whole.1 2 However, it is unclear to what extent the prevalence of HIV associated tuberculosis has increased in the capital, largely because notification of tuberculosis in the HIV infected population is unreliable and probably underestimates the problem.3 Nosocomial spread has occurred in …

Doxepin Rinse Versus Placebo in the Treatment of Acute Oral Mucositis Pain in Patients Receiving Head and Neck Radiotherapy With or Without Chemotherapy: A Phase III, Randomized, Double-Blind Trial (NCCTG-N09C6 [Alliance])

PURPOSE Painful oral mucositis (OM) is a significant toxicity during radiotherapy for head and neck cancers. The aim of this randomized, double-blind, placebo-controlled trial was to test the efficacy of doxepin hydrochloride in the reduction of radiotherapy-induced OM pain. PATIENTS AND METHODS In all, 155 patients were randomly allocated to a doxepin oral rinse or a placebo for the treatment of radiotherapy-related OM pain. Patients received a single dose of doxepin or placebo on day 1 and then crossed over to receive the opposite agent on a subsequent day. Pain questionnaires were administered at baseline and at 5, 15, 30, 60, 120, and 240 minutes. Patients were then given the option to continue doxepin. The primary end point was pain reduction as measured by the area under the curve (AUC) of the pain scale using data from day 1. RESULTS Primary end point analysis revealed that the AUC for mouth and throat pain reduction was greater for doxepin (-9.1) than for placebo (-4.7; P < .001). Crossover analysis of patients completing both phases confirmed that patients experienced greater mouth and throat pain reduction with doxepin (intrapatient changes of 4.1 for doxepin-placebo arm and -2.8 for placebo-doxepin arm; P < .001). Doxepin was associated with more stinging or burning, unpleasant taste, and greater drowsiness than the placebo rinse. More patients receiving doxepin expressed a desire to continue treatment than did patients with placebo after completion of each of the randomized phases of the study. CONCLUSION A doxepin rinse diminishes OM pain. Further studies are warranted to determine its role in the management of OM.

Stereotactic body radiotherapy in the treatment of adrenal metastases.

Objectives:To evaluate the dosimetry, clinical outcomes, and toxicity of patients treated with stereotactic body radiotherapy (SBRT) for adrenal metastases. Materials and Methods:From February 2009 to February 2011, a total of 13 patients were treated with SBRT for metastases to the adrenal glands. Median age was 71 years (range, 60.8 to 83.2). Primary sites included lung (n=6), kidney (n=2), skin (n=2), bladder (n=1), colon (n=1), and liver (n=1). Nine patients had metastases to the left adrenal gland and 4 to the right. The median prescribed total dose was 45 Gy (range, 33.75 to 60 Gy), all in 5 fractions. Results:Median follow-up for living patients was 12.3 months (range, 3.1 to 18 mo). Twelve of the 13 patients (92.3%) were evaluable for local control (LC). The crude LC rate was 100%, with no cases of local or marginal failure. Two patients had a complete response to treatment, 9 patients had a partial response, and 1 patient displayed stable disease. One-year overall survival and distant control were 62.9% and 55%, respectively. Median OS was 7.2 months (range, 2 to 18 mo). Grade 2 nausea was noted in 2 patients. Conclusions:SBRT seems to be a safe and effective measure to achieve LC for adrenal metastases.