TORPEdO: A phase III trial of intensity-modulated proton beam therapy versus intensity-modulated radiotherapy for multi-toxicity reduction in oropharyngeal cancer.

•There is a lack of prospective level I evidence for the use of PBT for most adult cancers including oropharyngeal squamous cell carcinoma (OPSCC).•TORPEdO is the UK's first PBT clinical trial and aims to determine the benefits of PBT for OPSCC.•Training and support has been provided before and during the trial to reduce variations of contouring and radiotherapy planning.•There is a strong translational component within TORPEdO. Imaging and physics data along with blood, tissue collection will inform future studies in refining patient selection for IMPT.

Clinical characteristics of primary psychotic disorders with concurrent substance abuse and substance-induced psychotic disorders: A systematic review.

BACKGROUND: Distinguishing between a primary psychotic disorder with concurrent substance abuse (PPD+SA) and a substance-induced psychotic disorder (SIPD) can be diagnostically challenging. We aimed to determine if these two diagnoses are clinically distinct, particularly in relation to psychopathology. In addition, we aimed to examine the specific clinical features of cannabis-induced psychotic disorder (CIPD) as compared to primary psychotic disorder with concurrent cannabis abuse (PPD+CA) and also to SIPD associated with any substance. METHODS: A systematic review of SIPD literature using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: Using strict inclusion criteria, a total of six studies examining SIPD were included in the review (two of which only considered psychosis induced by cannabis alone). The findings did not reveal many consistent differences in psychopathology. However, we did find that that compared to PPD+SA, individuals with SIPD have a weaker family history of psychotic disorder; a greater degree of insight; fewer positive symptoms and fewer negative symptoms; more depression (only in CIPD) and more anxiety. CONCLUSION: There remains a striking paucity of information on the psychopathology, clinical characteristics and outcome of SIPD. Our review highlights the need for further research in this area.

Presentation of life-threatening invasive nontyphoidal Salmonella disease in Malawian children: A prospective observational study.

Nontyphoidal Salmonellae commonly cause invasive disease in African children that is often fatal. The clinical diagnosis of these infections is hampered by the absence of a clear clinical syndrome. Drug resistance means that empirical antibiotic therapy is often ineffective and currently no vaccine is available. The study objective was to identify risk factors for mortality among children presenting to hospital with invasive Salmonella disease in Africa. We conducted a prospective study enrolling consecutive children with microbiologically-confirmed invasive Salmonella disease admitted to Queen Elizabeth Central Hospital, Blantyre, in 2006. Data on clinical presentation, co-morbidities and outcome were used to identify children at risk of inpatient mortality through logistic-regression modeling. Over one calendar year, 263 consecutive children presented with invasive Salmonella disease. Median age was 16 months (range 0-15 years) and 52/256 children (20%; 95%CI 15-25%) died. Nontyphoidal serovars caused 248/263 (94%) of cases. 211/259 (81%) of isolates were multi-drug resistant. 251/263 children presented with bacteremia, 6 with meningitis and 6 with both. Respiratory symptoms were present in 184/240 (77%; 95%CI 71-82%), 123/240 (51%; 95%CI 45-58%) had gastrointestinal symptoms and 101/240 (42%; 95%CI 36-49%) had an overlapping clinical syndrome. Presentation at <7 months (OR 10.0; 95%CI 2.8-35.1), dyspnea (OR 4.2; 95%CI 1.5-12.0) and HIV infection (OR 3.3; 95%CI 1.1-10.2) were independent risk factors for inpatient mortality. Invasive Salmonella disease in Malawi is characterized by high mortality and prevalence of multi-drug resistant isolates, along with non-specific presentation. Young infants, children with dyspnea and HIV-infected children bear a disproportionate burden of the Salmonella-associated mortality in Malawi. Strategies to improve prevention, diagnosis and management of invasive Salmonella disease should be targeted at these children.

Periodicity in the autocorrelation function as a mechanism for regularly occurring zero crossings or extreme values of a Gaussian process.

The problem of zero crossings is of great historical prevalence and promises extensive application. The challenge is to establish precisely how the autocorrelation function or power spectrum of a one-dimensional continuous random process determines the density function of the intervals between the zero crossings of that process. This paper investigates the case where periodicities are incorporated into the autocorrelation function of a smooth process. Numerical simulations, and statistics about the number of crossings in a fixed interval, reveal that in this case the zero crossings segue between a random and deterministic point process depending on the relative time scales of the periodic and nonperiodic components of the autocorrelation function. By considering the Laplace transform of the density function, we show that incorporating correlation between successive intervals is essential to obtaining accurate results for the interval variance. The same method enables prediction of the density function tail in some regions, and we suggest approaches for extending this to cover all regions. In an ever-more complex world, the potential applications for this scale of regularity in a random process are far reaching and powerful.

Bacteraemia in Malawian neonates and young infants 2002-2007: a retrospective audit.

