International treaties have mostly failed to produce their intended effects.

There are over 250,000 international treaties that aim to foster global cooperation. But are treaties actually helpful for addressing global challenges? This systematic field-wide evidence synthesis of 224 primary studies and meta-analysis of the higher-quality 82 studies finds treaties have mostly failed to produce their intended effects. The only exceptions are treaties governing international trade and finance, which consistently produced intended effects. We also found evidence that impactful treaties achieve their effects through socialization and normative processes rather than longer-term legal processes and that enforcement mechanisms are the only modifiable treaty design choice with the potential to improve the effectiveness of treaties governing environmental, human rights, humanitarian, maritime, and security policy domains. This evidence synthesis raises doubts about the value of international treaties that neither regulate trade or finance nor contain enforcement mechanisms.

Classifying European cigarette consumption trajectories from 1970 to 2015.

OBJECTIVES: To systematically code and classify longitudinal cigarette consumption trajectories in European countries since 1970. DESIGN: Blinded duplicate qualitative coding of periods of year-over-year relative increase, plateau, and decrease of national per capita cigarette consumption and categorisation of historical cigarette consumption trajectories based on longitudinal patterns emerging from the data. SETTING: 41 countries or former countries in the European region for which data are available between 1970 and 2015. RESULTS: Regional trends in longitudinal consumption patterns identify stable or decreasing consumption throughout Northern, Western and Southern European countries, while Eastern and Southeastern European countries experienced much greater instability. The 11 emergent classes of historical cigarette consumption trajectories were also regionally clustered, including a distinctive inverted U or sine wave pattern repeatedly emerging from former Soviet and Southeastern European countries. CONCLUSIONS: The open-access data produced by this study can be used to conduct comparative international evaluations of tobacco control policies by separating impacts likely attributable to gradual long-term trends from those more likely attributable to acute short-term events. The complex, regionally clustered historical trajectories of cigarette consumption in Europe suggest that the enduring normative frame of a gently sloping downward curve in cigarette consumption can offer a false sense of security among policymakers and can distract from plausible causal mechanisms among researchers. These multilevel and multisectoral causal mechanisms point to the need for a greater understanding of the political economy of regional and global determinants of cigarette consumption.

Beyond MPOWER: a systematic review of population-level factors that affect European tobacco smoking rates.

BACKGROUND: Population-level factors within and beyond the scope of the World Health Organization's (WHO) MPOWER policy package have significant impacts on smoking rates. However, no synthesis of the existing evidence exists. This systematic review identifies population-level factors that influence cigarette smoking rates in European countries. METHODS: We searched the ProQuest database collection for original, peer-reviewed quantitative evaluations that investigated the effects of population-level exposures on smoking rates in European countries. Of the 3122 studies screened, 62 were ultimately included in the review. A standardized data extraction form was used to identify key characteristics of each study including publication year, years evaluated, countries studied, population characteristics, study design, data sources, analytic methods, exposure studied, relevant covariates and effects on tobacco smoking outcomes. RESULTS: One hundred and fifty-five population-level exposures were extracted from the 62 studies included in the review, 99 of which were related to WHO MPOWER measures. An additional 56 exposures fell into eight policy realms: economic crises, education policy, macro-economic factors, non-MPOWER tobacco regulations, population welfare, public policy, sales to minors and unemployment rates. About one-half of the MPOWER exposures affected smoking rates (55/99) and did so in an overwhelmingly positive way (55/55). Over three-quarters of the non-MPOWER exposures were associated with statistically significant changes in smoking outcomes (43/56), with about two-thirds of these exposures leading to a decrease in smoking (29/43). CONCLUSIONS: Population-level factors that fall outside of the WHO's MPOWER measures are an understudied research area. The impacts of these factors on tobacco control should be considered by policymakers.

Vorinostat Improves Myotonic Dystrophy Type 1 Splicing Abnormalities in DM1 Muscle Cell Lines and Skeletal Muscle from a DM1 Mouse Model.

