International travel-related control measures to contain the COVID-19 pandemic: a rapid review

BACKGROUND: In late 2019, the first cases of coronavirus disease 2019 (COVID‐19) were reported in Wuhan, China, followed by a worldwide spread. Numerous countries have implemented control measures related to international travel, including border closures, travel restrictions, screening at borders, and quarantine of travellers. OBJECTIVES: To assess the effectiveness of international travel‐related control measures during the COVID‐19 pandemic on infectious disease transmission and screening‐related outcomes. SEARCH METHODS: We searched MEDLINE, Embase and COVID‐19‐specific databases, including the Cochrane COVID‐19 Study Register and the WHO Global Database on COVID‐19 Research to 13 November 2020. SELECTION CRITERIA: We considered experimental, quasi‐experimental, observational and modelling studies assessing the effects of travel‐related control measures affecting human travel across international borders during the COVID‐19 pandemic. In the original review, we also considered evidence on severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). In this version we decided to focus on COVID‐19 evidence only. Primary outcome categories were (i) cases avoided, (ii) cases detected, and (iii) a shift in epidemic development. Secondary outcomes were other infectious disease transmission outcomes, healthcare utilisation, resource requirements and adverse effects if identified in studies assessing at least one primary outcome. DATA COLLECTION AND ANALYSIS: Two review authors independently screened titles and abstracts and subsequently full texts. For studies included in the analysis, one review author extracted data and appraised the study. At least one additional review author checked for correctness of data. To assess the risk of bias and quality of included studies, we used the Quality Assessment of Diagnostic Accuracy Studies (QUADAS‐2) tool for observational studies concerned with screening, and a bespoke tool for modelling studies. We synthesised findings narratively. One review author assessed the certainty of evidence with GRADE, and several review authors discussed these GRADE judgements. MAIN RESULTS: Overall, we included 62 unique studies in the analysis; 49 were modelling studies and 13 were observational studies. Studies covered a variety of settings and levels of community transmission. Most studies compared travel‐related control measures against a counterfactual scenario in which the measure was not implemented. However, some modelling studies described additional comparator scenarios, such as different levels of stringency of the measures (including relaxation of restrictions), or a combination of measures. Concerns with the quality of modelling studies related to potentially inappropriate assumptions about the structure and input parameters, and an inadequate assessment of model uncertainty. Concerns with risk of bias in observational studies related to the selection of travellers and the reference test, and unclear reporting of certain methodological aspects. Below we outline the results for each intervention category by illustrating the findings from selected outcomes. Travel restrictions reducing or stopping cross‐border travel (31 modelling studies) The studies assessed cases avoided and shift in epidemic development. We found very low‐certainty evidence for a reduction in COVID‐19 cases in the community (13 studies) and cases exported or imported (9 studies). Most studies reported positive effects, with effect sizes varying widely; only a few studies showed no effect. There was very low‐certainty evidence that cross‐border travel controls can slow the spread of COVID‐19. Most studies predicted positive effects, however, results from individual studies varied from a delay of less than one day to a delay of 85 days; very few studies predicted no effect of the measure. Screening at borders (13 modelling studies; 13 observational studies) Screening measures covered symptom/exposure‐based screening or test‐based screening (commonly specifying polymerase chain reaction (PCR) testing), or both, before departure or upon or within a few days of arrival. Studies assessed cases avoided, shift in epidemic development and cases detected. Studies generally predicted or observed some benefit from screening at borders, however these varied widely. For symptom/exposure‐based screening, one modelling study reported that global implementation of screening measures would reduce the number of cases exported per day from another country by 82% (95% confidence interval (CI) 72% to 95%) (moderate‐certainty evidence). Four modelling studies predicted delays in epidemic development, although there was wide variation in the results between the studies (very low‐certainty evidence). Four modelling studies predicted that the proportion of cases detected would range from 1% to 53% (very low‐certainty evidence). Nine observational studies observed the detected proportion to range from 0% to 100% (very low‐certainty evidence), although all but one study observed this proportion to be less than 54%. For test‐based screening, one modelling study provided very low‐certainty evidence for the number of cases avoided. It reported that testing travellers reduced imported or exported cases as well as secondary cases. Five observational studies observed that the proportion of cases detected varied from 58% to 90% (very low‐certainty evidence). Quarantine (12 modelling studies) The studies assessed cases avoided, shift in epidemic development and cases detected. All studies suggested some benefit of quarantine, however the magnitude of the effect ranged from small to large across the different outcomes (very low‐ to low‐certainty evidence). Three modelling studies predicted that the reduction in the number of cases in the community ranged from 450 to over 64,000 fewer cases (very low‐certainty evidence). The variation in effect was possibly related to the duration of quarantine and compliance. Quarantine and screening at borders (7 modelling studies; 4 observational studies) The studies assessed shift in epidemic development and cases detected. Most studies predicted positive effects for the combined measures with varying magnitudes (very low‐ to low‐certainty evidence). Four observational studies observed that the proportion of cases detected for quarantine and screening at borders ranged from 68% to 92% (low‐certainty evidence). The variation may depend on how the measures were combined, including the length of the quarantine period and days when the test was conducted in quarantine. AUTHORS' CONCLUSIONS: With much of the evidence derived from modelling studies, notably for travel restrictions reducing or stopping cross‐border travel and quarantine of travellers, there is a lack of 'real‐world' evidence. The certainty of the evidence for most travel‐related control measures and outcomes is very low and the true effects are likely to be substantially different from those reported here. Broadly, travel restrictions may limit the spread of disease across national borders. Symptom/exposure‐based screening measures at borders on their own are likely not effective; PCR testing at borders as a screening measure likely detects more cases than symptom/exposure‐based screening at borders, although if performed only upon arrival this will likely also miss a meaningful proportion of cases. Quarantine, based on a sufficiently long quarantine period and high compliance is likely to largely avoid further transmission from travellers. Combining quarantine with PCR testing at borders will likely improve effectiveness. Many studies suggest that effects depend on factors, such as levels of community transmission, travel volumes and duration, other public health measures in place, and the exact specification and timing of the measure. Future research should be better reported, employ a range of designs beyond modelling and assess potential benefits and harms of the travel‐related control measures from a societal perspective

