Population monitoring of trisomy 21: problems and approaches.

Trisomy 21 (Down syndrome) is the most common autosomal aneuploidy among newborns. About 90% result from meiotic nondisjunction during oogenesis, which occurs around conception, when also the most profound epigenetic modifications take place. Thus, maternal meiosis is an error prone process with an extreme sensitivity to endogenous factors, as exemplified by maternal age. This contrasts with the missing acceptance of causal exogenous factors. The proof of an environmental agent is a great challenge, both with respect to ascertainment bias, determination of time and dosage of exposure, as well as registration of the relevant individual health data affecting the birth prevalence. Based on a few exemplary epidemiological studies the feasibility of trisomy 21 monitoring is illustrated. In the nearer future the methodical premises will be clearly improved, both due to the establishment of electronic health registers and to the introduction of non-invasive prenatal tests. Down syndrome is a sentinel phenotype, presumably also with regard to other congenital anomalies. Thus, monitoring of trisomy 21 offers new chances for risk avoidance and preventive measures, but also for basic research concerning identification of relevant genomic variants involved in chromosomal nondisjunction.

COVID-19 and vaccination induced changes in hospital activity in Malta, Q1 2020 to Q1 2021: a population-based study.

BACKGROUND: COVID-19 has severely impacted global healthcare services. Malta has only one acute state hospital, Mater Dei Hospital (MDH), and at the time of writing is the most vaccinated country in Europe. Malta thus provides an ideal setting to assess the impact of COVID-19 on healthcare services at population level, including the impact of vaccination on hospital admissions. METHODS: Hospital data was obtained as anonymised totals from MDH's Clinical Performance Unit and the European Centre for Disease Prevention and Control. COVID-19-related data was obtained from the Ministry of Health dashboard. Comparative assessments were performed to explore associations between the COVID-19 situation, vaccination, and hospital activity. Poisson regression was used to model the counts of monthly accident and emergency (A&E), outpatient clinics attendances and hospital admissions. RESULTS: A&E, hospital admissions, and outpatient clinics attendances declined (31.88%; 23.89%; 29.57%; p < 0.01 respectively) with onset of COVID-19 till April 2021 when compared to pre-COVID years (2017-2019). Admissions due to COVID-19 initially increased in parallel to the population's COVID positivity. Vaccination rollout led to a decline in COVID-19 admissions. CONCLUSIONS: The drastic drop in admissions and outpatient attendees was expected but not for A&E attendees as acutely ill patients should still have attended. This is of public health concern since delayed or deferred medical management increases population morbidity, mortality and increases the eventual burden on the healthcare system. Mass vaccination saw the return to normality with an increase in A&E burden.

No Local Birth Sex Ratio Changes following the August 2019 Shootings in Montgomery County, Ohio, and in El Paso County, Texas.

OBJECTIVE: In humans, males are born slightly in excess of females. Many factors have been shown to affect this ratio, including stressful events such as terrorist attacks. Two shootings occurred in early August 2019 in the Oregon District in Dayton, Montgomery County, Ohio, and in El Paso County, Texas, in the USA. This study was carried out in order to identify whether there were any effects on sex ratio at birth at the state or county level 3-5 months later. SUBJECT AND METHODS: Births by sex, month of birth (2015-2019), and county were obtained for Ohio and Texas from the website of the Centers for Disease Control and Prevention. Ordinary linear logistic regression was used to assess the time trend in the probability of boys and to investigate changes in the trend functions. Poisson regression (SAS GENMOD) and linear logistic regression using SAS procedure LOGISTIC was applied. RESULTS: This study analyzed 2,623,714 live births, 1,939,938 in Texas (sex odds [SO] 1.044) and 683,776 in Ohio (SO 1.045). The only significant effect noted was seasonality (month) at the state level. CONCLUSION: It has been postulated that male fetal loss in pregnant women during stressful periods may occur in accordance with the Trivers-Willard hypothesis. Several studies have found significant effects after terrorist attacks in the USA (as well as in other countries), but this study did not reveal such effects. This may be due to several reasons including underpowered datasets and the possibility that populations may be becoming relatively immured to these events.

The secondary sex ratio in Italy over the past eighty years (1940 to 2019) and potential impact of radiological contamination after atmospheric nuclear testing and after Chernobyl: Temporal change-point analysis using Markov Chain Monte Carlo.