Myotonic dystrophy type 1 (DM1), the most common form of adult muscular dystrophy, is caused by an abnormal expansion of CTG repeats in the 3' untranslated region of the dystrophia myotonica protein kinase (DMPK) gene. The expanded repeats of the DMPK mRNA form hairpin structures in vitro, which cause misregulation and/or sequestration of proteins including the splicing regulator muscleblind-like 1 (MBNL1). In turn, misregulation and sequestration of such proteins result in the aberrant alternative splicing of diverse mRNAs and underlie, at least in part, DM1 pathogenesis. It has been previously shown that disaggregating RNA foci repletes free MBNL1, rescues DM1 spliceopathy, and alleviates associated symptoms such as myotonia. Using an FDA-approved drug library, we have screened for a reduction of CUG foci in patient muscle cells and identified the HDAC inhibitor, vorinostat, as an inhibitor of foci formation; SERCA1 (sarcoplasmic/endoplasmic reticulum Ca2+-ATPase) spliceopathy was also improved by vorinostat treatment. Vorinostat treatment in a mouse model of DM1 (human skeletal actin-long repeat; HSALR) improved several spliceopathies, reduced muscle central nucleation, and restored chloride channel levels at the sarcolemma. Our in vitro and in vivo evidence showing amelioration of several DM1 disease markers marks vorinostat as a promising novel DM1 therapy.

F-actin flashes on phagosomes mechanically deform contents for efficient digestion in macrophages.

The mechanism and role of transient F-actin recruitment, or F-actin 'flashes', on phagosomes remains enigmatic. Here we provide a comprehensive characterization of F-actin flashing dynamics on phagosomes, including receptor and signaling involvement. F-actin flashes predominate during the integrin-driven complement receptor (CR)-mediated phagocytosis. F-actin flashes begin shortly after internalization and persist on phagosomes for approximately 3 minutes before disassembling and reassembling several times within the first hour. Strikingly, the appearance of F-actin flashes on phagosomes coincides with morphological deformation, lysis and occasional fission of internalized red blood cells. The cadence of flashes depends on particle stiffness, and the F-actin networks on phagosomes are enriched in mechanosensitive components including focal adhesion proteins, RhoA and actomyosin. Inhibiting Arp2/3 and myosin IIA activity significantly reduces the frequency at which phagosome cargo becomes deformed during transient F-actin accumulation. At later time points, post-F-actin flashing, enhanced degradation of phagosome contents is observed, compared with non-flashing phagosomes. Taken together, these data suggest that actomyosin-driven phagosome contractions serve to disrupt malleable particles physically, a process akin to mastication, to enhance later enzymatic digestion.

Is the lack of smartphone data skewing wealth indices in low-income settings?

BACKGROUND: Smartphones have rapidly become an important marker of wealth in low- and middle-income countries, but international household surveys do not regularly gather data on smartphone ownership and these data are rarely used to calculate wealth indices. METHODS: We developed a cross-sectional survey module delivered to 3028 households in rural northwest Burkina Faso to measure the effects of this absence. Wealth indices were calculated using both principal components analysis (PCA) and polychoric PCA for a base model using only ownership of any cell phone, and a full model using data on smartphone ownership, the number of cell phones, and the purchase of mobile data. Four outcomes (household expenditure, education level, and prevalence of frailty and diabetes) were used to evaluate changes in the composition of wealth index quintiles using ordinary least squares and logistic regressions and Wald tests. RESULTS: Households that own smartphones have higher monthly expenditures and own a greater quantity and quality of household assets. Expenditure and education levels are significantly higher at the fifth (richest) socioeconomic status (SES) quintile of full model wealth indices as compared to base models. Similarly, diabetes prevalence is significantly higher at the fifth SES quintile using PCA wealth index full models, but this is not observed for frailty prevalence, which is more prevalent among lower SES households. These effects are not present when using polychoric PCA, suggesting that this method provides additional robustness to missing asset data to measure underlying latent SES by proxy. CONCLUSIONS: The lack of smartphone data can skew PCA-based wealth index performance in a low-income context for the top of the socioeconomic spectrum. While some PCA variants may be robust to the omission of smartphone ownership, eliciting smartphone ownership data in household surveys is likely to substantially improve the validity and utility of wealth estimates.

