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The aim of the article is to analyze the calls to the Estonian Emergency Response Centre, focusing on instances where callers reduce the severity of incident or emergency in their first turn. The data comprise 39 calls from the Corpus of Emergency Calls of the University of Tartu. The analysis reveals that callers employ mitigating words and negative turn-initial utterances to reduce the severity. These words indicate the caller’s uncertainty about the information provided or suggest that the reported incident or emergency is minor. The utterances are syntactically and semantically (but not prosodically) completed clauses followed by a second part of the clause construction containing specific information about the caller’s issue. Functionally, these utterances serve as assessments falling into three groups based on the information they project. Some assessments project uncertain information, explicitly expressing uncertainty about the information or using the epistemic marker ma=i=tea ‘I don’t know’. The second group of assessments project information about an incident that the caller does not qualify as an emergency. The last group projects a potential incident or emergency using variants of the utterance ei juhtund midagi ‘nothing happened’. In addition, we offer explanations for why callers reduce the severity of the incident or emergency and demonstrate that reducing severity does not lower the probability of sending assistance. This indicates that call-takers do not rely on callers’ assessments when deciding whether the help is needed.

Measurements of carbon-14-containing carbon monoxide (14CO) in glacial ice are useful for studies of the past oxidative capacity of the atmosphere as well as for reconstructing the past cosmic ray flux. The 14CO abundance in glacial ice represents the combination of trapped atmospheric 14CO and in situ cosmogenic 14CO. The systematics of in situ cosmogenic 14CO production and retention in ice are not fully quantified, posing an obstacle to interpretation of ice core 14CO measurements. Here we provide the first comprehensive characterization of 14CO at an ice accumulation site (Summit, Greenland), including measurements in the ice grains of the firn matrix, firn air and bubbly ice below the firn zone. The results are interpreted with the aid of a firn gas transport model into which we implemented in situ cosmogenic 14C. We find that almost all (≈ 99.5 %) of in situ 14CO that is produced in the ice grains in firn is very rapidly (in <1 year) lost to the open porosity and from there mostly vented to the atmosphere. The timescale of this rapid loss is consistent with what is expected from gas diffusion through ice. The small fraction of in situ 14CO that initially stays in the ice grains continues to slowly leak out to the open porosity at a rate of ≈ 0.6 % yr−1. Below the firn zone we observe an increase in 14CO content with depth that is due to in situ 14CO production by deep-penetrating muons, confirming recent estimates of 14CO production rates in ice via the muon mechanisms and allowing for narrowing constraints on these production rates.

Abstract Introduction Serological surveys offer the most direct measurement to define the immunity status for numerous infectious diseases, such as COVID-19, and can provide valuable insights into understanding transmission patterns. This study describes seroprevalence changes over time in the context of the Democratic Republic of Congo, where COVID-19 case presentation was apparently largely oligo- or asymptomatic, and vaccination coverage remained extremely low. Methods A cohort of 635 health care workers (HCW) from 5 health zones of Kinshasa and 670 of their household members was interviewed and sampled in 6 rounds between July 2020 and January 2022. At each round, information on risk exposure and a blood sample were collected. Serology was defined as positive when binding antibodies against SARS-CoV-2 spike and nucleocapsid proteins were simultaneously present. Results The SARS-CoV-2 antibody seroprevalence was high at baseline, 17.3% (95% CI 14.4–20.6) and 7.8% (95% CI 5.5–10.8) for HCW and household members, respectively, and fluctuated over time, between 9% and 62.1%. Seropositivity was heterogeneously distributed over the health zones (p

IntroductionSoluble guanylate cyclase (sGC) stimulators and activators are known to enhance kidney function in various models of chronic kidney disease (CKD) by increasing cyclic guanosine monophosphate (cGMP). Their differential effects on CKD progression, particularly under conditions of oxidative stress, remain unexplored by direct comparative studies.MethodsWe conducted a side-by-side comparison using 5/6 nephrectomized rats on a high salt diet (5/6Nx+HSD) to evaluate the efficacy of the sGC stimulator BAY 41–8543 and the sGC activator BAY 60–2770 in CKD progression. BAY 41–8543 (1 mg/kg; twice daily) and BAY 60–2770 (1 mg/kg; once daily) were administered by gavage for 11 weeks.ResultsThe 5/6Nx+HSD model led to increased plasma creatinine, proteinuria, and blood pressure. Both BAY 41–8543 and BAY 60–2770 significantly reduced systolic and diastolic blood pressure to a similar extent but did not improve renal function parameters. Notably, BAY 60–2770 reduced renal fibrosis, including interstitial fibrosis and glomerulosclerosis, whereas BAY 41–8543 did not. These antifibrotic effects of BAY 60–2770 were independent of blood pressure reduction. Proteomic analysis revealed that BAY 60–2770 corrected the upregulation of 9 proteins associated with apoptosis and fibrosis, including Caspase-3, MKK6 (Mitogen-Activated Protein Kinase Kinase 6), Prdx5 (Peroxiredoxin-5), in the 5/6Nx+HSD group.DiscussionIn contrast, BAY 41–8543 had no significant impact on these proteins. sGC activators were more effective than sGC stimulators in reducing renal fibrosis in 5/6 nephrectomized rats on a high salt diet, and this effect was due to modulation of apoptosis-associated proteins beyond the control of blood pressure.

AimsTo assess the predictive value of estradiol (E2) related parameters on the incidence of gestational diabetes mellitus (GDM) in women undergoing fresh embryo transfer.Materials and methodsA Post-hoc analysis of a prospective cohort study.ResultsWe identified an optimal E2/follicle (E2/F) ratio threshold of 246.03 pg/ml on the day of human chorionic gonadotropin (hCG) administration. Women with an E2/F ratio exceeding this threshold had significantly lower rates of GDM (12.75% vs. 20.41%, P < 0.001) and ovarian hyperstimulation syndrome (OHSS) (11.75% vs. 15.48%, P = 0.03). Additional E2 parameters were also evaluated: baseline E2, E2 on hCG day, E2 increase, and E2 fold change. Lower GDM rates were observed in women with baseline E2 above 31.50 pg/ml (13.51% vs. 19.42%, P

