High breast cancer mortality rates have been reported in the northeastern part of the United States, with recent attention focused on Long Island, New York. In this study, the authors investigate whether the high breast cancer mortality is evenly spread over the Northeast, in the sense that any observed clusters of deaths can be explained by chance alone, or whether there are clusters of statistical significance. Demographic data and age-specific breast cancer mortality rates for women were obtained for all 244 counties in 11 northeastern states and for the District of Columbia for 1988-1992. A recently developed spatial scan statistic is used, which searches for clusters of cases without specifying their size or location ahead of time, and which tests for their statistical significance while adjusting for the multiple testing inherent in such a procedure. The basic analysis is adjusted for age, with further analyses examining how the results are affected by incorporating race, urbanicity, and parity as confounding variables. There is a statistically significant and geographically broad cluster of breast cancer deaths in the New York City-Philadelphia, Pennsylvania, metropolitan area (p = 0.0001), which has a 7.4% higher mortality rate than the rest of the Northeast. The cluster remains significant when race, urbanicity, and/or parity are included as confounding variables. Four smaller subclusters within this area are also significant on their own strength: Philadelphia with suburbs (p = 0.0001), Long Island (p = 0.0001), central New Jersey (p = 0.0001), and northeastern New Jersey (p = 0.0001). The elevated breast cancer mortality on Long Island might be viewed less as a unique local phenomenon and more as part of a more general situation involving large parts of the New York City-Philadelphia metropolitan area. The several known and hypothesized risk factors for which we could not adjust and that may explain the detected cluster are most notably age at first birth, age at menarche, age at menopause, breastfeeding, genetic mutations, and environmental factors.

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The authors discuss the interpretation of four alternative energy adjustment methods (Residual, Standard, Partition, and Nutrient Density) that have been proposed for the analysis of nutritional epidemiology studies. These methods have so far been compared under circumstances where intake of the nutrient of interest is measured as a continuous variable. Because it is common practice to categorize nutrient intakes in the analysis, the authors investigate the effect of such categorization on the interpretation of results from the four methods with the use of computer simulations and statistical theory. They consider four cases: where the nutrient intake is either divided into quartiles or ordered so as to investigate trend over the quartile groups, combined with using an adjusting variable that is either continuous or categorized. The results show: 1) the Residual, Standard, and Partition methods are no longer equivalent as they are in the continuous case; 2) compared with the Standard method, the Residual method appears to be more powerful for detecting trends in relative odds, is more robust to residual confounding when the adjustment variable is categorized, and provides more meaningful odds ratios; and 3) the Residual and Nutrient Density methods give closely similar results.

During the years 1994-1999, a nationwide ovarian cancer case-control study was conducted in Israel. The present analysis addresses the question: Is epithelial ovarian cancer associated with body mass index at age 18 years and/or with weight changes in body mass index between adolescence and adult life? The study is based on 1,269 women with epithelial ovarian cancer and 2,111 matched controls. A significant decrease in risk of ovarian cancer was observed with parity, oral contraceptive use, and postmenopausal status. A significant increase in risk with family history of ovarian/breast cancer was also found. No significant association with age at menarche or infertility was found. For body mass index at age 18 years, the odds ratio of the highest versus lowest body mass index quartile was 1.42 (95% confidence interval: 1.08, 1.85) and after adjusting for confounders was 1.54 (95% confidence interval: 1.17, 2.02). However, no statistically significant risk associated with change in weight from age 18 years to adult life was found. The authors conclude that, in their population, body mass index at age 18 years is an independent risk factor for ovarian cancer.

