Excess mortality in Europe coincides with peaks of COVID-19, influenza and respiratory syncytial virus (RSV), November 2023 to February 2024.

Since the end of November 2023, the European Mortality Monitoring Network (EuroMOMO) has observed excess mortality in Europe. During weeks 48 2023-6 2024, preliminary results show a substantially increased rate of 95.3 (95% CI:  91.7-98.9) excess all-cause deaths per 100,000 person-years for all ages. This excess mortality is seen in adults aged 45 years and older, and coincides with widespread presence of COVID-19, influenza and respiratory syncytial virus (RSV) observed in many European countries during the 2023/24 winter season.

The adverse effect of ambient temperature on respiratory deaths in a high population density area: the case of Malta.

BACKGROUND: The effect of ambient temperature on respiratory mortality has been consistently observed throughout the world under different climate change scenarios. Countries experiencing greater inter-annual variability in winter temperatures (and may not be lowest winter temperatures) have greater excess winter mortality compared to countries with colder winters. This study investigates the association between temperature and respiratory deaths in Malta which has one of the highest population densities in the world with a climate that is very hot in summer and mild in winter. METHODS: Daily number of respiratory deaths (7679 deaths) and meteorological data (daily average temperature, daily average humidity) were obtained from January 1992 to December 2017. The hot and cold effects were estimated at different temperatures using distributed lag non-linear models (DLNM) with a Poisson distribution, controlling for time trend, relative humidity and holidays. The reference temperature (MMT) for the minimum response-exposure relationship was estimated and the harvesting effects of daily temperature (0-27 lag days) were investigated for daily respiratory mortality. Effects were also explored for different age groups, gender and time periods. RESULTS: Cooler temperatures (8-15 °C) were significantly related to higher respiratory mortality. At 8.9 °C (1st percentile), the overall effect of daily mean temperature was related to respiratory deaths (RR 2.24, 95%CI 1.10-4.54). These effects were also found for males (95%CI 1.06-7.77) and males across different age groups (Males Over 65 years: RR 4.85, 95%CI 2.02-11.63 vs Males between 16 and 64 years: RR 5.00, 95%CI 2.08-12.03) but not for females. Interestingly, colder temperatures were related to respiratory deaths in the earliest time period (1992-2000), however, no strong cold effect was observed for later periods (2000-2017). In contrast, no heat effect was observed during the study period and across other groups. CONCLUSIONS: The higher risk for cold-related respiratory mortality observed in this study could be due to greater inter-annual variability in winter temperatures which needs further exploration after adjusting for potential physical and socio-demographic attributes. The study provides useful evidence for policymakers to improve local warning systems, adaptation, and intervention strategies to reduce the impact of cold temperatures.

When the patients stayed home: the impact of the COVID-19 pandemic on acute cardiac admissions and cardiac mortality in Malta.

Aim: This study aimed to investigate the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on all types of acute cardiac admissions (ACAs) and cardiac mortality in Malta. Methods: Number, characteristics and delay to presentation of ACAs to our institution during the study period (28 February-30 April 2020) were compared with the corresponding 2019 period. Non-parametric correlation analyses between daily SARS-CoV-2 cases in Malta, Italy and the UK and daily ACAs were performed. Differences in cardiac death distribution (community vs. in-hospital) during the two periods were analysed. Results: There was a significant decline in daily ACAs in 2020 (median 3 [IQR 3]) vs. 2019 (median 5 [IQR 4]), p < 0.001. Patient characteristics were comparable. Delay to presentation for 2020 ACAs was significantly higher across all categories (ST-elevation myocardial infarction [STEMI] median: 2019 [1 h, IQR 1] vs. 2020 [4 h, IQR 43.8], p = 0.009; non-ST-elevation-acute coronary syndrome [NSTE-ACS] median: 2019 [4 h, IQR 71] vs. 2020 [48 h, IQR 199], p = 0.001; non-ACS median: 2019 [24 h, IQR 95] vs. 2020 [84 h, IQR 499.8], p < 0.001). There was a significant negative correlation between ACAs and daily Malta SARS-CoV-2 infection cases (r s = -0.298, p = 0.018) but not with cases in Italy and the UK when controlling for Malta cases. Significantly more cardiac deaths occurred in the community in 2020 (107, 61.8%) compared to 2019 (87, 46.8%) (p = 0.004). Conclusion: Fear of SARS-CoV-2 infection led to a significant avoidance of acute cardiac care with an accompanying rise in community cardiac deaths, suggesting a need for better public education on recognising and addressing cardiovascular symptoms.

Real-time monitoring shows substantial excess all-cause mortality during second wave of COVID-19 in Europe, October to December 2020.