Abstract Background While healthcare policy has fostered implementation strategies to improve inclusion and access of under-served groups to clinical care, systemic and structural elements still disproportionately prevent service users from accessing research opportunities embedded within clinical settings. This contributes to the widening of health inequalities, as the absence of representativeness prevents the applicability and effectiveness of evidence-based interventions in under-served clinical populations. The present study aims to identify the individual (micro), organisational (meso) and structural (macro) barriers to clinical research access in patients with comorbid alcohol use disorder and alcohol-related liver disease. Methods A focused ethnography approach was employed to explore the challenges experienced by patients in the access to and implementation of research processes within clinical settings. Data were collected through an iterative-inductive approach, using field notes and patient interview transcripts. The framework method was utilised for data analysis, and themes were identified at the micro, meso and macro levels. Results At the micro-level, alcohol-related barriers included encephalopathy and acute withdrawal symptoms. Alcohol-unrelated barriers also shaped the engagement of service users in research. At the meso-level, staff and resource pressures, as well as familiarity with clinical and research facilities were noted as influencing intervention delivery and study retention. At the wider, macro-level, circumstances including the ‘cost of living crisis’ and national industrial action within healthcare settings had an impact on research processes. The findings emphasise a ‘domino effect’ across all levels, demonstrating an interplay between individual, organisational and structural elements influencing access to clinical research. Conclusions A combination of individual, organisational and structural barriers, exacerbated by the COVID-19 pandemic, and the socioeconomic landscape in which the study was conducted further contributed to the unequal access of under-served groups to clinical research participation. For patients with comorbid alcohol use disorder and alcohol-related liver disease, limited access to research further contributes towards a gap in effective evidence-based treatment, exacerbating health inequalities in this clinical population.

Abstract Background To analyse the nature of medical or technical emergency issues of ambulatory peritoneal dialysis (PD) patients calling a nurse-provided emergency PD support service of a reference centre that is provided all year in the after-hours. Methods We retrospectively analysed patients’ chief complaint, urgency, resolution of and association to current PD treatment and modality directed to an on-call nurse-provided PD support service from 2015–2021 based on routinely collected health data. Calls were systematically categorized being technical/procedural-, medical-, material-related or type of correspondence. Call urgency was categorized to have “immediate consequence”, inquiry was eligible for “processing next working day” or whether there was “no need for further action”. Call outcomes were classified according to whether patients were able to initiate, resume or finalize their treatments or whether additional interventions were required. Unexpected adverse events such as patients’ acute hospitalization or need for nurses’ home visits were evaluated and quantified. Results In total 753 calls were documented. Most calls were made around 7:30 a.m. (5:00–9:00; median, 25-75th CI) and 6:30 p.m. (5:00–8:15). 645 calls were assigned to continuous ambulatory- (CAPD) or automated PD (APD). Of those, 430 calls (66.7%) had an “immediate consequence”. Of those 77% (N = 331) were technical/procedural-, 12.8% (N = 55) medical- and 6.3% (N = 27) material related issues. 4% (N = 17) were categorized as other correspondence. Issues disrupting the course of PD were identified in 413 cases. In 77.5% (N = 320) patients were able to initiate, resume or finalize their treatment after phone consultation. Last-bag exchange was used in 6.1% enabling continued therapy in 83.6%. In 35 cases a nurse visit at patients’ home or patients' visit to the practice at the earliest possible date were required, while hospitalization was required in seven medical category cases (5.4% and 1.09% of total assessed calls, respectively). Conclusion The on-call PD-nurse provides patient support for acute and imminent issues enabling them to successfully initiate, resume or finalize their prescribed treatment. Nurses triage of acute conditions facilitated rapid diagnostics and therapy. Maintaining quality PD homecare, the provision of trained personnel is indispensable. The information gathered in this study may therefore be used as a foundation to tailor educational programs for nephrology nurses and doctors to further develop their competencies in PD.

Abstract Ice core records of carbon dioxide (CO2) throughout the last 2000 years provide context for the unprecedented anthropogenic rise in atmospheric CO2 and insights into global carbon cycle dynamics. Yet the atmospheric history of CO2 remains uncertain in some time intervals. Here we present measurements of CO2 and methane (CH4) in the Skytrain ice core from 1450 to 1700 CE. Results suggest a sudden decrease in CO2 around 1610 CE in one widely used record may be an artefact of a small number of anomalously low values. Our analysis supports a more gradual decrease in CO2 of 0.5 ppm per decade from 1516 to 1670 CE, with an inferred land carbon sink of 2.6 PgC per decade. This corroborates modelled scenarios of large-scale reorganisation of land use in the Americas following New World-Old World contact, whereas a rapid decrease in CO2 at 1610 CE is incompatible with even the most extreme land-use change scenarios.

Background Depression and anxiety are common in adolescents and have increased over the last decade. During that period, smartphone usage has become ubiquitous.Objectives The study aim was to assess the association between problematic smartphone usage (PSU) and anxiety.Methods Using a prospective mixed methods cohort study design, students aged 13–16 year old from two schools were enrolled regarding their smartphone use, mood and sleep via a semistructured questionnaire at baseline and week 4. The primary outcome was symptoms of anxiety (Generalised Anxiety Disorder Questionnaire, GAD-7) and exposure was PSU (Smartphone Addiction Scale Short Version). A linear regression was fitted to assess the change in anxiety. Thematic analysis of free-text responses was conducted.Findings The sample included 69 participants that were enrolled and followed up between 28 March and 3 June 2022. Of those with PSU, 44.4% exhibited symptoms of moderate to severe anxiety compared with 26.4% of those without PSU. There was a linear association between change in symptoms of anxiety and PSU β=0.18 (95% CI 0.04 to 0.32, p=0.013). Several themes were found: both positive and negative effects of smartphones on relationships; negative effects on school performance and productivity; mixed effects on mood; a desire to reduce the amount of time spent on smartphones.Conclusions Increased anxiety, depression and inability to sleep were seen in participants as their PSU score increased over time. Participants reported both positive and negative effects of smartphones and almost all used strategies to reduce use.Clinical implications Interventions need to be developed and evaluated for those seeking support.