Ansatz zur Generierung einer konditionalen, reversiblen Wt1 k.o.-Maus

Ansatz zur Generierung einer konditionalen, reversiblen Wt1 k.o.-Maus Der Wilms-Tumor (WT, Nephroblastom) ist ein embryonaler Nierentumor, der durch die maligne Transformation von undifferenziertem Nierengewebe, sog. nephrogenen Resten, entsteht. WT treten mit einer Inzidenz von 1 in 10.000 Lebendgeburten auf. Das Hauptmanifestationsalter, der normalerweise einseitig und sporadisch auftretenden Tumore, liegt zwischen dem 3. und 4. Lebensjahr. Etwa 10 % der Patienten entwickeln jedoch bilaterale Tumore. In diesen Fällen ist eine Assoziation mit komplexen genetischen Krankheitsbildern (u. a. WAGR-, Denys-Drash-, Frasier- und Beckwith-Wiedemann-Syndrom) festzustellen. In 15 % der sporadischen WT sind Mutationen im WT1 (Wilms-Tumor 1)-Gen beschrieben. WT1 besteht aus zehn Exons und weist typische Merkmale von Transkriptionsfaktoren (z. B. vier Zinkfinger) auf. Zwei alternative Spleißereignisse betreffen Exon 5 (+/−Exon 5) und Exon 9 (Transkripte mit bzw. ohne die codierenden Sequenzen für die AS Lysin-Threonin-Serin; +/−KTS). Die Lage der drei alternativ vorhandenen AS zwischen den Zinkfingern 3 und 4 bestimmt die verschiedenen Funktionen der WT1- Proteine (4 Isoformen) als Transkriptionsfaktor (−KTS) bzw. als RNA-bindendes Protein (+KTS). Das zunächst im Zusammenhang mit WT als Tumorsuppressorgen identifizierte WT1 ist ein Entwicklungsgen mit einem sehr komplexen Expressionsmuster in der Embryonalentwicklung. Dabei ist v. a. die Bedeutung in der Urogenitalentwicklung entscheidend. Konstitutive, homozygote Wt1−/− k.o.-Mäuse sind embryonal (~ E12,5 dpc) letal und bilden u. a. keine Gonaden und keine Nieren. Aus diesem Grund existiert bisher kein Wilms-Tumormodell. Die Herstellung eines konditionalen murinen Tiermodells auf Basis des Tet on/off-Systems zur Untersuchung der Nierenentwicklung bzw. zur Analyse der Wilms-Tumorpathogenese war Ziel dieser Arbeit. Hierfür wurden drei Mauslinien generiert: Zwei transgene sog. Responder-Linien, die eine chimäre spleißbare Wt1-cDNA der Variante musWt1+Exon 5;+/−KTS unter der Kontrolle eines Tet-responsiven Promotors im Genom tragen. Dieses tTA/Dox-abhängig regulierbare Wt1-Transgen (tgWt1) sollte ( exogen regulierbar) die Expression des endogenen Wt1-Lokus ausreichend nachahmen, um die kritischen Phasen der Embryogenese zu überwinden und lebensfähige Tiere zu erhalten. Parallel dazu wurde die Wt1-Effektor-Mauslinie (WE2) generiert. Diese trägt einen tetrazyklinabhängigen Transaktivator (tTA) zur Steuerung Tet-regulierbarer Transgene unter der Kontrolle des endogenen Wt1-Promotors. Die durch homologe Rekombination in ES-Zellen erreichte Integration des tTA direkt am Translationsstartpunkt des Wt1-Lokus hat in den Tieren einen heterozygoten Wt1 knock out/tTA knock in zur Folge. Die bisher vorgenommenen Verpaarungen doppelt transgener Wt1-tTA+/−/Resp-Mäuse ergaben keinen Rescue des letalen Wt1 k.o. und es konnten bislang keine Wilms-Tumore induziert werden. Alle im Verlauf der Arbeit generierten Mauslinien wurden umfassend charakterisiert. So konnte für die Tiere der Responder-Linien Wt1-Resp1 (mit zusätzlichen Isolator-Sequenzen zum Schutz des Transgens vor Positionseffekten) und Wt1-Resp2 (ohne Isolatoren) konnte die Tet-induzierbare Expression und die Spleißbarkeit des tgWt1 in MEF-Assays und mittels Effektor-Mäusen auf RNA-Ebene nachgewiesen werden. Die genomische Charakterisierung der WE2-Linie ergab eine ungeklärte etwa 120 kb große Inversion am Wt1-Lokus, die alle 5'-regulatorischen Sequenzen mitsamt des tTA vom Rest von Wt1 trennt. Tiere dieser Linie weisen aber dennoch einen funktionalen Wt1 k.o. auf: Unter den Nachkommen aus Intercross-Verpaarungen von Wt1-tTA+/−-Mäusen lassen sich auf Grund der Letalität keine Wt1−/−-Genotypen nachweisen. Die Charakterisierung der Effektor-Linie auf RNA-Ebene und mittels