Standardised mortality ratios in people exposed to sulphur mustard during the Iran-Iraq war: a retrospective study with 39-year follow-up.

OBJECTIVES: Sulphur mustard (SM) is a chemical weapon agent that was extensively used by Iraqi troops during the Iran-Iraq war (1980-1988), resulting in exposure among Iranian military personnel and civilians. However, there is limited and conflicting information about the long-term mortality effects of SM exposure. This study aimed to determine the standardised mortality ratios (SMRs) in individuals exposed to SM gas during the Iran-Iraq war. STUDY DESIGN: This was a retrospective follow-up study. METHODS: Data were obtained from the Veterans and Martyr Affair Foundation of Iran (VMAF) regarding all confirmed individuals who were exposed to SM during the Iran-Iraq war (1980-1988) up to 30 March 2019. The mortality rate, cumulative mortality and SMR with 95 % confidence intervals (CIs) were calculated to assess mortality in chemical warfare survivors (CWS), and results were compared with the general Iranian population. Overall survival was analysed using the Kaplan-Meier curve, and the log-rank test was employed to compare survival probability across different categories. RESULTS: Among the 48,067 confirmed CWS, a total of 4358 (9.1 %) individuals had died by the end of the study period (30 March 2019), with a mean age of 55.5 ± 14.4 years at the time of death. Overall, at the 39-year follow-up, the mortality rate due to all causes of death for people who were exposed to SM was lower than the general Iranian population (SMR: 0.70, 95 % CI: 0.68-0.72). However, cause-specific SMR analysis showed that the mortality rate due to liver cancer (SMR: 1.98, 95 % CI: 1.59-2.45), poisonings (SMR: 1.92, 95 % CI: 1.52-2.38), respiratory disorders (SMR: 1.59, 95 % CI: 1.46-1.73) and multiple myeloma (SMR: 1.72, 95 % CI: 1.06-2.62) were approximately twofold higher in CWS than the general population. CONCLUSIONS: This study provides valuable insights into the mortality effects of SM exposure among the Iranian population affected by the Iran-Iraq war. The results emphasise the importance of continued monitoring and support for individuals exposed to SM, particularly in the context of managing and addressing the heightened risks associated with liver cancer, poisonings, respiratory disorders and multiple myeloma. Further research and interventions may be necessary to mitigate these specific health challenges in the affected population.

Does AMH relate to timing of menopause? Results of an Individual Patient Data meta- analysis.

CONTEXT: Anti-Müllerian hormone based (AMH) age at menopause predictions remain cumbersome due to predictive inaccuracy. OBJECTIVE: To perform an Individual Patient Data (IPD) meta-analysis, regarding AMH based menopause prediction. DATA SOURCES: A systematic literature search was performed using PubMed, Embase and Cochrane databases. STUDY SELECTION: Prospective cohort studies regarding menopause prediction using serum AMH levels were selected by consensus discussion. DATA SELECTION: Individual cases were included if experiencing a regular cycle at baseline. Exclusion criteria were hormone use and gynecological surgery. DATA SYNTHESIS: 2596 women were included, 1077 experienced menopause. A multivariable Cox regression analysis assessed time to menopause (TTM) using age and AMH. AMH predicted TTM, however, added value on top of age was poor (age alone C-statistic 84%; age + AMH HR 0.66 95% CI 0.61-0.71, C-statistic 86%). Moreover, the capacity of AMH to predict early (≤45 years) and late menopause (≥55 years) was assessed. An added effect of AMH was demonstrated for early menopause (age alone C-statistic 52%; age + AMH HR 0.33, 95% CI 0.24-0.45, C-statistic 80%). A Weibull regression model calculating individual age at menopause revealed that predictive inaccuracy remained present and increased with decreasing age at menopause. Lastly, a check of non-proportionality of the predictive effect of AMH demonstrated a reduced predictive effect with increasing age. CONCLUSION: AMH was a significant predictor of TTM and especially of time to early menopause. However, individual predictions of age at menopause demonstrated a limited precision, particularly when concerning early age at menopause, making clinical application troublesome.

Age-specific serum anti-Müllerian hormone levels: estimates from a large population-based sample.