In Europe, the male to female ratio at birth (secondary sex ratio: SSR; sex odds: SO) is 1.04-1.06, is influenced by many factors and is declining in industrialized countries. This study was carried out to identify possible impacts of fallout by atomic bomb tests or by the Chernobyl event on SSR in Italy. Italy is a country without commercial nuclear power generation for the last four decades and thus nearly free of radiological confounders. Counts of annual male and female live births in Italy are provided by the World Health Organization (WHO) and by the Italian Istituto Nazionale di Statistica (ISTAT). This study included 57.7 million live births (1940-2019) with overall SSR 1.05829. The Italian SSR trend was modelled with linear and non-linear logistic regression. Trend changes, i.e., periods with level shifts were estimated with Markov Chain Monte Carlo (MCMC). Two distinct idealized level shifts were identified superimposed on a uniform secular downward trend. The first one is seen towards the end of the 1960s with a jump sex odds ratio (SOR) 1.00681, p < 0.0001. The second one occurred in 1987 with SOR 1.00474, p < 0.0001. In each of the 3 periods separated by the two jumps, SSR uniformly decreased with trend SOR per 100 years of 0.98549, p < 0.0001. In conclusion, the secular trend in the Italian SSR showed two marked level shifts, at the end of the 1960s and from 1987 onward. These follow the release of radioactivity by atmospheric atomic bomb tests during the 1960s and by Chernobyl in 1986 and corroborate the hypothesis that ionizing radiation increases SSR.

WITHDRAWN: Sharp decline in acute and elective hospital attendances and admissions due to COVID-19 in Malta (Q1 2020) - A population-based study.

This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.

Response to the "letter to the editor" by Sani Rachman Soleman et al., "spatiotemporal association of low birth weight with Cs-137 deposition at the prefecture level in Japan after the Fukushima nuclear power plant accidents".

We thank Sani Rachman Soleman et al. for three specific points of criticism concerning our investigation of the ecological association between low birth weight (LBW) and radioactive contamination in Japan after the Fukushima Daiichi Nuclear Power Plant (FDNPP) accidents: 1. Ecological variables are not justified enough to adjust potential confounding. 2. The spatiotemporal regression model does not consider temporal reduction in radiation dose rate. 3. Dose-response plot between dose rates and odds ratios overestimates R2 and underestimates p-value. This criticism is a good starting point to explain some of the technical backgrounds of our approach in more detail.

WITHDRAWN: COVID-19: Mathematical estimation of delay to deaths in relation to upsurges.

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Spatiotemporal association of low birth weight with Cs-137 deposition at the prefecture level in Japan after the Fukushima nuclear power plant accidents: an analytical-ecologic epidemiological study.

BACKGROUND: Perinatal mortality increased in contaminated prefectures after the Fukushima Daichi Nuclear Power Plant (FDNPP) accidents in Japan in 2011. Elevated counts of surgeries for cryptorchidism and congenital heart malformations were observed throughout Japan from 2012 onward. The thyroid cancer detection rate (2011 to 2016) was associated with the dose-rate at the municipality level in the Fukushima prefecture. Since the birth weight is a simple and objective indicator for gestational development and pregnancy outcome, the question arises whether the annual birth weight distribution was distorted in a dose-rate-dependent manner across Japan after Fukushima. METHODS: The Japanese Ministry of Health, Labour, and Welfare provides prefecture-specific annual counts for 26.158 million live births from 1995 to 2018, of which 2.366 million births (9.04%) with weights < 2500 g. Prefecture-specific spatiotemporal trends of the low birth weight proportions were analyzed. Logistic regression allowing for level-shifts from 2012 onward was employed to test whether those level-shifts were proportional to the prefecture-specific dose-rates derived from Cs-137 deposition in the 47 Japanese prefectures. RESULTS: The overall trend of the low birth weight prevalence (LBWp) in Japan discloses a jump in 2012 with a jump odds ratio (OR) 1.020, 95%-confidence interval (1.003,1.037), p-value 0.0246. A logistic regression of LBWp on the additional dose-rate after the FDNPP accidents adjusted for prefecture-specific spatiotemporal base-line trends yields an OR per µSv/h of 1.098 (1.058, 1.139), p-value < 0.0001. Further adjusting the logistic regression for the annual population size and physician density of the prefectures, as well as for the counts of the dead, the missing, and the evacuees due to earthquake and tsunami (as surrogate measures for medical infrastructure and stress) yields an OR per µSv/h of 1.109 (1.032, 1.191), p-value 0.0046. CONCLUSIONS: This study shows increased low birth weight prevalence related to the Cs-137 deposition and the corresponding additional dose-rate in Japan from 2012 onward. Previous evidence suggesting compromised gestational development and pregnancy outcome under elevated environmental ionizing radiation exposure is corroborated.

