Watch and wait for Rectal Cancer: A 9 year Experience.

Background: Neoadjuvant long course chemoradiotherapy has become the standard treatment for locally advanced rectal cancer. It can reduce tumour bulk, downstage, reduce the risk of local recurrence, and increase the possibility of clear resection margins. The aim of our study is to evaluate all patients over a 9 year period who underwent neoadjuvant chemoradiotherapy for rectal cancer and entered our watch and wait programme. Methods: Data were analysed from a prospective database for all patients diagnosed with rectal cancer over a 9 year period (2011-2019 inclusive). Findings: Over a 9 year period, 532 patients were treated for rectal cancer, with 180 patients receiving long course chemoradiotherapy. 61 (11%) patients entered a watch and programme as they had a complete clinical and radiological response following chemoradiotherapy. Within this programme, 40 patients (65%) remain disease free over the follow-up period (mean 38 months); 12 (20%) patients had regrowth and proceeded to surgery; and 9 (15%) proceeded to palliation due to being unfit for surgery or had distant metastatic disease. Overall (all cause) mortality was 18% during follow-up period in the watch and wait group. Conclusions: Neoadjuvant long course chemoradiotherapy is the standard treatment for locally advanced rectal cancer. 34% of our patient group who received long course chemoradiotherapy entered a watch and wait programme with the majority avoiding major rectal surgery.

Group B Streptococcus (GBS) colonization is dynamic over time, whilst GBS capsular polysaccharides-specific antibody remains stable.

Group B Streptococcus (GBS) is a leading cause of adverse pregnancy outcomes due to invasive infection. This study investigated longitudinal variation in GBS rectovaginal colonization, serum and vaginal GBS capsular polysaccharide (CPS)-specific antibody levels. Non-pregnant women were recruited in the UK and were sampled every 2 weeks over a 12-week period. GBS isolates were taken from recto-vaginal swabs and serotyped by polymerase chain reaction. Serum and vaginal immunoglobulin G (IgG) and nasal immunoglobulin A (IgA) specific to CPS were measured by Luminex, and total IgG/A by ELISA. Seventy women were enrolled, of median age 26. Out of the 66 participants who completed at least three visits: 14/47 (29.8%) women that were GBS negative at screening became positive in follow-up visits and 16/19 (84.2%) women who were GBS positive at screening became negative. There was 50% probability of becoming negative 36 days after the first positive swab. The rate of detectable GBS carriage fluctuated over time, although serum, vaginal, and nasal CPS-specific antibody levels remained constant. Levels of CPS-specific antibodies were higher in the serum of individuals colonized with GBS than in non-colonized, but similar in the vaginal and nasal mucosa. We found correlations between antibody levels in serum and the vaginal and nasal mucosa. Our study demonstrates the feasibility of elution methods to retrieve vaginal and nasal antibodies, and the optimization of immunoassays to measure GBS-CPS-specific antibodies. The difference between the dynamics of colonization and antibody response is interesting and further investigation is required for vaccine development.

Imaging biomarkers of adiposity and sarcopenia as potential predictors for overall survival among patients with endometrial cancer treated with bevacizumab.

OBJECTIVE: To examine associations of body mass index (BMI), subcutaneous fat area (SFA) and density (SFD), visceral fat area (VFA) and density (VFD) and total psoas area (TPA) to outcomes among patients receiving chemotherapy with or without bevacizumab for advanced or recurrent endometrial cancer (EC). METHODS: This was a multi-institutional, retrospective study of patients with EC treated with and without bevacizumab as part of front-line, platinum based chemotherapy. Demographics and clinical characteristics were collected. SFA, VFA, SFD, VFD, and TPA were determined from pre-treatment CT scans using a deep learning algorithm. Data was compared with overall survival (OS) and progression free survival (PFS). RESULTS: Seventy-eight patients were analyzed. The majority were Caucasian (87.2%) with a mean BMI of 34.7 kg/m2. PFS and OS did not differ between patients with BMI, SFA, VFA, SFD, VFD, or TPA ≥ the 50th percentile compared to <50th percentile (p = 0.91, 0.45, 0.71, 0.74, 0.60, and 0.74 respectively) and (p = 0.99, 0.59, 0.14, 0.77, and 0.85 respectively). When adjusting for prognostic factors, elevated VFA trended towards shorter OS (25.1 vs 59.5 months, HR = 1.68 [0.92-3.05]).Patients receiving bevacizumab had similar OS compared to those who did not (37.6 vs 44.5 months, p = 0.409). When stratified by adiposity markers, no subset demonstrated benefit from bevacizumab. CONCLUSION: Obesity has been associated with increased levels of vascular endothelial growth factor (VEGF), the main target for bevacizumab therapy. Imaging measurements of VFA may provide prognostic information for patients with EC but no adiposity marker was predictive of improved response to bevacizumab.