ObjectivesOur study tries to investigate the effect of the Mediterranean diet (MeDiet) on assisted reproductive treatment outcomes in women after COVID-19 infection.DesignA prospective observational cohort study in the Reproductive and Genetic Hospital of CITIC-Xiangya from February 2023 to August 2023.Subjects: A total of 605 participants previously infected with COVID-19 were enrolled.ExposureNone.Main outcome measurementThe primary outcomes are oocyte and embryo quality. The secondary outcomes are pregnancy outcomes.ResultsA majority of participants (n = 517) followed low to moderate MeDiet, and only a small group of them (n = 88) followed high MeDiet. The blastocyst formation rate is significantly higher in MeDiet scored 8–14 points women (46.08%), compared to the other two groups (which is 41.75% in the low adherence population and 40.07% in the moderate adherence population respectively) (p = 0.044). However, the follicle number on hCG day, yield oocytes, normal fertilized zygotes, fertilization rate, day three embryos (cleavage embryos), and embryo quality are comparable among the three groups. For those who received embryo transfer, we noticed an obvious trend that with the higher MeDiet score, the higher clinical pregnancy rate (62.37% vs. 76.09% vs. 81.25%, p = 0.197), implantation rate (55.84% vs. 66.44% vs. 69.23%, p = 0.240) and ongoing pregnancy rate (61.22% vs. 75.00% vs. 81.25%, p = 0.152) even though the p values are not significant. An enlarging sample size study, especially in a high adherence population should be designed to further verify the effects of MeDiet’s role in improving IVF performance.ConclusionHigh adherence to MeDiet is associated with improved blastocyst formation in women after COVID-19 infection. There is also a trend that high adherence to MeDiet might be beneficial to clinical pregnancy, embryo implantation as well as ongoing pregnancy in these women.

Video-supported reflection supports the professional development of student teachers and is a natural part of teacher education. The study aims to find out teacher education students' opinions about recording their teaching and analyzing it, to describe the experiences of recording and analyzing the videos, and to systematize their main areas of learning and development. Based on this, future video-based analysis tasks in teacher training could be planned more effectively. One hundred thirty-six teacher education students carrying out their teaching practicum participated in the study. Data was collected via a questionnaire after the teaching practicum (practical teaching course). The answers to the open questions were analyzed using the qualitative content analysis method, and the results of the answers to the closed questions are described using frequency indicators. The results show that the teacher education students who participated in the study expressed neutral opinions and positive expectations, as well as hesitation, uncertainty, discomfort, and fear before the first-time recording of their lesson and its analysis. For most of the study participants, the experience of recording and analyzing their lesson and observing a fellow student's lesson video was helpful and increased their self-confidence. The discussion highlights the possibilities of making the experience of video reflection more supportive and useful for teacher education students.

Background: In South Africa, infants who are HIV-exposed are tested for HIV at birth and 10 weeks of age. The COVID-19 pandemic lockdown restrictions resulted in reduced access to healthcare services and uncertain impact on early infant HIV testing. Objectives: To describe the effects of the COVID-19 pandemic lockdown restrictions on early infant HIV testing and diagnosis in Cape Town, South Africa. Method: This retrospective cohort study compares HIV-exposed infants born during the first COVID-19 pandemic lockdown (2020) to those born in the same period the year before (2019). Laboratory and other data were abstracted from the Provincial Health Data Centre. Results: A total of 2888 infants were included: 1474 born in 2020 and 1413 in 2019. Compared to 2019, there was an increase in the 10-week HIV polymerase chain reaction (PCR) uptake in 2020 (71% vs. 60%, P 0.001). There was also an increase in the proportion of infants who demised without 10-week testing or were lost to follow-up in 2020 compared to 2019 (8% vs. 5%, P = 0.017). Differences detected in birth HIV PCR positivity rates between the two groups (1.1% vs. 0.5%, P = 0.17) did not reach statistical significance; however, a significant increase in vertical transmission of HIV by 10 weeks old was found in the 2020 cohort (1.2% vs. 0.5%. P = 0.046). Conclusion: Vertical transmission of HIV at 10 weeks increased in the Cape Town Metropolitan during the initial COVID-19 lockdown. There was also an increase in the proportion of deaths without testing by 10 weeks in the 2020 group.

Abstract Introduction Monitoring mother‐infant pairs with HIV exposure is needed to assess the effectiveness of vertical transmission (VT) prevention programmes and progress towards VT elimination. Methods We used routinely collected data on infants with HIV exposure, born May 2018–April 2021 in the Western Cape, South Africa, with follow‐up through mid‐2022. We assessed the proportion of infants diagnosed with HIV at birth (≤7 days), 10 weeks (>1 to 14 weeks) and >14 weeks as proxies for intrauterine, intrapartum/early breastfeeding and late breastfeeding transmission, respectively. We used mixed‐effects Poisson regression to assess factors associated with VT in mothers known with HIV by delivery. Results We included 50,461 infants born to mothers known with HIV by delivery. HIV was diagnosed in 894 (1.8%) infants. Among mothers, 51% started antiretroviral treatment (ART) before and 27% during pregnancy; 17% restarted during pregnancy after ≥6 months interruption; and 6% had no recorded ART during pregnancy. Most pregnancy ART regimens included non‐nucleoside reverse transcriptase inhibitors (83%). Of mothers with available results (90% with viral load [VL]; 70% with CD4), VL nearest delivery was 14 weeks. Among these infants, 0.9%, 0.4% and 1.5% were diagnosed positive at birth, 10 weeks and >14 weeks, respectively. Among infants diagnosed with HIV, 43%, 16% and 41% were diagnosed at these respective time periods. Among mothers with VL

Abstract Background Despite the close relationship between pre-pregnancy body mass index (BMI), gestational weight gain (GWG) and postpartum weight (PPW), these factors are often studied separately. There are no data characterising longitudinal weight trajectories among pregnant and postpartum women in urban African populations. We examined maternal weight trajectories from pregnancy through to 12 months postpartum, factors associated with higher weight trajectory class membership and associations of weight trajectories with infant growth at 12 months. Methods Data from 989 women were examined for weight trajectories from first antenatal care visit in pregnancy to 12 months postpartum using latent-class growth models. Baseline factors associated with class membership were assessed using multinomial logistic regression. Of the enrolled women, 613 of their infants were assessed for growth at 12 months. Anthropometry measurements for mothers and infants were conducted by a trained study nurse. Associations between maternal weight trajectory class and infant weight-for-age (WAZ), length-for-age (LAZ), weight-for-length (WLZ) at 12 months of age were analysed using linear regression. Results Four distinct classes of maternal weight trajectories were identified. The classes included consistent low (29%), consistent medium (37%), medium–high (24%) and consistent high (10%) trajectories. Similar to trends observed with medium–high trajectory, baseline factors positively associated with consistent high class membership included age (OR 1.05, 95% CI 1.01–1.09), pre-pregnancy BMI (OR 2.24, 95% CI 1.97–2.56), stage 1 hypertension (OR 3.28, 95% CI 1.68–6.41), haemoglobin levels (OR 1.39, 95% CI 1.11–1.74) and parity (OR 1.39, 95% CI 1.15–1.67); living with HIV (OR 0.47, 95% CI 0.30–0.74) was inversely associated. In adjusted analyses, compared to consistent medium weight trajectory, consistent low weight trajectory (mean difference -0.41, 95% CI -0.71;-0.12) was associated with decreased, and consistent high weight trajectory (mean difference 1.21, 95% CI 0.59–1.83) with increased infant WAZ at 12 months of age. Conclusion Identification of unique longitudinal weight trajectory groupings might inform comprehensive efforts targeted at improving healthy maternal weight and infant outcomes.