The European monitoring of excess mortality for public health action (EuroMOMO) network monitors weekly excess all-cause mortality in 27 European countries or subnational areas. During the first wave of the coronavirus disease (COVID-19) pandemic in Europe in spring 2020, several countries experienced extraordinarily high levels of excess mortality. Europe is currently seeing another upsurge in COVID-19 cases, and EuroMOMO is again witnessing a substantial excess all-cause mortality attributable to COVID-19.

The effect of global warming on mortality.

There is a significant relationship between ambient temperature and mortality. In healthy individuals with no underlying co-morbid conditions, there is an efficient heat regulation system which enables the body to effectively handle thermal stress. However, in vulnerable groups, especially in elderly over the age of 65 years, infants and individuals with co-morbid cardiovascular and/or respiratory conditions, there is a deficiency in thermoregulation. When temperatures exceed a certain limit, being cold winter spells or heat waves, there is an increase in the number of deaths. In particular, it has been shown that at temperatures above 27 °C, the daily mortality rate increases more rapidly per degree rise compared to when it drops below 27 °C. This is especially of relevance with the current emergency of global warming. Besides the direct effect of temperature rises on human health, global warming will have a negative impact on primary producers and livestock, leading to malnutrition, which will in turn lead to a myriad of health related issues. This is further exacerbated by environmental pollution. Public health measures that countries should follow should include not only health-related information strategies aiming to reduce the exposure to heat for vulnerable individuals and the community, but improved urban planning and reduction in energy consumption, among many others. This will reduce the carbon footprint and help avert global warming, thus reducing mortality.

Excess all-cause mortality during the COVID-19 pandemic in Europe - preliminary pooled estimates from the EuroMOMO network, March to April 2020.

A remarkable excess mortality has coincided with the COVID-19 pandemic in Europe. We present preliminary pooled estimates of all-cause mortality for 24 European countries/federal states participating in the European monitoring of excess mortality for public health action (EuroMOMO) network, for the period March-April 2020. Excess mortality particularly affected ≥ 65 year olds (91% of all excess deaths), but also 45-64 (8%) and 15-44 year olds (1%). No excess mortality was observed in 0-14 year olds.

Adoption and uptake of the lateral flow urine LAM test in countries with high tuberculosis and HIV/AIDS burden: current landscape and barriers.

Background: Since 2015, the World Health Organization (WHO) has recommended a commercially available lateral-flow urine LAM test (Alere-LAM) to assist in the diagnosis of tuberculosis (TB) in severely ill people living with HIV (PLHIV). The test can rapidly detect TB in severely ill PLHIV and can identify PLHIV most at-risk of death, leading to mortality reductions. However, its uptake in countries with high burdens of TB and HIV has been slow. To assess the current use landscape and identify barriers to the adoption of Alere-LAM, we conducted a questionnaire-based study in 31 high TB and HIV/AIDS burden countries. Methods: Between November 2018 and December 2019, we collected responses to a semi-structured questionnaire that had been emailed to staff and affiliates of National TB Programs or HIV/AIDS Programs, Ministries of Health, and TB or HIV institutes of 31 high TB/HIV burden countries. Questions concerned country policies, adoption, and current use of Alere-LAM testing, as well as testing algorithms and barriers preventing Alere-LAM uptake. Results: We received questionnaire responses from 24 out of 31 (77%) high TB/HIV burden countries. Of these 24 countries, 11 (46%) had adopted Alere-LAM policies, with only five (21%) countries currently using Alere-LAM testing. Testing algorithms were generally aligned with WHO recommendations. Fifteen countries (63%) said they were planning to implement Alere-LAM testing in the near future. The most commonly cited constraint to adoption and implementation was budget limitations. Additional barriers to Alere-LAM implementation included lack of country-specific data and piloting, administrative hurdles such as regulatory agency approval, lack of coordination between National TB and HIV programs, and small perceived patient population. Conclusion: Responses to our questionnaire demonstrate the persistent gap between country-level policy and real-world use of Alere-LAM, as well as specific barriers that must be addressed to scale-up testing in PLHIV.

Cervical cancer and screening: knowledge, awareness and attitudes of women in Malta.