Delay from symptom onset to treatment start among tuberculosis patients in England, 2012-2015.

Improving access to tuberculosis (TB) care and ensuring early diagnosis are two major aims of the WHO End TB strategy and the Collaborative TB Strategy for England. This study describes risk factors associated with diagnostic delay among TB cases in England. We conducted a retrospective cohort study of TB cases notified to the Enhanced TB Surveillance System in England between 2012 and 2015. Diagnostic delay was defined as more than 4 months between symptom onset and treatment start date. Multivariable logistic regression was used to identify demographic and clinical factors associated with diagnostic delay. Between 2012 and 2015, 22 422 TB cases were notified in England and included in the study. A third (7612) of TB cases had a diagnostic delay of more than 4 months. Being female, aged 45 years and older, residing outside of London and having extra-pulmonary TB disease were significantly associated with a diagnostic delay in the multivariable model (aOR = 1.2, 1.2, 1.2, 1.3, 1.8, respectively). This study identifies demographic and clinical factors associated with diagnostic delay, which will inform targeted interventions to improve access to care and early diagnosis among these groups, with the ultimate aim of helping reduce transmission and improve treatment outcomes for TB cases in England.

Interaction of a dengue virus NS1-derived peptide with the inhibitory receptor KIR3DL1 on natural killer cells.

Killer immunoglobulin-like receptors (KIRs) interact with human leucocyte antigen (HLA) class I ligands and play a key role in the regulation and activation of NK cells. The functional importance of KIR-HLA interactions has been demonstrated for a number of chronic viral infections, but to date only a few studies have been performed in the context of acute self-limited viral infections. During our investigation of CD8(+) T cell responses to a conserved HLA-B57-restricted epitope derived from dengue virus (DENV) non-structural protein-1 (NS1), we observed substantial binding of the tetrameric complex to non-T/non-B lymphocytes in peripheral blood mononuclear cells (PBMC) from a long-standing clinical cohort in Thailand. We confirmed binding of the NS1 tetramer to CD56(dim) NK cells, which are known to express KIRs. Using depletion studies and KIR-transfected cell lines, we demonstrated further that the NS1 tetramer bound the inhibitory receptor KIR3DL1. Phenotypical analysis of PBMC from HLA-B57(+) subjects with acute DENV infection revealed marked activation of NS1 tetramer-binding natural killer (NK) cells around the time of defervescence in subjects with severe dengue disease. Collectively, our findings indicate that subsets of NK cells are activated relatively late in the course of acute DENV illness and reveal a possible role for specific KIR-HLA interactions in the modulation of disease outcomes.

MAIT cells are licensed through granzyme exchange to kill bacterially sensitized targets.

Mucosal-associated invariant T (MAIT) cells are an innate-like T-cell population restricted by the non-polymorphic, major histocompatibility complex class I-related protein 1, MR1. MAIT cells are activated by a broad range of bacteria through detection of riboflavin metabolites bound by MR1, but their direct cytolytic capacity upon recognition of cognate target cells remains unclear. We show that resting human MAIT cells are uniquely characterized by a lack of granzyme (Gr) B and low perforin expression, key granule proteins required for efficient cytotoxic activity, but high levels of expression of GrA and GrK. Bacterial activation of MAIT cells rapidly induced GrB and perforin, licensing these cells to kill their cognate target cells. Using a novel flow cytometry-based killing assay, we show that licensed MAIT cells, but not ex vivo MAIT cells from the same donors, can efficiently kill Escherichia coli-exposed B-cell lines in an MR1- and degranulation-dependent manner. Finally, we show that MAIT cells are highly proliferative in response to antigenic and cytokine stimulation, maintaining high expression of GrB, perforin, and GrA, but reduced expression of GrK following antigenic proliferation. The tightly regulated cytolytic capacity of MAIT cells may have an important role in the control of intracellular bacterial infections, such as Mycobacterium tuberculosis.

Infant botulism due to C. butyricum type E toxin: a novel environmental association with pet terrapins.