OBJECTIVES: To assess the causes of bacteraemia in young infants and susceptibility to first-line antibiotics (benzylpenicillin plus gentamicin) at the Queen Elizabeth Central Hospital (QECH), Malawi during 2002-2007. DESIGN: Retrospective analysis of demographic and microbiological data using laboratory records. SETTING: QECH is Malawi's largest hospital with 7000 neonates admitted annually, 9% for septicaemia. PATIENTS: All infants aged 60 days or less admitted to QECH that had a blood culture taken over the 6-year period. MAIN OUTCOME MEASURES: 6754 blood cultures were taken. 3323 organisms were isolated: one-third were pathogens, two-thirds contaminants. Gram-positive organisms (53%) were more common than gram-negatives (47%). Four organisms made up half of all pathogens: Staphylococcus aureus (15.3%), group B streptococci (13.5%), non-typhoidal salmonellae (12.6%) and Escherichia coli (10.5%). Apart from non-typhoidal salmonellae and Streptococcus pneumoniae, most organisms were more common in the first week of life than later. Overall, 28% of isolates during 2002-2007 were resistant to first-line antibiotic, higher than observed during 1996-2001 (22%). Penicillin susceptibility fluctuated while gram-negative resistance to gentamicin increased from 17% to 27% over the study period. CONCLUSIONS: In the QECH, pathogens causing young infant sepsis are an unusual mix of organisms seen in both developed and developing countries. Resistance to first-line antibiotics is higher than observed in most studies. Ongoing monitoring is needed and clinical outcome data would aid interpretation of findings. A high proportion of blood cultures were contaminated with skin flora-improved training and supervision of phlebotomists are needed to improve the utility of taking blood cultures.

Consistency, transitivity and inter-relationships between measures of choice in environmental preference tests with chickens.

Choice experiments are a widespread method of assessing the welfare requirements of domestic animals but prior predictions about what animals should choose to maximise their welfare are not possible. It is therefore important to analyse the data from sets of choice tests to establish whether intra-set and inter-set consistency in choice occurs. Strong inter-set consistency (transitivity) would provide support for the assumption that animals are maximising a complex utility (welfare) that may map onto their subjective state. We housed 56 hens Gallus gallus sequentially in three environments, experienced as three sets (A vs B; B vs C; A vs C), over a 40-week period. At the end of each set, each chicken made six choices between the items in that set, using T-maze testing procedures. The chickens showed significantly greater within-set consistency than expected by chance (p<0.001 for all sets). Although different chickens exhibited different environmental preferences, we also found that a high within-set consistency was associated with faster decision-making (p<0.001). When the three sets of choice trials for each hen were compared there was some evidence that the birds made more transitive choices (indicating consistent choices between sets) than expected by chance.

Epidemics of invasive Salmonella enterica serovar enteritidis and S. enterica Serovar typhimurium infection associated with multidrug resistance among adults and children in Malawi.

BACKGROUND: Nontyphoidal salmonellae (NTS) have become the most common cause of bacteremia in tropical Africa, particularly among susceptible children and HIV-infected adults. METHODS: We describe 4956 episodes of NTS bacteremia (2439 episodes in adults and 2517 episodes in children) that occurred in Blantyre, Malawi, during the 7-year period 1998-2004. RESULTS: A total of 75% of the cases of NTS bacteremia were due to Salmonella enterica serovar Typhimurium, and 21% were due to S. enterica serovar Enteritidis. Epidemic increases in the incidence of NTS bacteremia were seen sequentially, occurring first among cases caused by S. Enteritidis and then among cases caused by S. Typhimurium. Increased incidence of bacteremia was temporally associated with the acquisition of multidrug resistance to ampicillin, cotrimoxazole, and chloramphenicol by each serovar and occurred while the incidence of infection due to other common bloodstream pathogens remained constant. These epidemics were observed among adults and children. A seasonal pattern was also seen, with increased incidence during and after the rainy season. The median age of the patients was 32 years among adults and 22 months among children. Acquisition of multidrug-resistant infection was not associated with an increased case-fatality rate among children (22%), and the case-fatality rate among adults showed a significant trend toward decreasing (from 29% to 20%). CONCLUSIONS: These data have important implications for the treatment of severe febrile illness in adults and children in tropical Africa. Further understanding of the molecular basis of these epidemics of multidrug-resistant NTS infection, including ongoing whole-genome sequencing of multidrug-resistant isolates, will yield important tools for the study of NTS pathogenesis, transmission, epidemiology, and prevention.

Bacteremia in Malawian children with severe malaria: prevalence, etiology, HIV coinfection, and outcome.