OBJECTIVES: This study comes at an opportune time due to recent introduction of the National Cervical Cancer Screening programme in Malta. It aims to assess the knowledge of 25-64 year-old females on cervical cancer and attitudes towards screening. STUDY DESIGN: A cross-sectional, telephone-based, quantitative survey conducted in 2017. METHODS: The survey tool was based on the Cervical Cancer Awareness Measure questionnaire and was carried out among a random stratified sample of females of 25-64 years, resident in Malta. Multivariate logistic regression models were applied. RESULTS: 407 females (85% response rate) were interviewed. Knowledge of cervical cancer risk factors and symptoms was found to be significantly higher in women with a higher level of education (p < 0.001). Cervical screening was attended every 3 years by 69% of respondents. Regular attendees were more likely to have children (p = 0.001), have experienced cancer in a close family member (p = 0.002), and were between 35-44 and 45-54 years old (p < 0.001). The main reasons for non-attendance were embarrassment, fear of the test and fear of the result. CONCLUSION: This research provides a better understanding of who are the vulnerable groups with respect to cervical cancer knowledge and screening attendance. Improving health literacy and implementing health promotion campaigns will improve early symptom recognition, risk factor knowledge and attendance for screening.

Demographic trends and public health in Europe.

Demographic trends in Europe are currently being shaped by an ageing population, falling fertility rates and diverse migration flows. Fertility rates are lowest in Eastern and Southern Europe with Eastern Europe also experiencing the lowest net migration and an exodus of its working population. All regions in Europe are experiencing aging of their population with some countries having the added burden of high rates of unemployment among the working age population. The impact of these demographic changes on the current and future public health of the country depends on how countries have been preparing and adapting to demographic changes over the past years. Changes in age structure and ethnic composition will put further strain on health care and welfare systems and requires careful planning. A multi-faceted approach which goes beyond the health care system is required and countries need to look beyond their borders in search as to how countries are tackling these important issues. As Europe ages the concept of healthy aging should become an increasing priority focus for European Public Health.

The within-host population dynamics of Mycobacterium tuberculosis vary with treatment efficacy.

BACKGROUND: Combination therapy is one of the most effective tools for limiting the emergence of drug resistance in pathogens. Despite the widespread adoption of combination therapy across diseases, drug resistance rates continue to rise, leading to failing treatment regimens. The mechanisms underlying treatment failure are well studied, but the processes governing successful combination therapy are poorly understood. We address this question by studying the population dynamics of Mycobacterium tuberculosis within tuberculosis patients undergoing treatment with different combinations of antibiotics. RESULTS: By combining very deep whole genome sequencing (~1000-fold genome-wide coverage) with sequential sputum sampling, we were able to detect transient genetic diversity driven by the apparently continuous turnover of minor alleles, which could serve as the source of drug-resistant bacteria. However, we report that treatment efficacy has a clear impact on the population dynamics: sufficient drug pressure bears a clear signature of purifying selection leading to apparent genetic stability. In contrast, M. tuberculosis populations subject to less drug pressure show markedly different dynamics, including cases of acquisition of additional drug resistance. CONCLUSIONS: Our findings show that for a pathogen like M. tuberculosis, which is well adapted to the human host, purifying selection constrains the evolutionary trajectory to resistance in effectively treated individuals. Nonetheless, we also report a continuous turnover of minor variants, which could give rise to the emergence of drug resistance in cases of drug pressure weakening. Monitoring bacterial population dynamics could therefore provide an informative metric for assessing the efficacy of novel drug combinations.

Excess all-cause and influenza-attributable mortality in Europe, December 2016 to February 2017.

Since December 2016, excess all-cause mortality was observed in many European countries, especially among people aged ≥ 65 years. We estimated all-cause and influenza-attributable mortality in 19 European countries/regions. Excess mortality was primarily explained by circulation of influenza virus A(H3N2). Cold weather snaps contributed in some countries. The pattern was similar to the last major influenza A(H3N2) season in 2014/15 in Europe, although starting earlier in line with the early influenza season start.

Contribution of Congenital Anomalies to Neonatal Mortality Rates in Malta.

BACKGROUND: Neonatal mortality is a public health concern, and congenital anomalies contribute significantly to this mortality. This paper describes trends in neonatal mortality in Malta separately for congenital anomaly and non-congenital anomaly causes. METHODS: Data for neonatal deaths of 22-week gestation onwards registered between 1994-2013 were obtained from the National Mortality Register. Chi-square tests were used to analyse 5-year time trends and differences in proportions of causes of neonatal deaths. Neonatal mortality was compared with other European countries. RESULTS: Between 1994 and 2013, 441 neonatal deaths and 84 821 livebirths were registered, giving a neonatal mortality of 5.2 per 1000 livebirths. Congenital anomalies accounted for 36.7% (n = 162) of the neonatal deaths, while the remaining 63.3% (n = 279) were attributed to non-congenital causes. During the 20-year period, neonatal mortality due to non-congenital causes decreased from 4.6 per 1000 livebirths in 1994-98 to 2.5 per 1000 in 2009-13, while that due to congenital anomalies remained stable (2.0 per 1000 livebirths in 1994-98 and 2.2 per 1000 in 2009-13). This has resulted in comparatively higher proportions of neonatal deaths attributed to congenital anomalies in recent years (45.9% in 2009-13 vs. 29.9% in 1994-98). Comparing neonatal mortality reported from European countries, Malta has a high rate most marked for deaths due to congenital anomalies. CONCLUSIONS: During 1994-2013, neonatal mortality has decreased due to a decline of non-congenital causes of death, possibly related to improved health care. The proportionate neonatal mortality attributed to congenital anomalies has increased and is the highest reported from Europe. This may be explained by the fact that termination of pregnancy is illegal in Malta.