This paper proposes a method that leads to a highly accurate state-of-charge dependent multi-stage constant current (MCC) charging algorithm for electric bicycle batteries to reduce the charging time without accelerating aging by avoiding Li-plating. First, the relation between the current rate, state-of-charge, and Li-plating is experimentally analyzed with the help of three-electrode measurements. Therefore, a SOC-dependent charging algorithm is proposed. Secondly, a SOC estimation algorithm based on an Extended Kalman Filter is developed in MATLAB/Simulink to conduct high accuracy SOC estimations and control precisely the charging algorithm. The results of the experiments showed that the Root Mean Square Error (RMSE) of SOC estimation is 1.08%, and the charging time from 0% to 80% SOC is reduced by 30%.

In low- and middle-income countries where SARS-CoV-2 testing is limited, seroprevalence studies can help describe and characterise the extent of the pandemic, as well as elucidate protection conferred by prior exposure. We conducted repeated cross-sectional serosurveys (July 2020 -November 2021) using residual samples from patients from Cape Town, South Africa, sent for routine laboratory studies for non-COVID-19 conditions. SARS-CoV-2 anti-nucleocapsid antibodies and linked clinical information were used to investigate: (1) seroprevalence over time and risk factors associated with seropositivity, (2) ecological comparison of seroprevalence between subdistricts, (3) case ascertainment rates, and (4) the relative protection against COVID-19 associated with seropositivity and vaccination statuses. Among the subset sampled, seroprevalence of SARS-CoV-2 in Cape Town increased from 39.19% (95% confidence interval [CI] 37.23-41.19) in July 2020 to 67.8% (95%CI 66.31-69.25) in November 2021. Poorer communities had both higher seroprevalence and COVID-19 mortality. Only 10% of seropositive individuals had a recorded positive SARS-CoV-2 test. Using COVID-19 hospital admission and death data at the Provincial Health Data Centre, antibody positivity before the start of the Omicron BA.1 wave (28 November 2021) was strongly protective for severe disease (adjusted odds ratio [aOR] 0.15; 95%CI 0.05-0.46), with additional benefit in those who were also vaccinated (aOR 0.07, 95%CI 0.01-0.35). The high population seroprevalence in Cape Town was attained at the cost of substantial COVID-19 mortality. At the individual level, seropositivity was highly protective against subsequent infections and severe COVID-19 disease. In low-income communities, where diagnostic testing capacity is often limited, surveillance systems dependent on them will underestimate the true extent of an outbreak. Rapidly conducted seroprevalence studies can play an important role in addressing this.

Objectives Healthcare workers (HCWs) are on the frontline of combating COVID-19, hence are at elevated risk of contracting an infection with SARS-CoV-2. The present study aims to measure the impact of SARS-CoV-2 on HCWs in central sub-Saharan Africa.Setting A cross-sectional serological study was conducted at six urban and five rural hospitals during the first pandemic wave in the South Kivu province, Democratic Republic of the Congo (DRC).Participants Serum specimens from 1029 HCWs employed during the first pandemic wave were collected between August and October 2020, and data on demographics and work-related factors were recorded during structured interviews.Primary and secondary outcome measures The presence of IgG antibodies against SARS-CoV-2 was examined by ELISA. Positive specimens were further tested using a micro-neutralisation assay. Factors driving SARS-CoV-2 seropositivity were assessed by multivariable analysis.Results Overall SARS-CoV-2 seroprevalence was high among HCWs (33.1%), and significantly higher in urban (41.5%) compared with rural (19.8%) hospitals. Having had presented with COVID-19-like symptoms before was a strong predictor of seropositivity (31.5%). Personal protective equipment (PPE, 88.1% and 11.9%) and alcohol-based hand sanitizer (71.1% and 28.9%) were more often available, and hand hygiene was more often reported after patient contact (63.0% and 37.0%) in urban compared with rural hospitals, respectively. This may suggest that higher exposure during non-work times in high incidence urban areas counteracts higher work protection levels of HCWs.Conclusions High SARS-CoV-2 seropositivity indicates widespread transmission of the virus in this region of DRC. Given the absence of publicly reported cases during the same time period at the rural sites, serological studies are very relevant in revealing infection dynamics especially in regions with low diagnostic capacities. This, and discrepancies in the application of PPE between urban and rural sites, should be considered in future pandemic response programmes.

COVAX, the international initiative supporting COVID-19 vaccination campaigns globally, is budgeted to be the costliest public health initiative in low- and middle-income countries, with over 16 billion US dollars already committed. While some claim that the target of vaccinating 70% of people worldwide is justified on equity grounds, we argue that this rationale is wrong for two reasons. First, mass COVID-19 vaccination campaigns do not meet standard public health requirements for clear expected benefit, based on costs, disease burden and intervention effectiveness. Second, it constitutes a diversion of resources from more cost-effective and impactful public health programmes, thus reducing health equity. We conclude that the COVAX initiative warrants urgent review.

Abstract Secondary activation of the endothelin system is thought to be involved in toxic liver injury. This study tested the hypothesis that dual endothelin-converting enzyme / neutral endopeptidase blockade might be able to attenuate acute toxic liver injury. Male Sprague-Dawley rats were implanted with subcutaneous minipumps to deliver the novel compound SLV338 (10 mg/kg*d) or vehicle. Four days later they received two intraperitoneal injections of D-galactosamine (1.3 g/kg each) or vehicle at an interval of 12 hours. The animals were sacrificed 48 hours after the first injection. Injection of D-galactosamine resulted in very severe liver injury, reflected by strongly elevated plasma liver enzymes, hepatic necrosis and inflammation, and a mortality rate of 42.9 %. SLV338 treatment did not show any significant effect on the extent of acute liver injury as judged from plasma parameters, hepatic histology and mortality. Plasma measurements of SLV338 confirmed adequate drug delivery. Plasma concentrations of big endothelin-1 and endothelin-1 were significantly elevated in animals with liver injury (5-fold and 62-fold, respectively). Plasma endothelin-1 was significantly correlated with several markers of liver injury. SLV338 completely prevented the rise of plasma big endothelin-1 (p < 0.05) and markedly attenuated the rise of endothelin-1 (p = 0.055). In conclusion, dual endothelin-converting enzyme / neutral endopeptidase blockade by SLV338 did not significantly attenuate D-galactosamine-induced acute liver injury, although it largely prevented the activation of the endothelin system. An evaluation of SLV338 in a less severe model of liver injury would be of interest, since very severe intoxication might not be relevantly amenable to pharmacological interventions.