Reporter-Mäusen liefert ein Wt1-analoges tTA-Expressionsmuster: So findet man eine deutliche tTA-Expression u. a. in Niere (Glomeruli), Uterus, Ovar und Testis. Die hier vorgestellten Experimente ergeben darüber hinaus eindeutige Hinweise einer Beteiligung von Wt1 in der Entstehung der glatten Muskulatur bzw. in der Vaskulogenese.Aim of generating a conditional, revesible Wt1 k.o. mouse Wilms' tumor (nephroblastoma) is a malignant embryonic kidney cancer which affects 1:10.000 children, usually below the age of 5 years. Most patients present with sporadic unilateral neoplasms, whereas ~10 % develop bilateral tumors. These cases are often associated with complex genetic diseases like WAGR-, Denys-Drash-, Frasier- and Beckwith-Wiedemann-Syndrome. Wilms' tumor is intimately linked to early kidney development and is thought to arise from mesenchymal blastema cells that fail to differentiate into metanephric structures but continue to proliferate due to genetic and epigenetic changes in the persitent embryonic renal tissue (nephrogenic rests). The Wilms' tumor 1 gene (WT1), the first gene found to be inactivated in Wilms' tumor, is mutated in ~15 % of sporadic tumors. Alterations of WT1 are also observed in other malignancies such as leukemia, mesothelioma and desmoplastic small round cell tumor. Dependent on the tumor type, WT1 proteins might either function as tumor suppressor proteins or as a survival factor. WT1 is located at human chromosome 11p13 and on mouse chromosome 2, spanning ~ 50 kb genomic DNA and comprising 10 exons that encode mRNAs ~3 kb. WT1 exon 5 and exon 9 are alternatively spliced. The encoded protein exhibits typical characteristics of a transcription factor, namely four zinc fingers at the C-terminal domain. The use of the alternative splice donor site at the end of exon 9 leads to the incorporation of three amino acids (lysine, threonine, serine; KTS) between the zinc fingers 3 and 4, resulting in altering the function of WT1 proteins as a transcription factor (−KTS isoforms) or as a RNA binding protein (+KTS isoforms). WT1 is showing a complex expression pattern in embryogenesis demonstrating its importance for certain other mesodermally derived tissues, including gonads, cardiac vasculature and spleen. Constitutive Wt1 null mice (Wt1−/−) die at E12,5 (dependent on the genetic background) of failure in cardiac development. In addition, these mice show no development of the kidneys or the gonads, pointing to a key role for Wt1 in urogenital genesis. Up to date, no murine Wilms’ tumor model exists. To study Wilms’ tumorigenesis we generated mouse strains to simulate Wt1 ablation in nephrogenesis using the Tet on/off system: First: By homologous recombination a tTA was introduced at the Wt1 locus (tTA knock in), excising Wt1 exon 1 (Wt1 knock out) and leading to a Wt1+/−-tTA mouse strain, which could be used as an effector for tetO transgene strains. However, there are results pointing to an 120 kb inversion involving the recombinated Wt1 locus. Anyway, homozygous Wt1−/− mice are lethal, thus providing strong evidence for the inactivation of Wt1. Under control of the Wt1 promotor, the integrated tTA is resembling the Wt1 expression pattern. Using reporter mouse strains we documented a role for Wt1 in vasculogenesis and respectively in the development of smooth muscle cells in general. Second: Two responder strains were generated by pronucleus injection harbouring a tetOWt1 transgene consisiting of a tetOCMV-promotor driving a musWt1+ exon5; +/−KTS cDNA (tgWt1+ex5, +/−KTS) in presence of tTA. This chimeric Wt1 cDNA incorporates complete intron 9 to provide the alternative splice donor site. Both tgWt1 isoforms (+ex5, +KTS and +ex5, −KTS) could be detected. Crossing of the Wt1+/−-tTA and the tgWt1+ex5, +/−KTS mice revealed no rescue of the lethal Wt1−/− phenotype. In addition, no Wilms’ tumor could be induced

