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.

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.

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.

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.

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.

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).

ENCoRE: an efficient software for CRISPR screens identifies new players in extrinsic apoptosis.

BACKGROUND: As CRISPR/Cas9 mediated screens with pooled guide libraries in somatic cells become increasingly established, an unmet need for rapid and accurate companion informatics tools has emerged. We have developed a lightweight and efficient software to easily manipulate large raw next generation sequencing datasets derived from such screens into informative relational context with graphical support. The advantages of the software entitled ENCoRE (Easy NGS-to-Gene CRISPR REsults) include a simple graphical workflow, platform independence, local and fast multithreaded processing, data pre-processing and gene mapping with custom library import. RESULTS: We demonstrate the capabilities of ENCoRE to interrogate results from a pooled CRISPR cellular viability screen following Tumor Necrosis Factor-alpha challenge. The results not only identified stereotypical players in extrinsic apoptotic signaling but two as yet uncharacterized members of the extrinsic apoptotic cascade, Smg7 and Ces2a. We further validated and characterized cell lines containing mutations in these genes against a panel of cell death stimuli and involvement in p53 signaling. CONCLUSIONS: In summary, this software enables bench scientists with sensitive data or without access to informatic cores to rapidly interpret results from large scale experiments resulting from pooled CRISPR/Cas9 library screens.

EFFECTS OF STRESSFUL EVENTS IN FRANCE (1968) AND JAPAN (1995) ON THE SEX RATIO AT BIRTH.

Males are usually born in excess of females. The sex ratio at birth (SR) is often expressed as the ratio of male to total births. A wide variety of factors have been shown to influence SR, including terrorist attacks, which have been shown to reduce SR. This paper reviews the effects on SR outcomes of the stressful events in France in 1968 (in association with the student and worker riots) and in Japan following the Aum Shinrikyo religious cult's attack on the Tokyo subway using sarin nerve gas in 1995. Both countries displayed seasonal variation in SR. France exhibited a decline in SR in 1968 (p=0.042), with a particularly strong dip in May of that year (p=0.015). For Japan, there was no statistically significant dip for 1995 but there was a significant dip in June of that year (p=0.026). The SR dips follow catastrophic or tragic events if these are perceived to be momentous enough by a given populace. It is believed that SR slumps may be caused by population stress, which is known to lead to the culling of frail/small male fetuses. It has been observed that these fluctuations are comparable in intensity to a substantial proportion of quoted values for perinatal mortality, potentially making this a public health issue.

Hurricane Katrina: Influence on the Male-to-Female Birth Ratio.

OBJECTIVE: This study was carried out in order to ascertain whether or not Hurricane Katrina and related factors (i.e. the amount of rainfall) influenced the male-to-female birth ratio (M/F). MATERIALS AND METHODS: Monthly births by gender for the affected states (Alabama, Florida, Louisiana and Mississippi) for January 2003 to December 2012 were obtained from the Centers for Disease Control and Prevention (CDC Wonder, Atlanta, Ga., USA). Precipitation data was obtained from the US National Weather Service. Ordinary linear logistic regression was used for trend analysis. A p value ≤0.05 was taken to represent a statistically significant result. RESULTS: Of the total of 3,903,660 live births, 1,996,966 (51.16%) were male and 1,906,694 (48.84%) were female. Significant seasonal variation was noted (the maximum M/F in May was 1.055, the minimum M/F in September was 1.041, p = 0.0073). There was also a separate and significant rise in M/F 8-10 months after the storm (April to June 2006, peak M/F 1.078, p = 0.0074), which translated to an approximate deficit of 800 girls compared to 46,072 girls born in that period if the M/F increase was theoretically only due to a girls' deficit in the denominator of the ratio. This spike was only present in Alabama, Louisiana and Mississippi, all of which received heavy rainfall. Florida did not receive heavy rainfall and experienced no such M/F spike. CONCLUSION: In this study there was a dose-response relation between the amount of rainfall after Hurricane Katrina and the monthly sex ratio of live births in the US states of Alabama, Louisiana and Mississippi 8-10 months later. The well-known yet unexplained distinct sex ratio seasonality may be due to natural or man-made radiation contained in the rain.

Pooling samples for "top-down" molecular exposomics research: the methodology.

BACKGROUND: Exposomics is the cutting-edge concept of screening the environmental risk factors for disease. In the novel "top-down" approach, we estimate the molecular exposome by measuring all body fluid analytes in a case-controlled study. However, to detect diverse pollutants, a sufficient sample size and multiple analytical methods are required. This may lead to dramatically increased costs and research workload. METHODS: To help reduce complexity, we suggest a sample pooling strategy along with a scheme for combining both general unknown or multi-targeted screening with targeted analysis. The sample pooling method was tested using computer simulations. RESULTS: By comprehensively analysis of pooled samples, it is possible to identify environmental risk factors. Factors are initially screened in the pooled case and control population samples, then in the randomized grouped and pooled case and control subpopulation samples. In the sample grouping, five or more pools were suggested for groups having 30 individuals per pool. CONCLUSIONS: This study suggests that sample pooling is a useful strategy for exposomics research, which provides a hypothesis-free method for pollutant risk screening.