OBJECTIVE: Despite the wide use of anti-Müllerian hormone (AMH) measurement as a clinical marker for assessment of ovarian reserve, a population-based estimate for its reference values is not available. In this study, we have estimated age-specific AMH levels in a large sample of fertile women directly selected from a general population cohort. METHODS: All women who were naturally fertile and aged 18-50 years with regular menstrual cycles were selected from the Tehran Lipid and Glucose Study cohort and their blood levels of AMH were measured. Centiles for AMH distribution were estimated according to the exponential-normal 3-parameter model. We repeated the analysis after including a subgroup of women aged 40-50 years who met all the eligibility criteria except having entered natural menopause after age 40 years (n = 141). RESULTS: A total of 1015 women entered the study. The mean age was 36.7 years (standard deviation 7.5 years) and the mean body mass index was 27.0 kg/m(2) (standard deviation 4.6 kg/m(2)). A non-linear decline of serum AMH concentration with age was observed. Age-specific AMH levels for the 5th, 10th, 25th, 50th, 75th, 90th and 95th percentiles were calculated. RESULTS: were reproduced after inclusion of 141 women aged 40-50 years who met all the eligibility criteria except having entered natural menopause after 40 years. CONCLUSION: In this study, we have presented a nomogram of age-specific estimates of anti-Müllerian hormone in a large sample of naturally fertile women within the general population. This could help clinicians in more accurate individual interpretation of serum AMH levels in healthy women.

Predicting menopausal age with anti-Müllerian hormone: a cross-validation study of two existing models.

OBJECTIVE: This study aimed to cross-validate two comparable Weibull models of prediction of age at natural menopause from two cohorts, the Scheffer, van Rooij, de Vet (SRV) cohort and the Tehran Lipid and Glucose Study (TLGS) cohort. It summarizes advantages and disadvantages of the models and underlines the need for achieving correct time dependency in dynamic variables like anti-Müllerian hormone. METHODS: Models were fitted in the original datasets and then applied to the cross-validation datasets. The discriminatory capacity of each model was assessed by calculating C-statistics for the models in their own data and in the cross-validation data. Calibration of the models on the cross-validation data was assessed by measuring the slope, intercept and Weibull shape parameter. RESULTS: The C-statistic for the SRV model on the SRV data was 0.7 (95% confidence interval (CI) 0.7-0.8) and on the TLGS data it was 0.8 (95% CI 0.8-0.9). For the TLGS model on the TLGS data, it was 0.9 (95% CI 0.8-0.9) and on the SRV data it was 0.7 (95% CI 0.6-0.8). After calibration of the SRV model on the TLGS data, the slope was 1, the intercept -0.3 and the shape parameter 1.1. The TLGS model on the SRV data had a slope of 0.3, an intercept of 12.7 and a shape parameter of 0.6. CONCLUSIONS: Both models discriminate well between women that enter menopause early or late during follow-up. While the SRV model showed good agreement between the predicted risk of entering menopause and the observed proportion of women who entered menopause during follow-up (calibration) in the cross-validation dataset, the TLGS model showed poor calibration.

The long-term risk of malignancy following a diagnosis of coeliac disease or dermatitis herpetiformis: a cohort study.

BACKGROUND: People with coeliac disease are known to be at increased risk of malignancy; however, long-term risks of malignancy beyond 10-15 years are largely unstudied. AIM: To estimate how long an increased risk of malignancy among coeliac disease patients persists following diagnosis and treatment, using data from a cohort with an average follow-up of 25 years. METHODS: People with coeliac disease diagnosed in the Lothian region of Scotland, United Kingdom, were followed up from January 1970 or the date of coeliac disease diagnosis (whichever was later) until the first occurrence of death, emigration, cancer diagnosis or the end of 2004. Standardised incidence ratios were calculated to compare the cancer incidence rates among this group with those from the population of Scotland. RESULTS: Overall, the risk of any malignancy in coeliac disease patients compared with the general population was increased 40% [standardised incidence ratio (SIR) = 1.41; 95% CI 1.09-1.78]. An increased risk for cancer overall persisted for up to 15 years, beyond which no overall increase in malignancy risk was observed, although the risk of non-Hodgkin's lymphoma remained raised beyond 15 years (SIR = 5.15; 95% CI 1.40-13.2). In total, there were 14 non-Hodgkin's lymphomas in the cohort, providing an overall incidence of 1.3 per 1000 person-years. CONCLUSIONS: The overall risk of malignancy in coeliac patients declines with time after diagnosis and is not significantly increased after 15 years. Most of the increased risk can be attributed to the development of haematological malignancies, despite their very low absolute rate of occurrence.

The antecedents of biliary cancer: a primary care case-control study in the United Kingdom.

In a case-control study using a large UK primary care database, we found that non-steroidal anti-inflammatory drugs had no protective effect against biliary carcinomas (cholangiocarcinoma and gall bladder cancer). Increased risks were observed for cigarette smoking, diabetes, gallstone disease and obesity.