Abstract Introduction Maternal body mass index has an impact on maternal and fetal pregnancy outcome. An increased maternal BMI is known to be associated with admission of the newborn to a neonatal care unit. The reasons and impact of this admission on fetal outcome, however, are unknown so far. Objective The aim of our study was to investigate the impact of maternal BMI on maternal and fetal pregnancy outcome with special focus on the children admitted to a neonatal care unit. Methods A cohort of 2049 non-diabetic mothers giving birth in the Charite university hospital was prospectively studied. The impact of maternal BMI on maternal and fetal outcome parameters was tested using multivariate regression analysis. Outcome of children admitted to a neonatal ward (n = 505) was analysed. Results Increased maternal BMI was associated with an increased risk for hypertensive complications, peripheral edema, caesarean section, fetal macrosomia and admission of the newborn to a neonatal care unit, whereas decreased BMI was associated with preterm birth and lower birthweight. In the neonatal ward children from obese mothers are characterized by hypoglycaemia. They need less oxygen, and exhibit a shorter stay on the neonatal ward compared to children from normal weight mothers, whereas children from underweight mothers are characterized by lower umbilical blood pH and increased incidence of death corresponding to increased prevalence of preterm birth. Conclusion Pregnancy outcome is worst in babies from mothers with low body mass index as compared to healthy weight mothers with respect to increased incidence of preterm birth, lower birth weight and increased neonate mortality on the neonatal ward. We demonstrate that the increased risk for neonatal admission in children from obese mothers does not necessarily indicate severe fetal impairment.

Abstract Introduction Activation of the endothelin (ET) system promotes inflammation and fibrosis in various tissues including the kidney. Male ET-1 transgenic mice are characterized by chronic kidney inflammation and renal scarring. We hypothesized that this renal phenotype might be modulated by androgens. Thus the aim of our study was to elucidate the impact of gonadectomy in ET-1 transgenic mice on kidney function and morphology. Methods Male ET-1 transgenic mice at the age of 10 weeks were randomly allocated to the following groups: normal ET transgenic mice (ET; n = 17) and ET transgenic mice that underwent castration (ET+cas; n = 12). Study duration was 9 months. Creatinine clearance and protein excretion was monitored. At study end animals were sacrificed and kidneys were harvested for histology/immunhistochemistry. Results Castration significantly ameliorated glomerulosclerosis in ET-1 transgenic mice (ET glomerulosclerosis-score: 3.0 ± 0.17 vs ET+cas: 2.4 ± 0.17; p < 0.05) as well as renal perivascular fibrosis (ET fibrosis-score: 3.0 ± 0.14 vs ET+cas: 2.2 ± 0.14; p < 0.05). However, interstitial fibrosis and media/lumenratio of renal arteries remained unaffected by castration. Regarding inflammation, castration significantly reduced the number of CD4-positive cells in renal tissue of ET-1 transgenic mice (ET CD4-positive cells/10000 cells: 355 ± 72 vs ET+cas: 147 ± 28; p < 0.05). Renal tissue contents of CD8 positive cells as well as of macrophages were not affected by castration. Regarding kidney function castration significantly reduced proteinuria in ET-1 transgenic mice whereas creatinine clearance did not differ between study groups. Conclusion Our study demonstrates that the renal histopathological phenotype in male ET-1 transgenic mice with regard to glomerulosclerosis, proteinuria, perivascular fibrosis and immune cell immigration is ameliorated by castration. We thus conclude that the effects of ET-1 overexpression on renal tissue injury are modulated by androgens.

Abstract. A new ice core drilled at the South Pole provides a54 000-year paleoenvironmental record including the composition of the pastatmosphere. This paper describes the SP19 chronology for the South Poleatmospheric gas record and complements a previous paper (Winski et al., 2019)describing the SP19 ice chronology. The gas chronology is based on adiscrete methane (CH4) record with 20- to 190-year resolution. Toconstruct the gas timescale, abrupt changes in atmospheric CH4 duringthe glacial period and centennial CH4 variability during the Holocenewere used to synchronize the South Pole gas record with analogous data fromthe West Antarctic Ice Sheet Divide ice core. Stratigraphic matching basedon visual optimization was verified using an automated matching algorithm.The South Pole ice core recovers all expected changes in CH4 based onprevious records. Gas transport in the firn results in smoothing of theatmospheric gas record with a smoothing function spectral width that rangesfrom 30 to 78 years, equal to 3 % of the gas-age–ice-age difference, orΔage. The new gas chronology, in combination with the existing iceage scale from Winski et al. (2019), allows a model-independentreconstruction of the gas-age–ice-age difference through the whole record,which will be useful for testing firn densification models.