A sterilizing tuberculosis treatment regimen is associated with faster clearance of bacteria in cavitary lesions in marmosets.

Shortening the lengthy treatment duration for tuberculosis patients is a major goal of current drug development efforts. The common marmoset develops human-like disease pathology and offers an attractive model to better understand the basis for relapse and test regimens for effective shorter duration therapy. We treated Mycobacterium tuberculosis-infected marmosets with two drug regimens known to differ in their relapse rates in human clinical trials: the standard four-drug combination of isoniazid, rifampin, pyrazinamide, and ethambutol (HRZE) that has very low relapse rates and the combination of isoniazid and streptomycin that is associated with higher relapse rates. As early as 2 weeks, the more sterilizing regimen significantly reduced the volume of lung disease by computed tomography (P = 0.035) and also significantly reduced uptake of [(18)F]-2-fluoro-2-deoxyglucose by positron emission tomography (P = 0.049). After 6 weeks of therapy, both treatments caused similar reductions in granuloma bacterial load, but the more sterilizing, four-drug regimen caused greater reduction in bacterial load in cavitary lesions (P = 0.009). These findings, combined with the association in humans between cavitary disease and relapse, suggest that the basis for improved sterilizing activity of the four-drug combination is both its faster disease volume resolution and its stronger sterilizing effect on cavitary lesions. Definitive data from relapse experiments are needed to support this observation.

MadR1, a Mycobacterium tuberculosis cell cycle stress response protein that is a member of a widely conserved protein class of prokaryotic, eukaryotic and archeal origin.

Stress-induced molecular programs designed to stall division progression are nearly ubiquitous in bacteria, with one well-known example being the participation of the SulA septum inhibiting protein in the SOS DNA damage repair response. Mycobacteria similarly demonstrate stress-altered growth kinetics, however no such regulators have been found in these organisms. We therefore set out to identify SulA-like regulatory proteins in Mycobacterium tuberculosis. A bioinformatics modeling-based approach led to the identification of rv2216 as encoding for a protein with weak similarity to SulA, further analysis distinguished this protein as belonging to a group of uncharacterized growth promoting proteins. We have named the mycobacterial protein encoded by rv2216 morphology altering division regulator protein 1, MadR1. Overexpression of madR1 modulated cell length while maintaining growth kinetics similar to wild-type, and increased the proportion of bent or V-form cells in the population. The presence of MadR1-GFP at regions of cellular elongation (poles) and morphological differentiation (V-form) suggests MadR1 involvement in phenotypic heterogeneity and longitudinal cellular growth. Global transcriptional analysis indicated that MadR1 functionality is linked to lipid editing programs required for growth and persistence. This is the first report to differentiate the larger class of these conserved proteins from SulA proteins and characterizes MadR1 effects on the mycobacterial cell.

Anti-vascular endothelial growth factor treatment normalizes tuberculosis granuloma vasculature and improves small molecule delivery.

Tuberculosis (TB) causes almost 2 million deaths annually, and an increasing number of patients are resistant to existing therapies. Patients who have TB require lengthy chemotherapy, possibly because of poor penetration of antibiotics into granulomas where the bacilli reside. Granulomas are morphologically similar to solid cancerous tumors in that they contain hypoxic microenvironments and can be highly fibrotic. Here, we show that TB-infected rabbits have impaired small molecule distribution into these disease sites due to a functionally abnormal vasculature, with a low-molecular-weight tracer accumulating only in peripheral regions of granulomatous lesions. Granuloma-associated vessels are morphologically and spatially heterogeneous, with poor vessel pericyte coverage in both human and experimental rabbit TB granulomas. Moreover, we found enhanced VEGF expression in both species. In tumors, antiangiogenic, specifically anti-VEGF, treatments can "normalize" their vasculature, reducing hypoxia and creating a window of opportunity for concurrent chemotherapy; thus, we investigated vessel normalization in rabbit TB granulomas. Treatment of TB-infected rabbits with the anti-VEGF antibody bevacizumab significantly decreased the total number of vessels while normalizing those vessels that remained. As a result, hypoxic fractions of these granulomas were reduced and small molecule tracer delivery was increased. These findings demonstrate that bevacizumab treatment promotes vascular normalization, improves small molecule delivery, and decreases hypoxia in TB granulomas, thereby providing a potential avenue to improve delivery and efficacy of current treatment regimens.