The epidemiology of haemochromatosis: a population-based study.

BACKGROUND: The discovery of the HFE genotype has revolutionized the diagnosis of haemochromatosis, changing the associated mortality and morbidity. AIM: To investigate the clinical significance of a diagnosis of haemochromatosis. METHODS: In a cohort study, we identified 501 people with haemochromatosis and 4950 age- and gender-matched controls from the UK General Practice Research Database between 1987 and 2002. RESULTS: The incidence of a diagnosis of haemochromatosis increased approximately 2-fold over the study period and was associated with a 2.2-fold increase in mortality [hazard ratio, 95% confidence interval (95% CI), 1.6-3.0]. There was no increase in extra hepatic malignancy, but an absolute risk excess of liver cancer of 0.89% per year. Diabetes, impotence, osteoarthritis and crystal arthritis were associated with haemochromatosis with odds ratios of 5.4 (95% CI, 4.1-7.0), 2.7(95% CI, 1.8-4.0), 1.9(95% CI, 1.5-2.4) and 2.1(95% CI, 1.4-3.1) respectively. CONCLUSION: Increasing numbers of people are being diagnosed with haemochromatosis, and the mortality associated with this disease remains high. However, people are living with considerably lower levels of morbidity than previously reported. This encouragingly suggests earlier diagnoses are being made, prior to the development of complications.

Extrinsic allergic alveolitis: incidence and mortality in the general population.

BACKGROUND: Extrinsic allergic alveolitis (EAA) is an important clinical entity, but its incidence and significance in the general population are uncertain. AIM: To estimate the incidence of EAA, and resulting mortality, in the UK. DESIGN: General-population-based cohort study in a UK primary care database (THIN). METHODS: THIN patients with an incident diagnosis of EAA were compared with a general population cohort whose members were 4:1 matched with EAA patients by age, sex and GP practice. Follow-up started at the first diagnosis of EAA (and at the same date in the matched controls) and ended at death or end of follow-up, whichever came first. Poisson, logistic, and Cox proportional hazard regression models were used; mortality rate, odd ratios, and hazard ratios were calculated. RESULTS: We identified 271 incident cases of EAA (mean age at diagnosis 57 years, 51% male). Between 1991 and 2003, the incident rate for EAA was stable at approximately 0.9 cases per 100000 person-years. In comparison to the 1084 general population controls, patients with EAA were less likely to smoke (odds ratio 0.56, 95%CI 0.39-0.81), but had a marked increase in the risk of death (hazard ratio 2.98, 95%CI 2.05-4.33). DISCUSSION: The incidence of EAA in the UK population appears to be stable overtime, and suggests about 600 new cases of EAA each year. People with EAA are less likely to smoke than the general population, but have a markedly increased mortality rate.

Is an internal comparison better than using national data when estimating mortality in longitudinal studies?

BACKGROUND: Discrepancies between the results of different studies looking at mortality in similar disease cohorts led us to consider the impact of methodology upon outcome. METHODS: Cohort studies were carried out using age, sex, practice, and calendar time matched control groups in the general practice research database. Data were used on all subjects with inflammatory bowel disease, coeliac disease, or Barrett's oesophagus. Mortality data for the population of England and Wales were obtained from the UK Office for National Statistics. The study compared hazard ratios (HR) for mortality using the matched controls to those found when an indirect standardisation to the mortality experience of England and Wales was carried out. RESULTS: For all three conditions the mortality risk was slightly lower when the national population data were used compared with the internal comparison group (coeliac disease HR 1.33 v standardised mortality ratios (SMR) 1.25, Barrett's oesophagus HR 1.32 v SMR 1.32, inflammatory bowel disease HR 1.50 v SMR 1.34). CONCLUSIONS: A bias was found towards underestimating mortality risk when cohort studies use national population death rates as a comparator. Estimates obtained when an internal comparison group has been used are probably more appropriate.

Cross-transmission of nosocomial pathogens in an adult intensive care unit: incidence and risk factors.