Artikli teema on päästekorraldajate keeleline ebaviisakus helistaja suhtes Eesti hädaabikõnedes. Uurimuse eesmärk on leida, millistes suhtlustegevustes ebaviisakus esineb, mis selle esile kutsub ja milline on ebaviisakuse keeleline vorm. Analüüs tõi esile kolm rühma ebaviisakaid suhtlustegevusi: (a) etteheited helistajale, (b) ebaviisakalt vormistatud küsimused, infopalved, palved ning (c) ebaviisakad abipalve tagasilükkamised ja järsud ühepoolsed kõne lõpetamised. Valdavalt on ebaviisakuse vallandajaks helistaja. Ühe rühma moodustavad joobes või ebaviisakad helistajad ja inimesed, kes ei järgi suhtlusnorme. Teise rühma moodustavad juhtumid, milles helistaja antud info ei sobi päästekorraldaja rutiinidega või Häirekeskuse töönormidega. Üksikjuhtudel esineb päästekorraldaja ebaviisakus ka ilma helistajapoolse mõjurita. Päästekorraldajad vormistavad ebaviisakused samal viisil nagu teistes uuritud keeltes. Keeleliste vahendite seas on nii ebaviisakusega seotud häälduslikud, sõnavaralised ja süntaktilised vahendid kui ka kõnevoorude vormistamise võtted. Eraldi tõstame esile pragmaatilised partiklid ja järsud kõnelõpetamised, mida meie teada varasemas literatuuris välja toodud ei ole. Abstract. Tiit Hennoste, Andriela Rääbis, Piret Upser, Kirsi Laanesoo- Kalk, Andra Rumm, Andra Annuka-Loik: `Sellepärast tahate `kiirabi või. Call-takers impoliteness in Estonian emergency calls. The topic of the article is the linguistic impoliteness (rudeness, face attack) of call-takers towards the caller in Estonian emergency calls. The purpose of the research is to find out the social actions where impoliteness occurs, its triggers and the linguistic form of rudeness. The data consists of audio-recorded calls from the emergency call corpus of the University of Tartu. The analysis revealed that impoliteness could be divided into three groups: (a) reproaches to the caller, (b) rudely formulated questions, requests for information and directives and (c) rudely formulated refusals of help and unilateral closings of the call. Impoliteness is generally triggered by the caller. One group includes drunk or rude callers and callers who do not follow social norms of interaction. The second group consists of cases where the information provided by the caller does not meet the standards of the call-takers or the Emergency Response Center. Only in a few cases, the call-taker initiates an impolite social action without the influence of the caller. Estonian call-takers express rudeness using the similar means as in the other languages studied. Linguistic tools associated with rudeness are found in pronunciation, vocabulary, syntax, and techniques of formulating turns in dialogue. In particular, we highlight pragmatic particles/markers and unilateral closings that, as far as we know, have not been presented in previous literature.

Abstract Introduction With the scaling up of vertical HIV transmission prevention programmes, the HIV‐related population profile of children in South Africa has shifted. We described temporal changes in HIV‐related characteristics of children, aged ≤3 years (up to the third birthday), with infectious disease hospitalisations across the Western Cape province. Methods We used routinely collected electronic data to identify children born in the Western Cape with infectious disease hospital records for lower respiratory tract infections, diarrhoea, meningitis and tuberculous meningitis, from 2008 to 2021. Linked maternal and child unique identifiers were used to extract pregnancy, HIV‐related, laboratory, pharmacy and hospitalisation data. We described temporal changes in child HIV exposure and acquisition status, timing of maternal HIV diagnosis and antiretroviral therapy (ART) start, infant exposure to maternal ART and timing thereof, and maternal CD4 and HIV viral load closest to delivery. We used logistic and multinomial regression to assess changes in characteristics between the Pre‐Option B+ (2008–2013), Option B+ (2013–2016) and Universal ART periods (2016–2021). Results Among 52,811 children aged ≤3 years with hospitalisations, the proportion living with HIV dreased from 7.0% (2008) to 1.1% (2021), while those exposed to HIV and uninfected increased from 14.0% (2008) to 16.1% (2021) with a peak of 18.3% in 2017. Among mothers with HIV (n = 9873), the proportion diagnosed with HIV and starting ART before pregnancy increased from 20.2% to 69.2% and 5.8% to 59.0%, respectively, between 2008 and 2021. Children hospitalised during the Universal ART period had eight times higher odds (Odds Ratio: 8.41; 95% CI: 7.36–9.61) of exposure to maternal ART versus children admitted Pre‐Option B+. Among mothers of children exposed to HIV and uninfected with CD4 records (n = 7523), the proportion with CD4

Background. The first vertical transmission of HIV prevention (VTP) programme in South Africa was launched in 1999 in Khayelitsha, Western Cape Province (WC). Since then, VTP guidelines have expanded in complexity and scope. Objectives. To describe contemporary VTP uptake in Khayelitsha and quantify vertical transmission (VT) risk factors based on linked routine electronic health data. Methods. In the WC, all patients at public health facilities have a unique identifier allowing linkage across electronic health platforms through a health information exchange hosted within the WC Department of Health. We conducted a cohort analysis of mother-infant pairs where the mother was living with HIV and attended any obstetric care in Khayelitsha in 2017. Descriptive statistics assessed VTP coverage along the care cascade, including maternal viral load (VL) testing and early infant diagnosis (EID). Logistic regression analysis quantified a priori-defined risk factors associated with VT. Results. Antenatal HIV prevalence in the cohort was 31.3%, and VT was 1.8% by 12 months. Of women living with HIV, 88.3% knew of their positive status at the first antenatal visit and 77.9% were already receiving antiretroviral therapy (ART). Most women diagnosed prior to delivery (94.5%) were initiated on ART; 85.0% received an antenatal VL test, of whom 88.0% were virologically suppressed. Women who were not virally suppressed had a five-fold (adjusted odds ratio (aOR) 5.3; 95% confidence interval (CI) 2.5 - 12.3) increased VT risk compared with those who were suppressed. Women who attended no antenatal care were at higher risk of VT (aOR 1.6; 95% CI 0.7 - 3.6) than those who did attend. EID coverage was suboptimal: a birth HIV polymerase chain reaction (PCR) test was available for 79.2% of infants, and a low proportion with a negative birth test had a repeat test around 10 weeks (57.9%). Data linkage identified an additional 15 infants living with HIV who were not detected by HIV-PCR testing alone. Conclusion. Although most women presented to care already knowing their HIV status, ART initiation was suboptimal prior to the first antenatal visit but improved over the course of pregnancy. The VT rate based on laboratory HIV-PCR testing alone underestimated HIV transmission: linked data from multiple sources suggested higher VT than programme-reported rates based on HIV-PCR testing alone.

AimThis research aimed to describe how the characteristics of deaths following drug use changed during the COVID-19 pandemic in England, and how this can inform future strategy to support the health and social care of people who use drugs in future emergency scenarios.MethodAll deaths reported to the National Programme on Substance Abuse Deaths which occurred between January 2018 and December 2021 inclusive were extracted for analysis. Exponential smoothing models were constructed to determine any differences between forecasted vs. actual trends.Key resultsFollowing the first lockdown period in England there were significant increases in the proportion of people who died at home beyond the 95% confidence bounds of the exponential smoothing model and concurrent decreases in the proportion of people who died in hospital. Whilst the overall proportion of deaths attributable to opioids did not significantly deviate from the forecasted trend, there were significant increases in methadone-related deaths and decreases in heroin/morphine-related death beyond the 95% confidence bounds. The proportion of deaths concluded as suicide increased, as did those implicating antidepressant use. There were no changes in the proportion of deaths following use of other drug classes, alcohol use in combination with psychoactive drugs, or on decedent demographics (gender, age, and drug user status). A small number of deaths due to drug use had COVID-19 infection itself listed as a cause of death (n = 23).ConclusionFor people who use drugs, the impact of the restrictions due to the COVID-19 pandemic was greater than that of infection from the virus itself. The health and social care strategy for these people needs to be pre-emptively adapted to mitigate against the specific risk factors for fatal drug overdose associated with future emergency scenarios.