A randomised control trial of intravesical instillation of mitomycin C was conducted in 457 patients with cancer of the bladder that was confined to the submucosa on histological examination. The events studied were the recurrence free rate, the recurrence rate/year, and the number of new tumours developing/year. At the initial cystoscopy the tumours were completely resected and the patients randomised to have no instillation of mitomycin C, a single instillation of 40 mg in 40 ml of water at that cystoscopy, or a single instillation and then four further instillations. All patients had follow up cystoscopies every three months for the first year, twice in the second year, and yearly thereafter. After a median of 12 months, follow up information was available for 397 patients. Patients receiving both the single instillation of mitomycin C and the instillations at five cystoscopic examinations had significantly lower yearly recurrence rates and tumour rates than those in the control group, and the group receiving multiple instillations fared significantly better than those receiving a single instillation. The figures on progression to invasive cancer were too small to allow conclusions to be drawn.

globally each year. 6 In England, 17,000 people a year are estimated to die annually from flu, but this varies notably according to levels of pre-existing immunity to the prevalent strain, the take-up of the available vaccine and how well it has anticipated that year's strains of flu. Thus, in 2014-15 some 28,330 people died, while in 2018-19 the number was down to 1,692. 7 The 2019-20 seasonal winter flu was no more virulent than usual, did not impose great demands on hospitals and intensive-care units (ICUs) and did not lead to an exceptional number of deaths. 8 Pandemics occur when a new and highly contagious viral infection appears for which there is no population immunity, a vaccine has yet to be developed and treatments are unavailable. One pandemic regularly recalled from the pre-vaccination age is the 'Spanish' flu that lasted from 1918-20, infecting up to a billion people worldwide and killing between 50 and 100 million. 9 More recently, the 'Asian' flu of 1957-58, which began in southern China, and the Hong Kong flu of 1968-69 were both thought to have infected up to 500m people globally and led to 1-4m deaths. In 2009, the so-called 'swine' flu infected around a billion people with estimated deaths of at least 150,000, but more likely closer to 500,000. Not all outbreaks killed as many as feared: the Middle East respiratory syndrome (MERS), first reported in Saudi Arabia in 2012 and associated with camels, was deadly for about a third of those infected, but produced only around 2,000 cases. SARS, to which the current virus is most closely related, began, also in China, in November 2002, and by July 2003 had resulted in 8,437 cases and 813 deaths in 32 countries. Almost 95% of the cases were in the Western Pacific region. 10 The outbreak began with some atypical pneumonia cases in the southern Chinese province of Guangdong among people who handled food or sold wild animals. There were delays in reporting it, at first nationally and then internationally. Within China, administrative barriers and political disincentives prevented bad news getting to the capital. It was not until 11 February 2003 that the local authority reported the outbreak. Beijing resisted requests by the WHO for permission to send an investigative team. Soon it reached Vietnam,

Klotho is a transmembrane protein that can be shed and act as a circulating hormone and is a putative tumor suppressor in breast cancer. A functional variant of KLOTHO (KL-VS) contains two amino acid substitutions F352V and C370S and shows reduced activity. Germ-line mutations in BRCA1 and BRCA2 substantially increase lifetime risk of breast and ovarian cancers. Yet, penetrance of deleterious BRCA1 and BRCA2 mutations is incomplete even among carriers of identical mutations. We examined the association between KL-VS and cancer risk among 1115 Ashkenazi Jewish women: 236 noncarriers, 631 BRCA1 (185delAG, 5382insC) carriers and 248 BRCA2 (6174delT) carriers. Among BRCA1 carriers, heterozygosity for the KL-VS allele was associated with increased breast and ovarian cancer risk (hazard ratio 1.40, 95% confidence intervals 1.08-1.83, P ¼ 0.01) and younger age at breast cancer diagnosis (median age 48 vs 43 P ¼ 0.04). KLOTHO and BRCA2 are located on 13q12, and we identified linkage disequilibrium between KL-VS and BRCA2 6174delT mutation. Studies in breast cancer cells showed reduced growth inhibitory activity and reduced secretion of klotho F352V compared with wildtype klotho. These data suggest KL-VS as a breast and ovarian cancer risk modifier among BRCA1 mutation carriers. If validated in additional cohorts, the presence of KL-VS may serve as a predictor of cancer risk among BRCA1 mutation carriers.