Added value of the measles-rubella supplementary immunization activity in reaching unvaccinated and under-vaccinated children, a cross-sectional study in five Indian districts, 2018-20.

INTRODUCTION: Supplementary immunization activities (SIAs) aim to interrupt measles transmission by reaching susceptible children, including children who have not received the recommended two routine doses of MCV before the SIA. However, both strategies may miss the same children if vaccine doses are highly correlated. How well SIAs reach children missed by routine immunization is a key metric in assessing the added value of SIAs. METHODS: Children aged 9 months to younger than 5 years were enrolled in cross-sectional household serosurveys conducted in five districts in India following the 2017-2019 measles-rubella (MR) SIA. History of measles containing vaccine (MCV) through routine services or SIA was obtained from documents and verbal recall. Receipt of a first or second MCV dose during the SIA was categorized as "added value" of the SIA in reaching un- and under-vaccinated children. RESULTS: A total of 1,675 children were enrolled in these post-SIA surveys. The percentage of children receiving a 1st or 2nd dose through the SIA ranged from 12.8% in Thiruvananthapuram District to 48.6% in Dibrugarh District. Although the number of zero-dose children prior to the SIA was small in most sites, the proportion reached by the SIA ranged from 45.8% in Thiruvananthapuram District to 94.9% in Dibrugarh District. Fewer than 7% of children remained measles zero-dose after the MR SIA (range: 1.1-6.4%) compared to up to 28% before the SIA (range: 7.3-28.1%). DISCUSSION: We demonstrated the MR SIA provided considerable added value in terms of measles vaccination coverage, although there was variability across districts due to differences in routine and SIA coverage, and which children were reached by the SIA. Metrics evaluating the added value of an SIA can help to inform the design of vaccination strategies to better reach zero-dose or undervaccinated children.

Using models to shape measles control and elimination strategies in low- and middle-income countries: A review of recent applications.

After many decades of vaccination, measles epidemiology varies greatly between and within countries. National immunization programs are therefore encouraged to conduct regular situation analyses and to leverage models to adapt interventions to local needs. Here, we review applications of models to develop locally tailored interventions to support control and elimination efforts. In general, statistical and semi-mechanistic transmission models can be used to synthesize information from vaccination coverage, measles incidence, demographic, and/or serological data, offering a means to estimate the spatial and age-specific distribution of measles susceptibility. These estimates complete the picture provided by vaccination coverage alone, by accounting for natural immunity. Dynamic transmission models can then be used to evaluate the relative impact of candidate interventions for measles control and elimination and the expected future epidemiology. In most countries, models predict substantial numbers of susceptible individuals outside the age range of routine vaccination, which affects outbreak risk and necessitates additional intervention to achieve elimination. More effective use of models to inform both vaccination program planning and evaluation requires the development of training to enhance broader understanding of models and where feasible, building capacity for modelling in-country, pipelines for rapid evaluation of model predictions using surveillance data, and clear protocols for incorporating model results into decision-making.

Colorectal cancer in ulcerative colitis: a cohort study of primary referrals from three centres.

A retrospective cohort of 823 patients with ulcerative colitis who resided at the time of diagnosis in one of three defined geographical areas (West Midlands region, Oxford region, England and Stockholm County, Sweden) was assembled. The patients were first seen at named hospitals in these areas and the diagnosis of ulcerative colitis established within five years of onset of symptoms between 1945-1965. All patients were 15 years of age or more at onset of disease and were followed for a minimum of 17 years and a maximum of 38 years. Ninety seven per cent completeness of follow up was achieved. Examining the colorectal cancer risk in the series relative to the risk in the general population by standardised morbidity ratios, there was an eight fold increased risk of cancer in the series as a whole. Dividing the series by extent of colitis, extensive colitis patients showed a 19 fold increase in risk. A four fold increased risk was shown in the remainder of the series (left sided colitis, proctitis and extent unknown). Life table analyses in extensive colitis gave cumulative risks of 7.2% (CI 3.6-10.8) at 20 years from onset of disease and 16.5% (CI 9.0-24.0) at 30 years from onset. No significant effect of age at onset, sex or referral centre could be detected. Examination of the data by interval from onset to cancer and by actual age at development of cancer suggests that patients who develop colorectal cancer will do so in a distribution around 50 years of age independent of duration of disease in adult onset ulcerative colitis (greater than 15 years at onset of disease). An inverse relationship was shown between age at onset of disease and interval from onset of disease to cancer. Further age specific rates for cancer increased up to 50 years and decreased thereafter. These results suggest that extensive colitis patients have a genetic predisposition to colorectal cancer and that longstanding inflammation is not of primary importance in the initiation/promotion of cancer in this disease.

Evolution of olsalazine.