Geographic Targeting and Normative Frames: Revisiting the Equity of Conditional Cash Transfer Program Distribution in Bolivia, Colombia, Ecuador, and Peru.

BACKGROUND: Four Andean countries of Bolivia, Colombia, Ecuador, and Peru introduced national health-focused conditional cash transfer (CCT) programs in the 2000s. This study probes whether policymakers in these countries targeted CCT programs to subregions with the highest prevalence of ill-health or those with the lowest socioeconomic status (SES) to evaluate the equity of geographic targeting and means-testing, as well as the potential role of normative frames, bounded rationality, and clientelism as explanatory mechanisms for inequities in social spending. METHODS: The distribution of vaccination coverage, underweight, stunting, and child deaths is established both within and between subnational regions and SES quintiles from 1998 to 2012 using every available nationally representative household survey. The equity of CCT program targeting and strength of association with subregional SES and health outcomes are measured using generalized entropy index decomposition and meta-regression. Finally, simple predictive models for CCT targeting are created using lagged subregional SES, health outcomes, and concentration indices. RESULTS: Bolivia and Peru both effectively targeted at-risk subregions, but subregions in Peru with no CCT program coverage result in higher mistargeting rates for the country as a whole. Only Bolivia failed to attain CCT coverage concentration indices that are at least as large as the health inequalities they are targeting. Despite this insufficient progressivity, Bolivia has the most efficient subregional targeting, while the lowest rates of mistargeting for child deaths are found in Colombia and Ecuador. Finally, the simple predictive model performs as well or better than observed CCT coverage distribution for every country, year, and outcome. CONCLUSIONS: Both Peru and Ecuador have targeted programs to their poorest populations effectively, demonstrating that this is possible with both universal and geographic targeting. No clear evidence of clientelism was found, while the dominant normative frame underlying CCT program targeting decisions appears to be the relative SES of subregions, rather than absolute SES, prevalence of health outcomes, or health inequalities. To reduce the inequitable impacts of bounded rationality, policymakers can use simple predictive models to target CCT coverage effectively and without leaving behind the most vulnerable populations that happen to live in more affluent subregions.

Junctophilin-2 is a target of matrix metalloproteinase-2 in myocardial ischemia-reperfusion injury.

Junctophilin-2 is a structural membrane protein that tethers T-tubules to the sarcoplasmic reticulum to allow for coordinated calcium-induced calcium release in cardiomyocytes. Defective excitation-contraction coupling in myocardial ischemia-reperfusion (IR) injury is associated with junctophilin-2 proteolysis. However, it remains unclear whether preventing junctophilin-2 proteolysis improves the recovery of cardiac contractile dysfunction in IR injury. Matrix metalloproteinase-2 (MMP-2) is a zinc and calcium-dependent protease that is activated by oxidative stress in myocardial IR injury and cleaves both intracellular and extracellular substrates. To determine whether junctophilin-2 is targeted by MMP-2, isolated rat hearts were perfused in working mode aerobically or subjected to IR injury with the selective MMP inhibitor ARP-100. IR injury impaired the recovery of cardiac contractile function which was associated with increased degradation of junctophilin-2 and damaged cardiac dyads. In IR hearts, ARP-100 improved the recovery of cardiac contractile function, attenuated junctophilin-2 proteolysis, and prevented ultrastructural damage to the dyad. MMP-2 was co-localized with junctophilin-2 in aerobic and IR hearts by immunoprecipitation and immunohistochemistry. In situ zymography showed that MMP activity was localized to the Z-disc and sarcomere in aerobic hearts and accumulated at sites where the striated JPH-2 staining was disrupted in IR hearts. In vitro proteolysis assays determined that junctophilin-2 is susceptible to proteolysis by MMP-2 and in silico analysis predicted multiple MMP-2 cleavage sites between the membrane occupation and recognition nexus repeats and within the divergent region of junctophilin-2. Degradation of junctophilin-2 by MMP-2 is an early consequence of myocardial IR injury which may initiate a cascade of sequelae leading to impaired contractile function.