We describe two cases of infant botulism due to Clostridium butyricum producing botulinum type E neurotoxin (BoNT/E) and a previously unreported environmental source. The infants presented at age 11 days with poor feeding and lethargy, hypotonia, dilated pupils and absent reflexes. Faecal samples were positive for C. butyricum BoNT/E. The infants recovered after treatment including botulism immune globulin intravenous (BIG-IV). C. butyricum BoNT/E was isolated from water from tanks housing pet 'yellow-bellied' terrapins (Trachemys scripta scripta): in case A the terrapins were in the infant's home; in case B a relative fed the terrapin prior to holding and feeding the infant when both visited another relative. C. butyricum isolates from the infants and the respective terrapin tank waters were indistinguishable by molecular typing. Review of a case of C. butyricum BoNT/E botulism in the UK found that there was a pet terrapin where the infant was living. It is concluded that the C. butyricum-producing BoNT type E in these cases of infant botulism most likely originated from pet terrapins. These findings reinforce public health advice that reptiles, including terrapins, are not suitable pets for children aged <5 years, and highlight the importance of hand washing after handling these pets.

Standardisation and quality control of ultrasound measurements taken in the INTERGROWTH-21st Project.

Meticulous standardisation and ongoing monitoring of adherence to measurement protocols during data collection are essential to ensure consistency and to minimise systematic error in multicentre studies. Strict ultrasound fetal biometric measurement protocols are used in the INTERGROWTH-21(st) Project so that data of the highest quality from different centres can be compared and potentially pooled. A central Ultrasound Quality Unit (USQU) has been set up to oversee this process. After initial training and standardisation, the USQU monitors the performance of all ultrasonographers involved in the project by continuously assessing the quality of the images and the consistency of the measurements produced. Ultrasonographers are identified when they exceed preset maximum allowable differences. Corrective action is then taken in the form of retraining or simply advice regarding changes in practice. This paper describes the procedures used, which can form a model for research settings involving ultrasound measurements.

Managing data for the international, multicentre INTERGROWTH-21st Project.

The INTERGROWTH-21(st) Project data management was structured incorporating both a centralised and decentralised system for the eight study centres, which all used the same database and standardised data collection instruments, manuals and processes. Each centre was responsible for the entry and validation of their country-specific data, which were entered onto a centralised system maintained by the Data Coordinating Unit in Oxford. A comprehensive data management system was designed to handle the very large volumes of data. It contained internal validations to prevent incorrect and inconsistent values being captured, and allowed online data entry by local Data Management Units, as well as real-time management of recruitment and data collection by the Data Coordinating Unit in Oxford. To maintain data integrity, only the Data Coordinating Unit in Oxford had access to all the eight centres' data, which were continually monitored. All queries identified were raised with the relevant local data manager for verification and correction, if necessary. The system automatically logged an audit trail of all updates to the database with the date and name of the person who made the changes. These rigorous processes ensured that the data collected in the INTERGROWTH-21(st) Project were of exceptionally high quality.

Investigation and management of an outbreak of Salmonella Typhimurium DT8 associated with duck eggs, Ireland 2009 to 2011.

Salmonella Typhimurium DT8 was a very rare cause of human illness in Ireland between 2000 and 2008, with only four human isolates from three patients being identified. Over a 19-month period between August 2009 and February 2011, 34 confirmed cases and one probable case of Salmonella Typhimurium DT8 were detected, all of which had an MLVA pattern 2-10-NA-12-212 or a closely related pattern. The epidemiological investigations strongly supported a linkbetween illness and exposure to duck eggs. Moreover, S. Typhimurium with an MLVA pattern indistinguishable (or closely related) to the isolates from human cases, was identified in 22 commercial and backyard duck flocks, twelve of which were linked with known human cases. A range of control measures were taken at farm level, and advice was provided to consumers on the hygienic handling and cooking of duck eggs. Although no definitive link was established with a concurrent duck egg-related outbreak of S. Typhimurium DT8 in the United Kingdom, it seems likely that the two events were related. It may be appropriate for other countries with a tradition of consuming duck eggs to consider the need for measures to reduce the risk of similar outbreaks.

Shifting curves? Trends in thinness and obesity among Australian youth, 1985 to 2010.