Trends in births and the birth sex ratio in the vicinity of the Mainz research reactor in Germany.

INTRODUCTION: The human sex ratio or sex odds at birth (M/F) are influenced by many factors. Radiation is the only stressor known to elevate the ratio while dropping total births. The Mainz research nuclear reactor (FRMZ) underwent extensive refurbishment commencing in 1992 and with further upgrading in 2011. This study was carried out in order to investigate any possible effects of these events on M/F. METHODS: Annual municipality-specific births by sex were obtained from official government sources. Statistical methods used included ordinary linear logistic regression and Poisson regression. RESULTS: M/F rose significantly in 1993 only close to the FRMZ (<10 km) with sex odds ratio (SOR) 1.023 (p = 0.0074) and this rise was associated with numerically equivalent drops in male births of 4.01% (p = 0.0251) and female births of 6.17% (p = 0.0005). No such effects were seen beyond 10 km. DISCUSSION: These findings add to the corpus of evidence that man-made radiation may have significant effects on total births and on M/F with a skew toward male births. While the authors are certain that suitable precautions were taken when the reactor in Mainz was handled, the findings imply that these may not have been sufficient. Perhaps even greater care and even more stringent precautions need to be employed when dealing with radioactive elements. It clearly behoves humanity to exercise extreme caution when handling, processing, and storing radioactive materials and waste.

Association between the detection rate of thyroid cancer and the external radiation dose-rate after the nuclear power plant accidents in Fukushima, Japan.

A thyroid cancer ultrasonography screening for all residents 18 years old or younger living in the Fukushima prefecture started in October 2011 to investigate the possible effect of the radiological contamination after the Fukushima Daiichi Nuclear Power Plant accidents as of March 12 to 15, 2011. Thyroid cancer in 184 cases was reported by February 2017. The question arises to which extent those cancer cases are a biological consequence of the radiation exposure or an artefactual result of the intense screening of a large population.Experiences with the Chernobyl accident suggest that the external dose may be considered a valid surrogate for the internal dose of the thyroid gland. We, therefore, calculated the average external effective dose-rate (µSv/h) for the 59 municipalities of the Fukushima prefecture based on published data of air and soil radiation. We further determined the municipality-specific absolute numbers of thyroid cancers found by each of the two screening rounds in the corresponding municipality-specific exposed person-time observed. A possible association between the radiation exposure and the thyroid cancer detection rate was analyzed with Poisson regression assuming Poisson distributed thyroid cancer cases in the exposed person-time observed per municipality.The target populations consisted of 367,674 and 381,286 children and adolescents for the 1st and the 2nd screening rounds, respectively. In the 1st screening, 300,476 persons participated and 270,489 in the 2nd round. From October 2011 to March 2016, a total of 184 cancer cases were found in 1,079,786 person-years counted from the onset of the exposure to the corresponding examination periods in the municipalities. A significant association between the external effective dose-rate and the thyroid cancer detection rate exists: detection rate ratio (DRR) per µSv/h 1.065 (1.013, 1.119). Restricting the analysis to the 53 municipalities that received less than 2 µSv/h, and which represent 176 of the total 184 cancer cases, the association appears to be considerably stronger: DRR per µSv/h 1.555 (1.096, 2.206).The average radiation dose-rates in the 59 municipalities of the Fukushima prefecture in June 2011 and the corresponding thyroid cancer detection rates in the period October 2011 to March 2016 show statistically significant relationships.

Secondary sex ratio and trends in the associated gender-specific births near nuclear facilities in France and Germany: Update of birth counts.