Sulphasalazine was first produced nearly 50 years ago through the inspiration of a Swedish doctor, Dr Nanna Svartz. Later, in controlled trials, this compound was shown to reduce substantially the frequency of recurrent attacks of ulcerative colitis when used as long-term maintenance therapy. Studies into the metabolism of sulphasalazine have shown that, when taken orally, most of the ingested dose reaches the colon intact, and within the colonic lumen, bacteria split sulphasalazine into two breakdown products, sulphapyridine and 5-ASA. 5-ASA was shown to be the active therapeutic moiety while sulphapyridine served simply as a carrier. Olsalazine was developed to retain the property of sulphasalazine of reaching the colon intact, but also to liberate two molecules of 5-ASA with no residual carrier.

Water and electrolyte balance in subjects with a permanent ileostomy.

Water and electrolyte balance has been studied in 39 patients with a permanent ileostomy, who had had a proctocolectomy for ulcerative colitis. The findings have been compared with those in 39 healthy subjects who were matched for age and sex. The ileostomists were found to lose excessive quantities of water and sodium in the ileostomy effluent compared with the corresponding losses in normal faeces. The mean plasma total protein and albumin concentrations were increased in the ileostomists suggesting a state of chronic dehydration. The daily urinary output of sodium was low and the output of potassium was high. The urinary pH was low. The ileostomists had raised mean concentration of aldosterone in the plasma (p less than 0.001) and it is suggested that this is responsible for the body's partial compensation for the depletion of sodium and water, including the so-called ileostomy adaptation.

Tissue and bacterial splitting of sulphasalazine.

1. The cleavage of sulphasalazine at the azo bond by bacterial suspensions and tissue homogenates has been studied in vitro. 2. For maximum activity the azo reductase system requires anaerobic conditions and the presence of cofactors, namely NADPH and FAD. In this respect, sulphasalazine resembles other azo dyes. 3. Under optimum conditions all the species of bacteria tested were capable of splitting sulphasalazine and there were no major differences in the degree of activity shown by different species. The enzyme system is located within the bacterial cell and does not leak out of it. 4. All the tissues tested, both human and rat, showed azo reductase activity. The liver showed a much higher activity than the other tissues.

Split ileostomy and ileocolostomy for Crohn's disease of the colon and ulcerative colitis: a 20 year survey.

The clinical course of 140 patients who have had a split ileostomy for ulcerative colitis or colonic Crohn's disease over a 20 year period is reported. In 37 patients with ulcerative colitis there was no sustained improvement. In the 102 patients with Crohn's disease there was an immediate clinical improvement in 95, which was sustained in 65. Thirty patients have subsequently required a proctocolectomy for persistent inflammation, and 28 are still defunctioned. Bowel continuity was restored after 61 split ileostomies and in 44 patients intestinal continuity remains intact at the present time (mean follow up since closure = 62.5 months, range 0-231 months). It is concluded that a split ileostomy is a safe conservative operation producing at least temporary improvement in severely ill and malnourished patients with Crohn's colitis, and that if a subsequent resection becomes necessary it may be less extensive than was thought applicable at the initial operation. In 27 patients a resection has not been required.

Calcium metabolism in subjects living with a permanent ileostomy.

Several indices of calcium metabolism have been studied in 39 subjects living with a permanent ileostomy after proctocolectomy for ulcerative colitis, and in a control group of 39 healthy volunteers, matched for age and sex. No significant differences were found in plasma levels of calcium, phosphate, magnesium, parathyroid hormone, calcitonin and 25-hydroxy-vitamin D nor in the urinary excretion of calcium and phosphate, but the alkaline phosphatase was raised in the ileostomists. The bone density of the ileostomists was rather low, but the difference from the control subjects was not statistically significant. The absorption of calcium was measured by means of a total body counter. The ileostomists retained significantly more calcium than expected. It is suggested that this may represent the correction of a state of calcium deficiency at the time of proctocolectomy, due to the effects of the colitis and its medical treatment with corticosteroids.

Distribution and metabolism in healthy volunteers of disodium azodisalicylate, a potential therapeutic agent for ulcerative colitis.

A series of experiments has been performed in healthy male volunteers to investigate the disposition of orally administered disodium azodisalicylate, a potentially useful drug for the treatment of ulcerative colitis. The drug was given by mouth in doses of up to 2 g a day for six weeks and there were no adverse effects. Serum concentrations of the intact compound were low and the serum half-time was 4-12.8 days, probably because of a combination of a low clearance rate and a high apparent volume of distribution. Less than 5% of the ingested dose was excreted unchanged in the urine. Circulating concentrations of 5-ASA and N-acetyl-5-ASA were low and 30% of the equivalent daily dose was excreted in the urine, predominantly as N-acetyl-5-ASA. In most subjects more than 30% of the equivalent daily dose of 5-ASA was recovered from the faeces, either as 5-ASA itself or as the acetylated derivative. As 5-ASA has been shown to be the active therapeutic moiety of sulphasalazine, disodium azodisalicylate appears to be suitable for therapeutic trial in ulcerative colitis.

Haematological aspects of life with an ileostomy.