OBJECTIVE: To describe 25-year trends in the prevalence of ≤Grade 2 thinness and obesity among Australian children by sex, age and socioeconomic (SES) background. METHODS: Cross-sectional surveys of New South Wales school-aged children aged 6.0-16.9 years conducted in 1985-1997-2004-2010 (n = 19 434). Height/weight were measured, and thinness and obesity were defined by international standards. SES was derived from children's residential postcode using the Australian Bureau of Statistics' Index of Relative Socioeconomic Disadvantage, most proximal to the survey year. RESULTS: Since 1985, the prevalence of thinness has not varied by survey year. Age was not associated with thinness; however, thinness was lower among middle SES boys, compared with high SES (OR: 0.45, 95%CI: 0.21, 0.97). The prevalence of obesity trebled between 1985 and 1997 (1.7% vs. 5.1% P = 0.000); however, since 1997, obesity prevalence has not significantly changed. Since 1997, obesity was higher among younger compared with older girls (OR: 2.11, 95%CI: 1.48, 3.00) and SES was inversely associated with obesity in boys (OR: 2.05, 95%CI: 1.44, 2.92) and girls (OR: 1.86, 95%CI: 1.27, 2.74). CONCLUSIONS: The apparent plateau in child obesity is a welcome finding; however, the SES gradients are of concern. If the obesity stabilization is associated with the impact of multiple lifestyle behavioural interventions, the findings suggest obesity programmes have done 'no harm', but potentially the dose/delivery of interventions has not been sufficient or appropriate to reduce child obesity levels.

Moxifloxacin and pyrazinamide susceptibility testing in a complex case of multidrug-resistant tuberculosis.

Multidrug-resistant tuberculosis (MDR-TB) is a public health problem of global concern. It is critical that drug susceptibility testing (DST) methods accurately predict clinical response. We present a patient with a challenging case of MDR-TB with additional resistance to quinolones and pyrazinamide. Treatment with a regimen including high-dosage moxifloxacin, based on additional genotypic and phenotypic DST, produced excellent results. This case highlights the possibility of treatment with high-dose fluoroquinolones despite apparent bacterial resistance to these agents. Improved DST methods are necessary for both agents. Development of genotypic approaches may offer a susceptibility profile rapidly, enabling early introduction of individualised treatments.

Barriers to targeted HIV testing on an acute admissions unit: evaluation of the UK guideline.

BACKGROUND: One-quarter of people living with human immunodeficiency virus (HIV) in the UK are unaware of their infection, leading to late presentation with consequent increased morbidity and mortality, as well as ongoing transmission of infection. Recent UK guidelines advise HIV testing of patients with 'indicator diseases' in secondary care. There are limited seroprevalence data to support this recommendation, and acute medical settings present operational difficulties that may limit its feasibility. METHODS: We conducted an audit of HIV testing rates over a 3-month period in an inner London acute admissions unit. RESULTS: Lower respiratory tract infection and fever were the most frequent indicator diseases. A total of 14% were known to be HIV positive on admission, indicating a high prevalence of HIV infection among patients presenting with indicator diseases. Of the remaining 56 patients, 29% were tested for HIV infection, with one new positive diagnosis. CONCLUSION: Longer hospital admission and infectious disease consult were associated with testing. Introduction of an HIV testing protocol based on the UK recommendations had no impact on testing rates. Given the high prevalence of HIV infection in these acute hospital settings, more intensive strategies are needed to facilitate testing.

Ability of SPI2 mutant of S. typhi to effectively induce antibody responses to the mucosal antigen enterotoxigenic E. coli heat labile toxin B subunit after oral delivery to humans.

We have evaluated an oral vaccine based on an Salmonella enteric serovar typhi (S. typhi) Ty2 derivative TSB7 harboring deletion mutations in ssaV (SPI-2) and aroC together with a chromosomally integrated copy of eltB encoding the B subunit of enterotoxigenic Escherichia coli heat labile toxin (LT-B) in volunteers. Two oral doses of 10(8) or 10(9)CFU were administered to two groups of volunteers and both doses were well tolerated, with no vaccinemia, and only transient stool shedding. Immune responses to LT-B and S. typhi lipopolysaccharide were demonstrated in 67 and 97% of subjects, respectively, without evidence of anti-carrier immunity preventing boosting of LT-B responses in many cases. Further development of this salmonella-based (spi-VEC) system for oral delivery of heterologous antigens appears warranted.

Paediatric preputial pathology: are we circumcising enough?