Increases in childhood cancer near nuclear facilities in France and in Germany as well as elevated human birth sex ratios after the atmospheric atomic bomb tests and after Chernobyl motivated the inspection of the secondary sex ratio and the corresponding gender-specific birth counts in the vicinity of nuclear facilities. Focus is on which changes in the birth counts go along with significant changes in the sex ratios. Official municipality-specific annual birth counts by sex for all of France and for whole Germany are updated until 2016 and 2017, respectively. Using logistic regression, we determine significant change-points (jumps) after distinct radiological events in sex ratio time-trends in circular areas around pertinent nuclear facilities. With Poisson regression, we quantify the corresponding change-points in the trends of absolute annual birth counts for boys and girls. In the 35-km vicinity of the 'Centre de l'Aube Nuclear Disposal Facility (CSA)' in France in the year 2000, we observe a jump in the sex odds (SO) with sex odds ratio (SOR) 1.101; 95% CI: (1.033, 1.175), p-value 0.0033. This jump in the sex odds can be associated with a drop in boys of 3.44% (-4.02, 10.37), p-value 0.3561, and a drop in girls of 8.44% (1.33, 15.04), p-value 0.0208. In the highly populated area around the nuclear power plant Philippsburg in Germany from 2001 onward, we see a similar effect: SOR 1.027 (1.008, 1.046), p-value 0.0045; drop in boys 5.56% (2.24, 8.76), p-value 0.0012; drop in girls 6.92% (3.62, 10.10), p-value <0.0001. The presented findings corroborate and specify earlier observations and call for intensifying bio-physical research in exposure mechanisms and exposure pathways of natural or artificial ionizing radiation including neutron radiation and neutron activation. Reinforced biological and epidemiological research should aim at clarifying the associated genetic and carcinogenic consequences at the population level.

Modeling of radon exhalation from soil influenced by environmental parameters.

Atmospheric radioactive noble gas radon (Rn-222) originates from soil gas exhaled in the atmospheric surface layer. Radon exhalation rates from soil as well as corresponding meteorological and soil parameters were recorded for two subsequent years. Based on long-term field data, a statistical regression model for the radon exhalation and the most important influencing parameters soil water content, temperature of soil and air, air pressure and autocorrelation of the exhalation rate was established. The fitting result showed that the multivariate model can explain up to 61% of the variation of the exhalation rate. First, the exhalation rate increases up to 80 Bq m-2 h-1 with increasing soil water content. Later, at water content >10%, increasing soil wetness suppressed the exhalation rate: at values higher than 24% to approximately one third. The air temperature had a distinct positive effect while the soil temperature had a strong negative effect on the exhalation rate, indicating their different influencing-mechanisms on the exhalation. The air pressure was negligible. The lagged values of radon exhalation had to be included in the model, as the variable shows strong autocorrelation.

An inhibitory antibody targeting carbonic anhydrase XII abrogates chemoresistance and significantly reduces lung metastases in an orthotopic breast cancer model in vivo.

Carbonic anhydrase XII (CAXII) is a membrane-tethered ectoenzyme involved in intracellular pH regulation and overexpressed across various types of human cancer. Because CAXII inhibition shows antitumor activity in vitro, it is thought that the enzyme is mandatory for maximum tumor growth, above all under hypoxic conditions. Recently, it has been shown that CAXII is co-expressed along with the P-glycoprotein (P-GP) on many tumor cells and that both proteins physically interact. Of interest, blocking CAXII activity also decreases P-GP activity in cancer cells both in vitro and in vivo. Previously, we have reported on the development of a monoclonal antibody, termed 6A10, which specifically and efficiently blocks human CAXII activity. Here, we demonstrate that 6A10 also indirectly reduces P-GP activity in CAXII/P-GP double-positive chemoresistant cancer cells, resulting in enhanced chemosensitivity as revealed by enhanced accumulation of anthracyclines and increased cell death in vitro. Even more important, we show that mice carrying human triple-negative breast cancer xenografts co-treated with doxorubicin (DOX) and 6A10 show a significantly reduced number of metastases. Collectively, our data provide evidence that the inhibition of CAXII with 6A10 is an attractive way to reduce chemoresistance of cancer cells and to interfere with the metastatic process in a clinical setting.

Intrauterine smoke exposure deregulates lung function, pulmonary transcriptomes, and in particular insulin-like growth factor (IGF)-1 in a sex-specific manner.