The incidence and determinants of cross-transmission in an adult intensive care unit (ICU) were examined under normal conditions. Four hundred and thirty patients were followed for 3947 patient-days. Cross-transmitted pathogens were identified by genetic typing. A cross-transmission episode was defined as when two or more patients had indistinguishable isolates and had been treated in the ICU during intervals up to seven days apart. The direction of cross-transmission was confirmed if the incriminated pathogen was isolated from the donor before admission of the recipient; otherwise, both patients could potentially be a donor or a recipient. These patients were excluded from the risk factor analysis. Recipients of pathogens were compared with those who were not involved in cross-transmission. Out of 22 056 examined specimens, 275 isolates were typed and 40 episodes of cross-transmission were detected. The overall incidence of cross-transmission was 10.7 [95% confidence intervals (CI) 7.6-14.5] per 1000 patient-days. In multivariate analysis, those who were nursed in an understaffed environment [odds ratio (OR) = 3.3, 95% CI 1.4-7.8], had a nasogastric tube (OR = 2.9, 95% CI 1.1-7.8) and were ventilated (OR = 2.5, 95% CI 1.1-6.0) for all of their stay, compared with none or part of their stay, showed an increase in the risk of cross-transmission. Repeated bronchoscopy (OR = 5.1, 95% CI 1.04-25) compared with no bronchoscopy and immunosuppresion (OR = 3.9, 95% CI 1.2-12.5) also increased the risk. This study showed that cross-transmission of nosocomial pathogens in the ICU is associated with understaffing, immunosuppression and factors that result in multiple staff/patient contacts, thus emphasizing the importance of hand hygiene.

Risk of extra-oesophageal malignancies and colorectal cancer in Barrett's oesophagus and gastro-oesophageal reflux.

BACKGROUND: The relationship between Barrett's oesophagus and colorectal cancer and other extra-oesophageal malignancies (EOM) has been a matter of controversy. These relationships have therefore been examined in a prospective study design in the General Practice Research Database. METHODS: Cohorts of patients having Barrett's oesophagus (n=1677), oesophagitis (n=6392), and simple reflux (n=6328), and a standard reference cohort representing the general population in the UK (n=13,416) were selected. The last three cohorts were matched to the Barrett's cohort by general practice, age and sex. Incident outcomes occurring beyond the first year of the follow-up were used for analyses. Hazard ratios and 95% confidence intervals were calculated using Cox's proportional hazards regression. The associations with cataract and oesophageal cancer were explored for comparison. RESULTS: Incident cases of 567 EOM (including 74 colorectal cancers), 448 cataract and 43 oesophageal cancers were used in the final analysis. The relative risks for colorectal cancer compared to the standard reference cohort were 1.16 (0.42-3.21) in the Barrett's cohort, 1.39 (0.76-2.54) in the oesophagitis cohort, and 0.93 (0.45-1.90) in the simple reflux cohort. The corresponding relative risks in the Barrett's cohort were 1.29 (0.90-1.85), 1.60 (1.10-2.32), and 10.56 (5.07-21.99) for EOM, cataract and oesophageal cancer, respectively. CONCLUSIONS: The risk of colorectal cancer was not higher in any of the Barrett's oesophagus, oesophagitis, or reflux cohorts compared to the general population. The explanations for the modest increase in the risk of EOM and cataract in the above cohorts are unclear but they may be mediated by ascertainment bias or shared risk factors.

Risk of oesophageal cancer in Barrett's oesophagus and gastro-oesophageal reflux.

BACKGROUND AND AIMS: While patients with Barrett's oesophagus develop oesophageal adenocarcinoma more frequently than the general population, it has controversially been suggested that gastro-oesophageal reflux (GORD) itself is a more important determinant of risk. In order to assess the validity of this suggestion, we examined the risk of oesophageal cancer in patients with Barrett's and with GORD compared with the general population in a community based cohort study. METHODS: Cohorts of patients with Barrett's (n = 1677), oesophagitis (n = 6392), and simple reflux (n = 6328), and a reference cohort (n = 13416) were selected from the General Practice Research Database. The last three cohorts were matched to the Barrett's cohort by general practitioner practice, age, and sex. Cox's regression analysis was used to calculate relative risks for oesophageal cancer. Standardised incidence ratio methodology was used to estimate the relative risks for oesophageal adenocarcinoma. RESULTS: A total of 137 oesophageal cancers were identified, of which 94 prevalent cases were excluded. The hazard ratios for oesophageal cancer were 10.6 (5.1-22.0), 2.2 (0.9-5.2), and 1.7 (0.7-4.5) in the Barrett's, oesophagitis, and reflux cohorts compared with the reference cohort, respectively. The corresponding relative risks for oesophageal adenocarcinoma were 29.8 (9.6-106), 4.5 (1.04-19.6), and 3.1 (0.6-14.2). CONCLUSION: Barrett's oesophagus increases the risk of oesophageal cancer approximately 10 times and oesophageal adenocarcinoma approximately 30 times compared with the general population. There is only a modestly increased risk of oesophageal cancer in patients with reflux who have no record of Barrett's oesophagus. Our findings therefore do not support the suggestion that gastro-oesophageal reflux disease itself predisposes to cancer.