Bacteria as drug delivery vehicles

Doctor of PhilosophyDepartment of Chemical EngineeringStefan H. BossmannBoth chemotherapy for cancer treatment and antibiotic therapy for bacterial infections require systemic applications of the drug and a systemic application is always linked to a number of disadvantages. To circumvent these a targeted drug delivery system was developed. It utilizes the ability of phagocytes from the hosts own immune system to recognize and internalize antigens. Deactivated M. luteus, a non-pathogenic gram positive bacteria was loaded with high concentrations (exceeding the IC50 at least 60 fold in local intracellular concentration) the chemotherapeutics doxorubicin or DP44mt or with the bactericidal chlorhexidine. The modified bacteria is fed to phagocytes (Monocytes/Macrophages or neutrophils) and serves as protective shell for the transporting and targeting phagocyte. The phagocyte is recruited to the tumor site or site of infection and releases the drug along with the processed M. luteus via the exosome pathway upon arrival. The chlorhexidine drug delivery system was successfully tested both in vitro and in vivo, reducing the pathogen count and preventing systemic spread of a F. necrophorum infection in a mouse model. The doxorubicin drug delivery system reduced the viability of 4T1 cancer cells to 20% over the course of four days in vitro

Global age-sex-specific mortality, life expectancy, and population estimates in 204 countries and territories and 811 subnational locations, 1950–2021, and the impact of the COVID-19 pandemic: a comprehensive demographic analysis for the Global Burden of Disease Study 2021

Background: Estimates of demographic metrics are crucial to assess levels and trends of population health outcomes. The profound impact of the COVID-19 pandemic on populations worldwide has underscored the need for timely estimates to understand this unprecedented event within the context of long-term population health trends. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 provides new demographic estimates for 204 countries and territories and 811 additional subnational locations from 1950 to 2021, with a particular emphasis on changes in mortality and life expectancy that occurred during the 2020–21 COVID-19 pandemic period. Methods: 22 223 data sources from vital registration, sample registration, surveys, censuses, and other sources were used to estimate mortality, with a subset of these sources used exclusively to estimate excess mortality due to the COVID-19 pandemic. 2026 data sources were used for population estimation. Additional sources were used to estimate migration; the effects of the HIV epidemic; and demographic discontinuities due to conflicts, famines, natural disasters, and pandemics, which are used as inputs for estimating mortality and population. Spatiotemporal Gaussian process regression (ST-GPR) was used to generate under-5 mortality rates, which synthesised 30 763 location-years of vital registration and sample registration data, 1365 surveys and censuses, and 80 other sources. ST-GPR was also used to estimate adult mortality (between ages 15 and 59 years) based on information from 31 642 location-years of vital registration and sample registration data, 355 surveys and censuses, and 24 other sources. Estimates of child and adult mortality rates were then used to generate life tables with a relational model life table system. For countries with large HIV epidemics, life tables were adjusted using independent estimates of HIV-specific mortality generated via an epidemiological analysis of HIV prevalence surveys, antenatal clinic serosurveillance, and other data sources. Excess mortality due to the COVID-19 pandemic in 2020 and 2021 was determined by subtracting observed all-cause mortality (adjusted for late registration and mortality anomalies) from the mortality expected in the absence of the pandemic. Expected mortality was calculated based on historical trends using an ensemble of models. In location-years where all-cause mortality data were unavailable, we estimated excess mortality rates using a regression model with covariates pertaining to the pandemic. Population size was computed using a Bayesian hierarchical cohort component model. Life expectancy was calculated using age-specific mortality rates and standard demographic methods. Uncertainty intervals (UIs) were calculated for every metric using the 25th and 975th ordered values from a 1000-draw posterior distribution. Findings: Global all-cause mortality followed two distinct patterns over the study period: age-standardised mortality rates declined between 1950 and 2019 (a 62·8% [95% UI 60·5–65·1] decline), and increased during the COVID-19 pandemic period (2020–21; 5·1% [0·9–9·6] increase). In contrast with the overall reverse in mortality trends during the pandemic period, child mortality continued to decline, with 4·66 million (3·98–5·50) global deaths in children younger than 5 years in 2021 compared with 5·21 million (4·50–6·01) in 2019. An estimated 131 million (126–137) people died globally from all causes in 2020 and 2021 combined, of which 15·9 million (14·7–17·2) were due to the COVID-19 pandemic (measured by excess mortality, which includes deaths directly due to SARS-CoV-2 infection and those indirectly due to other social, economic, or behavioural changes associated with the pandemic). Excess mortality rates exceeded 150 deaths per 100 000 population during at least one year of the pandemic in 80 countries and territories, whereas 20 nations had a negative excess mortality rate in 2020 or 2021, indicating that all-cause mortality in these countries was lower during the pandemic than expected based on historical trends. Between 1950 and 2021, global life expectancy at birth increased by 22·7 years (20·8–24·8), from 49·0 years (46·7–51·3) to 71·7 years (70·9–72·5). Global life expectancy at birth declined by 1·6 years (1·0–2·2) between 2019 and 2021, reversing historical trends. An increase in life expectancy was only observed in 32 (15·7%) of 204 countries and territories between 2019 and 2021. The global population reached 7·89 billion (7·67–8·13) people in 2021, by which time 56 of 204 countries and territories had peaked and subsequently populations have declined. The largest proportion of population growth between 2020 and 2021 was in sub-Saharan Africa (39·5% [28·4–52·7]) and south Asia (26·3% [9·0–44·7]). From 2000 to 2021, the ratio of the population aged 65 years and older to the population aged younger than 15 years increased in 188 (92·2%) of 204 nations. Interpretation: Global adult mortality rates markedly increased during the COVID-19 pandemic in 2020 and 2021, reversing past decreasing trends, while child mortality rates continued to decline, albeit more slowly than in earlier years. Although COVID-19 had a substantial impact on many demographic indicators during the first 2 years of the pandemic, overall global health progress over the 72 years evaluated has been profound, with considerable improvements in mortality and life expectancy. Additionally, we observed a deceleration of global population growth since 2017, despite steady or increasing growth in lower-income countries, combined with a continued global shift of population age structures towards older ages. These demographic changes will likely present future challenges to health systems, economies, and societies. The comprehensive demographic estimates reported here will enable researchers, policy makers, health practitioners, and other key stakeholders to better understand and address the profound changes that have occurred in the global health landscape following the first 2 years of the COVID-19 pandemic, and longer-term trends beyond the pandemic