Health and economic impact of improved glucose, blood pressure and lipid control among German adults with type 2 diabetes: a modelling study

Aims/hypothesisThe aim of this study was to estimate the long-term health and economic consequences of improved risk factor control in German adults with type 2 diabetes.MethodsWe used the UK Prospective Diabetes Study Outcomes Model 2 to project the patient-level health outcomes and healthcare costs of people with type 2 diabetes in Germany over 5, 10 and 30 years. We parameterised the model using the best available data on population characteristics, healthcare costs and health-related quality of life from German studies. The modelled scenarios were: (1) a permanent reduction of HbA1c by 5.5 mmol/mol (0.5%), of systolic BP (SBP) by 10 mmHg, or of LDL-cholesterol by 0.26 mmol/l in all patients, and (2) achievement of guideline care recommendations for HbA1c (≤53 mmol/mol [7%]), SBP (≤140 mmHg) or LDL-cholesterol (≤2.6 mmol/l) in patients who do not meet the recommendations. We calculated nationwide estimates using age- and sex-specific quality-adjusted life year (QALY) and cost estimates, type 2 diabetes prevalence and population size.ResultsOver 10 years, a permanent reduction of HbA1c by 5.5 mmol/mol (0.5%), SBP by 10 mmHg or LDL-cholesterol by 0.26 mmol/l led to per-person savings in healthcare expenditures of €121, €238 and €34, and 0.01, 0.02 and 0.015 QALYs gained, respectively. Achieving guideline care recommendations for HbA1c, SBP or LDL-cholesterol could reduce healthcare expenditure by €451, €507 and €327 and gained 0.03, 0.05 and 0.06 additional QALYs in individuals who did not meet the recommendations. Nationally, achieving guideline care recommendations for HbA1c, SBP and LDL-cholesterol could reduce healthcare costs by over €1.9 billion.Conclusions/interpretationSustained improvements in HbA1c, SBP and LDL-cholesterol control among diabetes patients in Germany can lead to substantial health benefits and reduce healthcare expenditures

An inversion involving the mouse Shh locus results in brachydactyly through dysregulation of Shh expression

Short digits (Dsh) is a radiation-induced mouse mutant. Homozygous mice are characterized by multiple defects strongly resembling those resulting from Sonic hedgehog (Shh) inactivation. Heterozygous mice show a limb reduction phenotype with fusion and shortening of the proximal and middle phalanges in all digits, similar to human brachydactyly type A1, a condition caused by mutations in Indian hedgehog (IHH). We mapped Dsh to chromosome 5 in a region containing Shh and were able to demonstrate an inversion comprising 11.7 Mb. The distal breakpoint is 13.298 kb upstream of Shh, separating the coding sequence from several putative regulatory elements identified by interspecies comparison. The inversion results in almost complete downregulation of Shh expression during E9.5–E12.5, explaining the homozygous phenotype. At E13.5 and E14.5, however, Shh is upregulated in the phalangeal anlagen of Dsh/+ mice, at a time point and in a region where WT Shh is never expressed. The dysregulation of Shh expression causes the local upregulation of hedgehog target genes such as Gli1-3, patched, and Pthlh, as well as the downregulation of Ihh and Gdf5. This results in shortening of the digits through an arrest of chondrocyte differentiation and the disruption of joint development