Prenatal exposure to tobacco smoke is a significant risk-factor for airway disease development. Furthermore, the high prevalence of pregnant smoking women requires the establishment of strategies for offspring lung protection. Therefore, we here aimed to understand the molecular mechanism of how prenatal smoke exposure affects fetal lung development. We used a mouse model recapitulating clinical findings of prenatally exposed children, where pregnant mice were exposed to smoke until c-section or spontaneous delivery, and offspring weight development and lung function was monitored. Additionally, we investigated pulmonary transcriptome changes in fetal lungs (GD18.5) by mRNA/miRNA arrays, network analyses and qPCR. The results demonstrated that prenatally exposed mice showed intrauterine and postnatal growth retardation, and impaired lung function. 1340 genes and 133 miRNAs were found to be significantly dysregulated by in utero smoke exposure, and we identified Insulin-like growth factor 1 (Igf1) as a top hierarchical node in a network analysis. Moreover, Igf1 mRNA was increased in female murine offspring and in prenatally exposed children. These findings suggest that prenatal smoking is associated with a dysregulation of several genes, including Igf1 in a sex-specific manner. Thus, our results could represent a novel link between smoke exposure, abberant lung development and impaired lung function.

Influence of polygamous versus monogamous mating on embryo production in four different strains of mice after superovulatory treatment.

We determined the effect of monogamous or polygamous mating with 2 females on vaginal plug (VP) rate, embryo donors (ED), 2-cell embryo production, and male performance after superovulation of females aging 24d or 45-48d. C57BL/6NCrl (B6N), BALB/cAnCrl (BALB/cN), FVB/NCrl (FVB/N), and Crl:CD1(ICR) (CD-1) females received 5 IU eCG and 5 IU hCG (24d) or 7.5 IU eCG and 7.5 IU hCG (45-48d) 48 h apart. After the hCG injection, females were paired with males, which alternated weekly in monogamous or polygamous mating. Significant differences in the percentage of VP-positive females between monogamous and polygamous mating were observed for B6N (71% vs. 49%), FVB/N (77% vs. 51%), and CD-1 (90% vs. 67%) at 45-48d. BALB/cN and CD-1 showed higher VP rates than B6N and FVB/N. A significantly higher percentage of ED was found for monogamous than for polygamous mating for FVB/N (87% vs. 61%) at 24d and for B6N (91% vs. 53%) and CD-1 (90% vs. 68%) at 45-48d. In all strains of mice and in both age groups, no significant differences were observed in the number of intact 2-cells per VP-positive female, ED or treated female between monogamous and polygamous mating except in the B6N strain where monogamous mating resulted in a significantly higher number of intact 2-cell embryos per treated female than polygamous mating at both ages. The present results imply that polygamous mating can be implemented for 2-cell embryo production in all strains studied except for B6N when all females are euthanized. However, when only VP+ females are sacrificed polygamous mating can be employed for all 4 strains studied.

Adjuvant stereotactic fractionated radiotherapy to the resection cavity in recurrent glioblastoma - the GlioCave study (NOA 17 - ARO 2016/3 - DKTK ROG trial).

BACKGROUND: Glioblastoma relapses in the vast majority of cases within 1 year. Maximum safe resection of the recurrent glioblastoma can be offered in some cases. Re-irradiation has been established for the treatment of recurrent glioblastoma, too. In both cases, adjuvant treatment, mostly using temozolomide, can improve PFS and OS after these interventions. However, combining gross tumor resection and adjuvant re-radiotherapy to the resection cavity has not been tested so far. METHODS/DESIGN: In the multicenter two-armed randomized Phase II GlioCave Study, fractionated stereotactic radiotherapy to the resection cavity, after gross tumor resection of recurrent glioblastoma, will be compared to observation. Depending on the size of the target volume, a total dose of 46 Gy in 2 Gy per fraction or a total dose if 36 Gy in 3 Gy per fraction will be applied. Progression free survival will be the primary endpoint of the study. DISCUSSION: Adjuvant treatment after gross tumor resection of recurrent glioblastoma is currently deemed to be limited to chemotherapy. However, re-irradiation has proven safety and tolerability in the treatment of macroscopic disease. Performing re-irradiation as an adjuvant measure after gross tumor resection has not been tested so far. The GlioCave Study will investigate the efficacy and the safety profile of this approach. TRIAL REGISTRATION: The trial was prospectively registered at clinicaltrials.gov ( NCT02715297 , registration date February 29th, 2016). The protocol presented hereby refers to the version 1.2 of the protocol (January 11th, 2017).