The haematological aspects of life with an ileostomy have been studies in 51 patients, of whom 39 had had ulcerative colitis and 12 had Crohn's disease. The findings in these patients have been compared with those in 39 healthy volunteers who were matched for age and sex with the 39 patient who had had ulcerative colitis. There was evidence of a mild degree of iron deficiency in the patients with an ileostomy. This was partly due to a pre-existing iron deficiency resulting from their preceding illness and operation, as the abnormality was less pronounced in the patients in whom the ileostomy had been established for more than 3 years. There was some evidence of excessive iron loss and a controlled trial of ferrous fumurate showed that the iron deficiency was largely corrected by this means. Circulating levels of vitamin B12 were normal, but it is relevant that some of the Crohn's disease group were receiving parenteral supplements. The absorption of vitamin B12 wa low in the patients with Crohn's disease who had had an ileal resection of more than 17 cm. The absorption of vitamin B12 in the patients who had had ulcerative colitis was increased and possible mechanisms are discussed. All but one of the patients had normal levels of plasma folate and in all the red cell blood folate was normal, which can be taken as an indication of a good dietary intake and adequate absorption.

Urinary stones in subjects with a permanent ileostomy.

The prevalence of urinary stones in a group of subjects living with a permanent ileostomy has been determined by intravenous urography. Thirty-nine of the ileostomists had previously suffered from ulcerative colitis, while the remaining 12 suffered from Crohn's disease. Four of the ileostomists who had had ulcerative colitis had urinary stones (10.3 per cent). These four subjects were all male, so that among the 23 male ileostomists who had had ulcerative colitis 17.4 per cent had urinary stones. No urinary stones were found in the ileostomists with Crohn's disease. Various factors thought to be associated with a liability to urolithiasis have been examined in the ileostomists and also in a control group of 39 healthy subjects matched for age and sex with the ileostomists who had had ulcerative colitis. The ileostomists commonly showed a reduced urinary volume, a low urinary sodium and magnesium content and low urinary pH. The ileostomists were much more prone to be hyperuricaemic than the controls, and hyperuricaemia was strongly associated with the presence of urinary stones.

The disposition and metabolism of sulphasalazine (salicylazosulphapyridine) in man.

1 We have investigated the disposition and metabolism of sulphasalazine (SASP) in eight adults with and without inflammatory bowel disease. 2 SASP is poorly absorbed (less than 12%) and the half-time measured in the serum, 10.2 h, is probably the half-time of absorption and therefore an overestimate of the true half-time. The apparent volume of distribution is low (less than 9 l). Renal and biliary clearance rates are low (5.5 and 2.1 ml min-1 respectively) probably due to a high degree of protein binding. Of the absorbed SASP, two thirds is excreted in the urine and one third in the bile. 3 Most of the SASP reaches the colon and is there split by bacteria, forming sulphapyridine (SP) and 5-aminosalicylic acid (5-ASA). 4 SP is almost completely absorbed and, with its metabolites, is excreted in the urine (SP renal clearance rate 32.1 ml min-1). There is no enterohepatic recirculation. 5 Of the 5-ASA released in the colon at least 25% is absorbed and rapidly eliminated in the urine after acetylation. At least 50% is eliminated in the faeces. 6 There are no differences in disposition characteristics when comparing patients with and without inflammatory bowel disease but the metabolism of SASP is markedly reduced in patients taking antibiotics and after removal of the large bowel.

Luminal ions and short chain fatty acids as markers of functional activity of the mucosa in ulcerative colitis.

Luminal concentrations of short chain fatty acids (SCFA), ammonia, sodium and potassium were measured in colonic dialysate of 16 control subjects and in 65 cases with ulcerative colitis (UC), which were graded according to mucosal changes into mild (1), moderate (2), or severe (3) inflammatory activity. Sodium concentrations were mildly but not significantly increased in severe ulcerative colitis while luminal potassium concentrations were markedly decreased in severe ulcerative colitis (p less than 0.025). Concentrations of SCFA were increased in severe ulcerative colitis. Butyrate concentrations were significantly raised in all stages of active ulcerative colitis even when other fatty acids were not raised. Of all the parameters a lowered pH and raised butyrate concentration most strikingly correlate with the severity of mucosal change. Results indirectly suggest that control of luminal pH, potassium secretion and utilisation of butyrate by the colonic mucosa are impaired with progressive mucosal inflammation.

Gut hormone responses in subjects with a permanent ileostomy.

The fasting and postprandial levels of insulin, gastric inhibitory polypeptide, gastrin, motilin, human pancreatic polypeptide, enteroglucagon and neurotensin have been measured in 10 subjects with a permanent ileostomy and in 10 healthy control subjects matched for age and sex. Most of the levels were similar in the two groups but the group that had undergone ileostomies had significantly raised basal motilin and postprandial neurotensin levels while the basal enteroglucagon levels were significantly low. The possible implications of these findings are discussed.