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

First operation of the KATRIN experiment with tritium

The determination of the neutrino mass is one of the major challenges in astroparticle physics today. Direct neutrino mass experiments, based solely on the kinematics of β β -decay, provide a largely model-independent probe to the neutrino mass scale. The Karlsruhe Tritium Neutrino (KATRIN) experiment is designed to directly measure the effective electron antineutrino mass with a sensitivity of 0.2 eV 0.2 eV (90% 90% CL). In this work we report on the first operation of KATRIN with tritium which took place in 2018. During this commissioning phase of the tritium circulation system, excellent agreement of the theoretical prediction with the recorded spectra was found and stable conditions over a time period of 13 days could be established. These results are an essential prerequisite for the subsequent neutrino mass measurements with KATRIN in 2019

Transverse polarisation measurement of Λ\Lambda hyperons in ppNe collisions at sNN\sqrt{s_{NN}}=68.4 GeV with the LHCb detector

A measurement of the transverse polarization of the $\Lambda$ and $\bar{\Lambda}$hyperons in $p$Ne fixed-target collisions at $\sqrt{s_{NN}}$=68.4 GeV is presented using data collected by the LHCb detector. The polarization is studied using the decay $\Lambda \rightarrow p \pi^-$ together with its charge conjugated process, the integrated values measured are $$P_{\Lambda} = 0.029 \pm 0.019 \, (\rm{stat}) \pm 0.012 \, (\rm{syst}) \, ,$$ $$P_{\bar{\Lambda}} = 0.003 \pm 0.023 \, (\rm{stat}) \pm 0.014 \,(\rm{syst}) \,$$ Furthermore, the results are shown as a function of the Feynman $x$ variable, transverse momentum, pseudorapidity and rapidity of the hyperons, and are compared with previous measurements.A measurement of the transverse polarization of the $\Lambda$ and $\bar{\Lambda}$ hyperons in $p$Ne fixed-target collisions at $\sqrt{s_{NN}}$ = 68.4 GeV is presented using data collected by the LHCb detector. The polarization is studied using the decay $\Lambda \rightarrow p \pi^-$ together with its charge conjugated process, the integrated values measured are $$P_{\Lambda} = 0.029 \pm 0.019 \, (\rm{stat}) \pm 0.012 \, (\rm{syst}) \, ,$$ $$P_{\bar{\Lambda}} = 0.003 \pm 0.023 \, (\rm{stat}) \pm 0.014 \,(\rm{syst}) \,.$$ Furthermore, the results are shown as a function of the Feynman~$x$~variable, transverse momentum, pseudorapidity and rapidity of the hyperons, and are compared with previous measurements