Systematic review and updated meta-analysis of the use of drug-coated balloon angioplasty versus plain old balloon angioplasty for femoropopliteal arterial disease.

OBJECTIVE: An endovascular-first approach is usually recommended in femoropopliteal occlusive disease. However, despite high technical success, plain old balloon angioplasty (POBA) is burdened with high restenosis rates. To reduce this phenomenon, local delivery of drugs has been proposed by way of drug-coated balloons (DCBs). Our goal was to review the evidence for the use of DCBs in the management of femoropopliteal disease and to determine whether it is associated with improved outcomes compared with POBA. METHODS: Electronic searches of PubMed (MEDLINE), Embase, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and proceedings of international conferences were performed to identify randomized controlled trials (RCTs) and observational registries evaluating the use of DCBs for femoropopliteal arterial occlusive disease. RESULTS: This meta-analysis included 13 RCTs, 6 global registries, and 3 global registries focusing on long lesions. They all used paclitaxel in the DCB arm. There was heterogeneity between trials, and the frequency of stent deployment and duration of dual antiplatelet therapy differed. At 2 years, there were significantly better outcomes for DCBs in terms of target lesion revascularization (odds ratio [OR], 0.29; 95% confidence interval [CI], 0.20-0.40), primary patency (OR, 0.38; 95% CI, 0.27-0.54), late lumen loss (mean diameter, -0.80 mm; 95% CI, -1.44 to -0.16), and Rutherford category (OR, 0.82; 95% CI, 0.57-1.19). There was no significant difference between DCBs and POBA in amputation or change in ankle-brachial index. A subgroup analysis revealed that male patients treated with DCBs performed significantly better than female patients and that diabetics, heavily calcified lesions, and popliteal lesions performed significantly worse than nondiabetics, noncalcified and mild to moderately calcified lesions, and exclusive superficial femoral artery lesions, respectively. Secondarily stented and nonpredilated lesions did not perform significantly worse, but standard-dose (3 µg/mm2) DCBs were significantly more effective than low-dose (2 µg/mm2) DCBs in reducing binary restenosis. In addition, in a low-dose DCB, the polyethylene glycol excipient performed significantly better than polysorbate and sorbitol, whereas binary restenosis was significantly less frequent with the urea excipient, associated with a standard-dose DCB, compared with the polysorbate and sorbitol excipient, associated with a low-dose DCB. CONCLUSIONS: DCB angioplasty is an effective treatment associated with high procedural success. In a meta-analysis of industry-sponsored trials, it consistently reduced late lumen loss, binary restenosis, and target lesion revascularization compared with POBA alone in the treatment of femoropopliteal disease. Further independent, non-industry-sponsored RCTs are necessary to better delineate the role of DCBs in the treatment of infrainguinal occlusive disease.

Midterm Results with the Open Chimney Technique during Endovascular Aneurysm Repair.