CombiSimilarity, an innovative method to compare environmental and health data sets with different attribute sizes example: eighteen Organochlorine Pesticides in soil and human breast milk samples.

Human health and the health of the environment have entwined. In this paper we underpin this position by presenting a modeling approach named CombiSimilarity, which has been developed by the first author in the software tool PyHasse comprising a wide variety of partial ordering tools. A case study of 18 Organochlorine Pesticides (OCPs) detected in soil as well as in human breast milk samples in the Taurus Mountains in Turkey is carried out. Seven soil samples and 44 breast milk samples were measured. We seek to answer the question whether the contamination pattern in breast milk is associated with the contamination pattern in soil by studying the mutual quantitative relationships of the chemicals involved. We could demonstrate that there is a similarity with respect to the concentration profiles between the soil and breast milk pollution. Therefore the hypothesis may be formulated that the concentrations of chemicals in the milk samples are strongly related to the soil contamination. This supports the concept that soil could be a surrogate for human exposure at background locations.

Evidence for an increase in trisomy 21 (Down syndrome) in Europe after the Chernobyl reactor accident.

The objective of this study is to investigate the prevalence of Down syndrome (DS) associated with Chernobyl fallout. Maternal age-adjusted DS data and corresponding live birth data from the following seven European countries or regions were analyzed: Bavaria and West Berlin in Germany, Belarus, Hungary, the Lothian Region of Scotland, North West England, and Sweden from 1981 to 1992. To assess the underlying time trends in the DS occurrence, and to investigate whether there have been significant changes in the trend functions after Chernobyl, we applied logistic regression allowing for peaks and jumps from January 1987 onward. The majority of the trisomy 21 cases of the previously reported, highly significant January 1987 clusters in Belarus and West Berlin were conceived when the radioactive clouds with significant amounts of radionuclides with short physical half-lives, especially (131)iodine, passed over these regions. Apart from this, we also observed a significant longer lasting effect in both areas. Moreover, evidence for long-term changes in the DS prevalence in several other European regions is presented and explained by exposure, especially to (137)Cs. In many areas, (137)Cs uptake reached its maximum one year after the Chernobyl accident. Thus, the highest increase in trisomy 21 should be observed in 1987/1988, which is indeed the case. Based on the fact that maternal meiosis is an error prone process, the assumption of a causal relationship between low-dose irradiation and nondisjunction is the most likely explanation for the observed increase in DS after the Chernobyl reactor accident.

Increased sex ratio in Russia and Cuba after Chernobyl: a radiological hypothesis.

BACKGROUND: The ratio of male to female offspring at birth may be a simple and non-invasive way to monitor the reproductive health of a population. Except in societies where selective abortion skews the sex ratio, approximately 105 boys are born for every 100 girls. Generally, the human sex ratio at birth is remarkably constant in large populations. After the Chernobyl nuclear power plant accident in April 1986, a long lasting significant elevation in the sex ratio has been found in Russia, i.e. more boys or fewer girls compared to expectation were born. Recently, also for Cuba an escalated sex ratio from 1987 onward has been documented and discussed in the scientific literature. PRESENTATION OF THE HYPOTHESIS: By the end of the eighties of the last century in Cuba as much as about 60% of the food imports were provided by the former Soviet Union. Due to its difficult economic situation, Cuba had neither the necessary insight nor the political strength to circumvent the detrimental genetic effects of imported radioactively contaminated foodstuffs after Chernobyl. We propose that the long term stable sex ratio increase in Cuba is essentially due to ionizing radiation. TESTING OF THE HYPOTHESIS: A synoptic trend analysis of Russian and Cuban annual sex ratios discloses upward jumps in 1987. The estimated jump height from 1986 to 1987 in Russia measures 0.51% with a 95% confidence interval (0.28, 0.75), p value < 0.0001. In Cuba the estimated jump height measures 2.99% (2.39, 3.60), p value < 0.0001. The hypothesis may be tested by reconstruction of imports from the world markets to Cuba and by radiological analyses of remains in Cuba for Cs-137 and Sr-90. IMPLICATIONS OF THE HYPOTHESIS: If the evidence for the hypothesis is strengthened, there is potential to learn about genetic radiation risks and to prevent similar effects in present and future exposure situations.

Evaluation of organochlorine pesticides in breast milk samples in Turkey applying features of the partial order technique.

Exposure data to organochlorine pesticides (OCPs) of mothers' breast milk samples were measured in different locations in the Taurus Mountains/Turkey. Villages at five altitudes were looked upon. The data analysis method applied is the Hasse diagram technique, based on Discrete Mathematics. For each of the five regions, one Hasse diagram was calculated and showed the same maximal object, namely, p-p'-Dichlorodiphenyldichloroethane (DDE). In a further data investigation step, we performed the similarity analyses of the locations in order to quantify the similarities and incomparabilities. It was revealed that no correlation exists between most altitudes and the pattern of contamination of breast milk samples. The two lowest situated areas, Sahil at sea level and Ciftlikköy at 121 m above sea level were similar. We reduced the datasets by applying the interval analysis followed by similarity analyses. We observed that endrin (END1), mirex (MIRE), and pentachlorobenzene (PECB) reduce most severely the similarity.

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.

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.