Tracking of charged particles with nanosecond lifetimes at LHCb

A method is presented to reconstruct charged particles with lifetimes between 10 ps and 10 ns, which considers a combination of their decay products and the partial tracks created by the initial charged particle. Using the $\Xi^-$ baryon as a benchmark, the method is demonstrated with simulated events and proton-proton collision data at $\sqrt{s}=13$ TeV, corresponding to an integrated luminosity of 2.0 fb${}^{-1}$ collected with the LHCb detector in 2018. Significant improvements in the angular resolution and the signal purity are obtained. The method is implemented as part of the LHCb Run 3 event trigger in a set of requirements to select detached hyperons. This is the first demonstration of the applicability of this approach at the LHC, and the first to show its scaling with instantaneous luminosity

Measurement of D0−D‾0D^0-\overline{D}^0 mixing and search for CPCP violation with D0→K+π−D^0\rightarrow K^+\pi^- decays

International audienceA measurement of the time-dependent ratio of the $D^0\rightarrow K^+\pi^-$ to $\overline{D}^0\rightarrow K^+\pi^-$ decay rates is reported. The analysis uses a sample of proton-proton collisions corresponding to an integrated luminosity of 6 fb$^-1$ recorded by the LHCb experiment from 2015 through 2018 at a center-of-mass energy of 13 TeV. The $D^0$ meson is required to originate from a $D^{*+}\rightarrow D^0\pi^+$ decay, such that its flavor at production is inferred from the charge of the accompanying pion. The measurement is performed simultaneously for the $K^+\pi^-$ and $K^-\pi^+$ final states, allowing both mixing and $CP$-violation parameters to be determined. The value of the ratio of the decay rates at production is determined to be $R_{K\pi} = (343.1 \pm 2.0) \times 10^{-5}$. The mixing parameters are measured to be $c_{K\pi} = (51.4 \pm 3.5) \times 10^{-4}$ and $c_{K\pi}^{\prime} = (13 \pm 4) \times 10^{-6}$, where $\sqrt{R_{K\pi}}c_{K\pi}$ is the linear coefficient of the expansion of the ratio as a function of decay time in units of the $D^0$ lifetime, and $c_{K\pi}^{\prime}$ is the quadratic coefficient, both averaged between the $K^+\pi^-$ and $K^-\pi^+$ final states. The precision is improved relative to the previous best measurement by approximately 60%. No evidence for $CP$ violation is found

Tracking of charged particles with nanosecond lifetimes at LHCb

International audienceA method is presented to reconstruct charged particles with lifetimes between 10 ps and 10 ns, which considers a combination of their decay products and the partial tracks created by the initial charged particle. Using the $\Xi^-$ baryon as a benchmark, the method is demonstrated with simulated events and proton-proton collision data at $\sqrt{s}=13$ TeV, corresponding to an integrated luminosity of 2.0 fb${}^{-1}$ collected with the LHCb detector in 2018. Significant improvements in the angular resolution and the signal purity are obtained. The method is implemented as part of the LHCb Run 3 event trigger in a set of requirements to select detached hyperons. This is the first demonstration of the applicability of this approach at the LHC, and the first to show its scaling with instantaneous luminosity

Amplitude analysis and branching fraction measurement of B+→D∗−Ds+π+B^{+}\to D^{*-}D^{+}_{s}\pi^{+} decays

International audienceThe decays of the $B^{+}$ meson to the final state $D^{*-}D^{+}_{s}\pi^{+}$ are studied in proton-proton collision data collected with the LHCb detector at centre-of-mass energies of 7, 8, and 13 TeV, corresponding to a total integrated luminosity of 9 fb$^{-1}$. The ratio of branching fractions of the $B^{+}\to D^{*-}D^{+}_{s}\pi^{+}$ and $B^{0}\to D^{*-}D^{+}_{s}$ decays is measured to be $0.173\pm 0.006\pm 0.010$, where the first uncertainty is statistical and the second is systematic. Using partially reconstructed $D^{*+}_{s}\to D^{+}_{s}\gamma$ and $D^{+}_{s}\pi^{0}$ decays, the ratio of branching fractions between the $B^{+}\to D^{*-}D^{*+}_{s}\pi^{+}$ and $B^{+}\to D^{*-}D^{+}_{s}\pi^{+}$ decays is determined as $1.31\pm 0.07\pm 0.14$. An amplitude analysis of the $B^{+}\to D^{*-}D^{+}_{s}\pi^{+}$ decay is performed for the first time, revealing dominant contributions from known excited charm resonances decaying to the $D^{*-}\pi^{+}$ final state. No significant evidence of exotic contributions in the $D^{+}_{s}\pi^{+}$ or $D^{*-}D^{+}_{s}$ channels is found. The fit fraction of the scalar state $T_{c\bar{s} 0}^{\ast}(2900)^{++}$ observed in the $B^{+}\to D^{-}D^{+}_{s}\pi^{+}$ decay is determined to be less than 2.3% at a 90% confidence level