BACKGROUND: Previous prospective studies of bacteremia in African children with severe malaria have mainly included children with cerebral malaria, and no study has examined the impact of human immunodeficiency virus (HIV) infection. We examined the prevalence and etiology of bacteremia and the impact of HIV infection on bacteremia in Malawian children with severe malaria, as well as the impact of bacteremia and HIV infection on outcome. METHODS: From 1996 until 2005, blood for culture was obtained on admission from all children admitted with severe malaria during the rainy season to the Paediatric Research Ward at the Queen Elizabeth Central Hospital in Blantyre, Malawi. HIV testing was performed prospectively from 2001 to 2005 and retrospectively for those admitted from 1996 to 2000. Multivariate regression analysis examined independent risk factors for bacteremia and death. RESULTS: Sixty-four (4.6%) of 1388 children with severe malaria had bacteremia; nontyphoidal Salmonellae (NTS) accounted for 58% of all bacteremias. The prevalence of any bacteremia and of NTS bacteremia was highest in children with severe malarial anemia (11.7% and 7.6%), compared with the prevalence in children with cerebral malaria and severe anemia (4.7% and 3.8%) and in those with cerebral malaria alone (3.0% and 0.9%). HIV infection status was determined in 1119 patients. HIV prevalence was 16% (and was highest in those with severe malaria anemia, at 20.4%), but HIV infection was not significantly associated with bacteremia. Neither bacteremia nor HIV infection was associated with death. CONCLUSIONS: Antibiotics are not routinely indicated for children with severe malaria in this region, in which HIV is endemic. However, antibiotic therapy should be used to treat NTS infection if bacteremia is suspected in children with severe malarial anemia.

Identification and characterization of ceftriaxone resistance and extended-spectrum beta-lactamases in Malawian bacteraemic Enterobacteriaceae.

OBJECTIVES: To enumerate and characterize extended-spectrum beta-lactamases (ESBLs) amongst ceftriaxone-resistant coliforms in Blantyre, Malawi, where third-generation cephalosporin use is currently highly restricted. METHODS: Over the period April 2004-March 2005 all ceftriaxone-resistant isolates from blood cultures were examined for the presence of ESBLs. Isoelectric focusing was performed on enzyme extracts. PCR and DNA sequencing of amplicons were used to identify the underlying genetic determinants responsible for the ESBL phenotypes. Transferability of the ESBL phenotypes was tested by conjugation to a susceptible Escherichia coli J53. RESULTS: Enterobacteriaceae were isolated from 1191 blood cultures, of which 19 (1.6%) were ceftriaxone resistant. Ten isolates (0.7% of all isolates) demonstrated an ESBL phenotype but only eight were characterized as three isolates were from the same patient. Genotypes SHV-11 (n = 1), SHV-12 (n = 3), SHV-27 (n = 1), TEM-63 (n = 2) and CTX-M-15 (n = 1) were detected. Plasmid transfer of the ESBL resistance phenotype was successful for all the isolates. CONCLUSIONS: In a clinical setting of minimal cephalosporin usage there is already a diversity of ESBL genotypes. Increased use of cephalosporins in this setting is likely to result in a rapid expansion of ESBLs and their prevalence will need to be carefully monitored.

A community-based study of the incidence of trimethoprim-sulfamethoxazole-preventable infections in Malawian adults living with HIV.

The benefits of trimethoprim-sulfamethoxazole (TS) prophylaxis reported for persons living with HIV in Cote d'Ivoire are difficult to extrapolate to sub-Saharan African countries where bacterial resistance to TS is higher and cross-resistance between TS and sulfadoxine-pyrimethamine (SP) may impair SP efficacy for malaria treatment. We conducted a community-based cohort study to measure the incidence of potentially TS-preventable illnesses in Blantyre, Malawi. We found a high incidence of malaria, invasive bacterial infections, and probable bacterial pneumonias but low rates of Pneumocystis jiroveci pneumonia, isosporiasis, and Toxoplasma encephalitis. Most bacterial isolates were resistant to TS but sensitive to azithromycin, a possible alternative to TS. Clinical trials are needed to determine the role of TS or alternative regimens for prophylaxis against secondary infections among people living with HIV in sub-Saharan Africa. These should also assess benefit in patients receiving antiretroviral therapy.

HIV infected adults do not have an excess of colonising bacteria in their large airways.

BACKGROUND: HIV infected adults have increased susceptibility to bacterial pneumonia but the underlying immune defect is poorly understood. We tested the hypothesis that HIV infection might be associated with increased bacterial colonisation of distal airways by nasal flora, which would then predispose patients to bacterial pneumonia. METHODS: Healthy volunteer adults with normal chest radiographs were recruited. Bronchoscopy was carried out and uncontaminated mucosal samples were collected from proximal and distal sites in the large airways using a protected specimen brush. Samples were cultured to detect typical respiratory tract colonising organisms, and the proportion of samples found to contain colonising bacteria compared between HIV infected and uninfected subjects using non-parametric tests. RESULTS: Forty-nine subjects were studied of whom 27 were HIV infected. Colonising bacteria were identified in the nasopharynx of all subjects including Streptococcus pneumoniae in 6/49 subjects (5 HIV uninfected). Colonising bacteria were found in the distal airway of 6 subjects (3/27 HIV infected vs 3/22 HIV uninfected; chi2 = 0.07, p = 0.8). Streptococcus pneumoniae was identified in the trachea of all subjects with nasal colonisation but in the distal airway of only 1 subject. CONCLUSIONS: There was no evidence to support a hypothesis of increased airway bacterial colonisation in healthy HIV infected subjects.