The risk of HIV acquisition is higher during pregnancy and postpartum than other times. Newly acquired maternal HIV infection associated with high primary viraemia, substantially increases the risk of vertical HIV transmission. Pre-exposure prophylaxis (PrEP) reduces the risk of HIV acquisition. Currently available products include oral tenofovir/emtricitabine (TDF/FTC) and tenofovir alafenamide (TAF)/FTC), long-acting cabotegravir (CAB-LA) and the dapivirine ring (DVR). All except oral TDF/FTC have limited safety data available for use in pregnant and breastfeeding women. The safety of new PrEP agents for pregnant women and the fetus, infant and child, either exposed in utero or during breastfeeding is an ongoing concern for health care workers and pregnant and breastfeeding women, particularly as the safety risk appetite for antiretroviral (ARV) agents used as PrEP is lower in pregnant and breastfeeding women who are HIV-uninfected, compared to women living with HIV taking ARVs as treatment. With the widespread rollout of TDF/FTC among pregnant women in South Africa and other low-middle income countries (LMIC) and the potential introduction of new PrEP agents for pregnant women, there is a need for safety surveillance systems to identify potential signals of risk to either the mother or fetus, measure the burden of such a risk, and where appropriate, provide specific reassurance to PrEP users. Safety data needs to be collected across the continuum of the product life cycle from pre-licensure into the post-marketing period, building a safety profile through both passive and active surveillance systems, recognising the strengths and limitations of each, and the potential for bias and confounding. Pharmacovigilance systems that aim to assess the risk of adverse birth outcomes in pregnant women exposed to PrEP and other agents need to consider the special requirements of pregnancy epidemiology to ensure that the data derived from surveillance are sufficiently robust to inform treatment policies. Here we review the known safety profiles of currently available PrEP candidates in women of child-bearing potential, pregnancy and breastfeeding and discuss pragmatic approaches for such surveillance in HIV-endemic LMICs.

Abstract. A new ice core drilled at the South Pole provides a 54 000-year paleoenvironmental record including the composition of the past atmosphere. This paper describes the SP19 chronology for the South Pole atmospheric gas record and complements a previous paper (Winski et al., 2019) describing the SP19 ice chronology. The gas chronology is based on a discrete methane (CH4) record with 20- to 190-year resolution. To construct the gas time scale abrupt changes in atmospheric CH4 during the glacial period and centennial CH4 variability during the Holocene were used to synchronize the South Pole gas record with analogous data from the West Antarctic Ice Sheet Divide ice core. Stratigraphic matching based on visual optimization was verified using an automated matching algorithm. The South Pole ice core recovers all expected changes in CH4 based on previous records. Smoothing of the atmospheric record due to gas transport in the firn is evident but relatively minor, despite the deep lock-in depth in the modern South Pole firn column. The new gas chronology, in combination with the existing ice age scale from Winski et al. (2019), allows a model-independent reconstruction of the gas age-ice age difference through the whole record, which will be useful for testing firn densification models.

Permafrost and methane hydrates are large, climate-sensitive old carbon reservoirs that have the potential to emit large quantities of methane, a potent greenhouse gas, as the Earth continues to warm. We present ice core isotopic measurements of methane (Δ14C, δ13C, and δD) from the last deglaciation, which is a partial analog for modern warming. Our results show that methane emissions from old carbon reservoirs in response to deglacial warming were small (

Cosmic rays entering the Earth's atmosphere produce showers of secondary particles such as protons, neutrons, and muons. The interaction of these particles with oxygen-16 (16O) in minerals such as ice and quartz can produce carbon-14 (14C). In glacial ice, 14C is also incorporated through trapping of 14C-containing atmospheric gases (14CO2, 14CO, and 14CH4). Understanding the production rates of in situ cosmogenic 14C is important to deconvolve the in situ cosmogenic and atmospheric 14C signals in ice, both of which contain valuable paleoenvironmental information. Unfortunately, the in situ 14C production rates by muons (which are the dominant production mechanism at depths of >6 m solid ice equivalent) are uncertain. In this study, we use measurements of in situ 14C in ancient ice (>50 ka) from the Taylor Glacier, an ablation site in Antarctica, in combination with a 2D ice flow model to better constrain the compound-specific rates of 14C production by muons and the partitioning of in situ 14C between CO2, CO, and CH4. Our measurements show that 33.7 % (±11.4 %; 95 % confidence interval) of the produced cosmogenic 14C forms 14CO and 66.1 % (±11.5 %; 95 % confidence interval) of the produced cosmogenic 14C forms 14CO2. 14CH4 represents a very small fraction (%) of the total. Assuming that the majority of in situ muogenic 14C in ice forms 14CO2, 14CO, and 14CH4, we also calculated muogenic 14C production rates that are lower by factors of 5.7 (3.6–13.9; 95 % confidence interval) and 3.7 (2.0–11.9; 95 % confidence interval) for negative muon capture and fast muon interactions, respectively, when compared to values determined in quartz from laboratory studies (Heisinger et al., 2002a, b) and in a natural setting (Lupker et al., 2015). This apparent discrepancy in muogenic 14C production rates in ice and quartz currently lacks a good explanation and requires further investigation.

In the first two years of the pandemic, COVID-19 response policies have aimed to break Corona waves through non-pharmaceutical interventions and mass vaccination. However, for long-term strategies to be effective and efficient, and to avoid massive disruption and social harms, it is crucial to introduce the role of natural immunity in our thinking about COVID-19 (or future “Disease-X”) control and prevention. We argue that any Corona or similar virus control policy must appropriately balance five key elements simultaneously: balancing the various fundamental interests of the nation, as well as the various interventions within the health sector; tailoring the prevention measures and treatments to individual needs; limiting social interaction restrictions; and balancing the role of vaccinations against the role of naturally induced immunity. Given the high infectivity of SARS-CoV-2 and its differential impact on population segments, we examine this last element in more detail and argue that an important aspect of ‘living with the virus’ will be to better understand the role of naturally induced immunity in our overall COVID-19 policy response. In our eyes, a policy approach that factors natural immunity should be considered for persons without major comorbidities and those having ‘encountered’ the antigen in the past.