INTRODUCTION: Preputial problems are a common reason for referral to the paediatric surgical out-patient department. Many boys referred do not need surgical intervention. One indication for intervention is balanitis xerotica obliterans (BXO), a potentially serious condition previously considered rare in childhood. PATIENTS AND METHODS: Consecutive boys referred to a paediatric general surgical out-patient department with problems relating to their prepuce during a period of 4 years were included. The out-patient diagnosis and management was recorded. All foreskins excised were sent for histological analysis. RESULTS: A total of 422 boys were referred, median age 6 years 2 months (range, 3 months to 16 years). Over half the boys referred simply required re-assurance that all was normal with their penis. However, 186 boys (44.1%) were listed for surgical procedures - 148 circumcision, 33 preputial adhesiolysis, and 5 frenuloplasty. There were histological abnormalities in 110 specimens (84.8%); chronic inflammation (n = 69; 46.6%), BXO (n = 51; 34.5%), and fibrosis (n = 4; 2.7%). Nineteen (12.8%) specimens were reported as histologically normal. The overall prevalence of BXO in the boys referred was 12.1%. CONCLUSIONS: In this series, the percentage of boys circumcised and the prevalence of BXO were both higher than in other published series. BXO may be more common and present at a younger age than previously thought.

Coamplification of Leucocytozoon by PCR diagnostic tests for avian malaria: a cautionary note.

A number of PCR assays have now been described for detecting species of the avian malaria parasites Plasmodium and Haemoproteus from blood samples. The published protocols amplify both genera simultaneously, owing to the high degree of sequence similarity between them in target genes. However, the potential for coamplification in these assays of a third, closely related hematozoan parasite, Leucocytozoon spp. has been largely overlooked. In this paper, we highlight the importance of this issue, showing that coamplification of Leucocytozoon spp. occurs in several of the protocols designed to amplify avian malaria parasites. This leads not only to scoring of false positives but, in cases of mixed Leucocytozoon/malaria infections, may also lead to scoring of false negatives. We, therefore, advocate the use of a post-PCR diagnostic step, such as RFLP analysis or sequencing, to assess the contribution of Leucocytozoon spp. to overall prevalence.

Interactions between Schistosoma intercalatum (Zaire strain) and S. mansoni.

Schistosoma mansoni and S. intercalatum, two schistosomes from different evolutionary lineages, are parasitic in humans and therefore able to co-infect the same host where they occur sympatrically in Africa. Previous studies of mating interactions between these species in mice, using the Lower Guinea strain of S. intercalatum, have demonstrated the competitive dominance of S. mansoni over S. intercalatum in terms of pairing ability, which is potentially an important mechanism restricting the distribution of S. intercalatum in Africa. The study presented here examines the mating interactions in mice between S. mansoni and the Zaire (Democratic Republic of Congo) strain of S. intercalatum, which differs from the Lower Guinea strain in many biological characteristics. Analysis of the data showed a preponderance of intraspecific pairs over interspecific, demonstrating a specific mate preference system for both species. Mating competition between these species and the ability of males of both species to effect a change of mate by pulling paired females away from their partners was indicated. Comparisons are made between the competitive mating abilities of both strains of S. intercalatum relative to those of S. mansoni, with the data suggesting that S. mansoni is competitively dominant to S. intercalatum (Zaire) in sequential infections but to a lesser extent than for S. intercalatum (Lower Guinea). Additional factors which may contribute to the confinement of S. intercalatum (Zaire) to the Democratic Republic of Congo are discussed.

Competitive mating interactions between Schistosoma haematobium and S. intercalatum (Lower Guinea strain).

Schistosoma haematobium and S. intercalatum belong to the S. haematobium group of schistosomes and can hybridize in nature where they are sympatric. They are therefore able to co-infect the same human host. Hybridization and competitive mating interactions with S. haematobium have been implicated in restricting the distribution of S. intercalatum in Africa and in the remarkably rapid replacement of S. intercalatum by S. haematobium at Loum, Cameroon. Previous studies have demonstrated the greater pairing ability of S. haematobium over S. intercalatum in hamsters infected with both species simultaneously or infected first with S. intercalatum (Lower Guinea strain) and later with S. haematobium. The present study demonstrates the greater pairing ability of S. haematobiumover S. intercalatum in hamsters infected first with S. intercalatum (Lower Guinea) and later with S. haematobium, and indicates that S. intercalatumis unlikely to spread to areas where S. haematobium is already established.