Drivers of Inpatient Hospital Experience Using the HCAHPS Survey in a Canadian Setting.

OBJECTIVE: To identify factors associated with patients' overall rating of inpatient hospital care. DATA SOURCES: Two years of patient interview data (April 1, 2011 to March 31, 2013), linked to inpatient administrative records. STUDY DESIGN: Patients rated their overall health on a scale of 0 (worst care) to 10 (best care) using the HCAHPS instrument administered via telephone, up to 42 days postdischarge. Logistic regression was used to generate odds ratios for each independent predictor. DATA EXTRACTION: HCAHPS data were linked to inpatient records based on health care numbers and dates of service. The outcome (overall health experience) was collapsed into two groups (10 vs. 0-9). PRINCIPAL FINDINGS: Overall hospital experience of 0-9 was associated with younger age, male gender, higher level of education, being born in Canada, urgent admission, not having a family practitioner as the most responsible provider service, and not being discharged home. A length of stay of less than 3 days was protective. The c-statistic for the multivariate model was 0.635. CONCLUSIONS: Our results are novel in the Canadian population. Several questions for future research have been generated, in addition to opportunities for quality improvement within our own organization.

MazF6 toxin of Mycobacterium tuberculosis demonstrates antitoxin specificity and is coupled to regulation of cell growth by a Soj-like protein.

BACKGROUND: Molecular programs employed by Mycobacterium tuberculosis (Mtb) for the establishment of non-replicating persistence (NRP) are poorly understood. In order to investigate mechanisms regulating entry into NRP, we asked how cell cycle regulation is linked to downstream adaptations that ultimately result in NRP. Based on previous reports and our recent studies, we reason that, in order to establish NRP, cells are halted in the cell cycle at the point of septum formation by coupled regulatory mechanisms. RESULTS: Using bioinformatic consensus modeling, we identified an alternative cell cycle regulatory element, Soj(Mtb) encoded by rv1708. Soj(Mtb) coordinates a regulatory mechanism involving cell cycle control at the point of septum formation and elicits the induction of the MazF6 toxin. MazF6 functions as an mRNA interferase leading to bacteriostasis that can be prevented by interaction with its cognate antitoxin, MazE6. Further, MazEF6 acts independently of other Maz family toxin:antitoxin pairs. Notably, soj(Mtb) and mazEF6 transcripts where identified at 20, 40 and 100 days post-infection in increasing abundance indicating a role in adaption during chronic infection. CONCLUSIONS: Here we present the first evidence of a coupled regulatory system in which cell cycle regulation via Soj(Mtb) is linked to downstream adaptations that are facilitated through the activity of the MazEF6 TA pair.

Meropenem-clavulanic acid shows activity against Mycobacterium tuberculosis in vivo.

The carbapenems imipenem and meropenem in combination with clavulanic acid reduced the bacterial burden in Mycobacterium tuberculosis-infected macrophages by 2 logs over 6 days. Despite poor stability in solution and a short half-life in rodents, treatment of chronically infected mice revealed significant reductions of bacterial burden in the lungs and spleens. Our results show that meropenem has activity in two in vivo systems, but stability and pharmacokinetics of long-term administration will offer significant challenges to clinical evaluation.

Lessons learned about pneumonic plague diagnosis from two outbreaks, Democratic Republic of the Congo.

Pneumonic plague is a highly transmissible infectious disease for which fatality rates can be high if untreated; it is considered extremely lethal. Without prompt diagnosis and treatment, disease management can be problematic. In the Democratic Republic of the Congo, 2 outbreaks of pneumonic plague occurred during 2005 and 2006. In 2005, because of limitations in laboratory capabilities, etiology was confirmed only through retrospective serologic studies. This prompted modifications in diagnostic strategies, resulting in isolation of Yersinia pestis during the second outbreak. Results from these outbreaks demonstrate the utility of a rapid diagnostic test detecting F1 antigen for initial diagnosis and public health management, as well as the need for specialized sampling kits and trained personnel for quality specimen collection and appropriate specimen handling and preservation for plague confirmation and Y. pestis isolation. Efficient frontline management and a streamlined diagnostic strategy are essential for confirming plague, especially in remote areas.