Abstract Background In the absence of clinical trials, data on the safety of medicine exposures in pregnancy are dependent on observational studies conducted after the agent has been licensed for use. This requires an accurate history of antenatal medicine use to determine potential risks. Medication use is commonly determined by self-report, clinician records, and electronic pharmacy data; different data sources may be more informative for different types of medication and resources may differ by setting. We compared three methods to determine antenatal medicine use (self-report, clinician records and electronic pharmacy dispensing records [EDR]) in women attending antenatal care at a primary care facility in Cape Town, South Africa in a setting with high HIV prevalence. Methods Structured, interview-administered questionnaires recorded self-reported medicine use. Data were collected from clinician records and EDR on the same participants. We determined agreement between these data sources using Cohen’s kappa and, lacking a gold standard, used Latent Class Analysis to estimate sensitivity, specificity and positive predictive value (PPV) for each data source. Results Between 55% and 89% of 967 women had any medicine use documented depending on the data source (median number of medicines/participant = 5 [IQR 3–6]). Agreement between the datasets was poor regardless of class except for antiretroviral therapy (ART; kappa 0.6–0.71). Overall, agreement was better between the EDR and self-report than with either dataset and the clinician records. Sensitivity and PPV were higher for self-report and the EDR and were similar for the two. Self-report was the best source for over-the-counter, traditional and complementary medicines; clinician records for vaccines and supplements; and EDR for chronic medicines. Conclusions Medicine use in pregnancy was common and no single data source included all the medicines used. ART was the most consistently reported across all three datasets but otherwise agreement between them was poor and dependent on class. Using a single data collection method will under-estimate medicine use in pregnancy and the choice of data source should be guided by the class of the agents being investigated.

Background25-hydroxyvitamin D (25(OH)D) and potentially also 1,25-dihydroxyvitamin D (1,25(OH)2D) inhibits the synthesis of parathyroid hormone (PTH) in the chief cells of the parathyroid gland. Clinical studies showing a negative correlation between (25(OH)D and PTH are in good agreement with these findings in basic science studies. However, PTH was measured in these studies with the currently clinically used 2nd or 3rd generation intact PTH (iPTH) assay systems. iPTH assays cannot distinguish between oxidized forms of PTH and non-oxidized PTH. Oxidized forms of PTH are the by far most abundant form of PTH in the circulation of patients with impaired kidney function. Oxidation of PTH causes a loss of function of PTH. Given that the clinical studies done so far were performed with an PTH assay systems that mainly detect oxidized forms of PTH, the real relationship between bioactive non-oxidized PTH and 25(OH)D as well as 1,25(OH)2D is still unknown.MethodsTo address this topic, we compared for the first time the relationship between 25(OH)D as well as 1,25(OH)2D and iPTH, oxPTH as well as fully bioactive n-oxPTH in 531 stable kidney transplant recipients in the central clinical laboratories of the Charité. Samples were assessed either directly (iPTH) or after oxPTH (n-oxPTH) was removed using a column that used anti-human oxPTH monoclonal antibodies, a monoclonal rat/mouse parathyroid hormone antibody (MAB) was immobilized onto a column with 500 liters of plasma samples. Spearman correlation analysis and Multivariate linear regression were used to evaluate the correlations between the variables.ResultsThere was an inverse correlation between 25(OH)D and all forms of PTH, including oxPTH (iPTH: r=-0.197, p

The aim of this scoping review was to determine the scope, objectives and methodology of contemporary published research on congenital anomalies (CAs) in sub-Saharan Africa (SSA), to inform activities of the newly established sub-Saharan African Congenital Anomaly Network (sSCAN). MEDLINE was searched for CA-related articles published between January 2016 and June 2021. Articles were classified into four main areas (public health burden, surveillance, prevention, care) and their objectives and methodologies summarized. Of the 532 articles identified, 255 were included. The articles originated from 22 of the 49 SSA countries, with four countries contributing 60% of the articles: Nigeria (22.0%), Ethiopia (14.1%), Uganda (11.7%) and South Africa (11.7%). Only 5.5% of studies involved multiple countries within the region. Most articles included CA as their primary focus (85%), investigated a single CA (88%), focused on CA burden (56.9%) and care (54.1%), with less coverage of surveillance (3.5%) and prevention (13.3%). The most common study designs were case studies/case series (26.6%), followed by cross-sectional surveys (17.6%), retrospective record reviews (17.3%), and cohort studies (17.2%). Studies were mainly derived from single hospitals (60.4%), with only 9% being population-based studies. Most data were obtained from retrospective review of clinical records (56.1%) or via caregiver interviews (34.9%). Few papers included stillbirths (7.5%), prenatally diagnosed CAs (3.5%) or terminations of pregnancy for CA (2.4%).This first-of-a-kind-scoping review on CA in SSA demonstrated an increasing level of awareness and recognition among researchers in SSA of the contribution of CAs to under-5 mortality and morbidity in the region. The review also highlighted the need to address diagnosis, prevention, surveillance and care to meet Sustainable Development Goals 3.2 and 3.8. The SSA sub-region faces unique challenges, including fragmentation of efforts that we hope to surmount through sSCAN via a multidisciplinary and multi-stakeholder approach.

Background: Since the beginning of the pandemic, COVID-19 has been regarded as an exceptional disease. Control measures have exclusively focused on ‘the virus’, while failing to account for other biological and social factors that determine severe forms of the disease. Aim: We argue that although COVID-19 was initially considered a new challenge, justifying extraordinary response measures, this situation has changed — and so should our response. Main arguments: We now know that COVID-19 shares many features of common infectious respiratory diseases, and can now ascertain that SARS-CoV-2 has not suddenly presented new problems. Instead, it has exposed and exacerbated existing problems in health systems and the underlying health of the population. COVID-19 is evidently not an ‘extraterrestrial’ disease. It is a complex zoonotic disease, and it needs to be managed as such, following long-proven principles of medicine and public health. Conclusion: A complex disease cannot be solved through a simple, magic-bullet cure or vaccine. The heterogeneity of population profiles susceptible to developing a severe form of COVID-19 suggests the need to adopt varying, targeted measures that are able to address risk profiles in an appropriate way. The critical role of comorbidities in disease severity calls for short-term, virus-targeted interventions to be complemented with medium-term policies aimed at reducing the burden of comorbidities, as well as mitigating the risk of transition from infection to disease. Strategies required include upstream prevention, early treatment, and consolidation of the health system.