PURPOSE: To report the midterm experience with chimney-endovascular aneurysm repair (Ch-EVAR) with the use of open self-expending stents for branch vessel preservation. MATERIALS AND METHODS: From July 2010 to May 2017, 67 patients underwent open Ch-EVAR because their proximal landing zones were adjacent to, or covered, the renal or mesenteric arteries (Zones 7-9), and they were not suitable for standard or fenestrated endovascular aneurysm repair. The proximal landing zone was relocated below the highest renal artery in 46 cases, the superior mesenteric artery in 17 cases, and the celiac artery in 4 cases, using 84 open chimneys (131 stents). A subgroup analysis was performed between an early (2010-2014) and a later (2015-2017) time period. Thirty-two patients were treated during the early period, and 35 were treated during the later period. In the later period, open chimneys were strengthened by a second self-expanding stent. RESULTS: The primary technical success rate was 89.6%; the early mortality rate was 9.0%; and the median follow-up duration was 13 months (range, 1-76 months). The estimated actuarial survival rate was 85.7% in year 1 and 79.2% in year 2, and the estimated patency rate of open chimneys reached 95.2% at 2 years. Aneurysm sac regression >5 mm and sac stability rates were 39.0% and 57.6%, respectively. Freedom from aneurysm-related reintervention was lower in the later period (log-rank P = .04), while type Ia endoleaks tended to be twice as likely. CONCLUSIONS: Midterm results of open Ch-EVAR show high technical success with acceptable midterm patency and lack of endoleak in appropriately selected patients. The advantages over covered stents are lower-profile delivery systems and maintenance of branch vessel patency in early bifurcations and overlying visceral vessels.

Doxorubicin induces de novo expression of N-terminal-truncated matrix metalloproteinase-2 in cardiac myocytes.

Anthracyclines, such as doxorubicin, are commonly prescribed antineoplastic agents that cause irreversible cardiac injury. Doxorubicin cardiotoxicity is initiated by increased oxidative stress in cardiomyocytes. Oxidative stress enhances intracellular matrix metalloproteinase-2 (MMP-2) by direct activation of its full-length isoform and (or) de novo expression of an N-terminal-truncated isoform (NTT-MMP-2). As MMP-2 is localized to the sarcomere, we tested whether doxorubicin activates intracellular MMP-2 in neonatal rat ventricular myocytes (NRVM) and whether it thereby proteolyzes two of its identified sarcomeric targets, α-actinin and troponin I. Doxorubicin increased oxidative stress within 12 h as indicated by reduced aconitase activity. This was associated with a twofold increase in MMP-2 protein levels and threefold higher gelatinolytic activity. MMP inhibitors ARP-100 or ONO-4817 (1 µM) prevented doxorubicin-induced MMP-2 activation. Doxorubicin also increased the levels and activity of MMP-2 secreted into the conditioned media. Doxorubicin upregulated the mRNA expression of both full-length MMP-2 and NTT-MMP-2. α-Actinin levels remained unchanged, whereas doxorubicin downregulated troponin I in an MMP-independent manner. Doxorubicin induces oxidative stress and stimulates a robust increase in MMP-2 expression and activity in NRVM, including NTT-MMP-2. The sarcomeric proteins α-actinin and troponin I are, however, not targeted by MMP-2 under these conditions.

Monocentric Evaluation of Chimney Versus Fenestrated Endovascular Aortic Repair for Juxtarenal Abdominal Aortic Aneurysm.

BACKGROUND: With approval of on-label fenestrated (F-) endovascular aortic repair (EVAR), concerns regarding long-term patency and endoleaks (ELs) after chimney graft (CG)-EVAR were raised. To add supportive data on the value of this technique, we chose to report the midterm results of CG-EVAR in a single center with standardized methods and to compare them to F-EVAR. METHODS: A retrospective analysis of prospectively gathered data from January 2010 to January 2015 was conducted, and patients with excessive comorbidities for open repair treated by CG-EVAR or F-EVAR were included. RESULTS: Ninety patients were treated by F-EVAR (88 men, 198 targets vessels) and 31 by CG-EVAR (26 men, 39 targets vessels, 12.9% treated in emergency; P = 0.001). Mean age was significantly higher in the CG group (71.3 ± 8.2 years in the FG group vs. 75.3 ± 6.6; P = 0.02), and there were significantly more patients suffering from preoperative chronic kidney disease (CKD) (13 [14.4%] treated by F-EVAR vs. 12 [38.7%]; P = 0.009). Target vessels were successfully reconstructed in 99.0% (196/198 target vessels) vs. 97.4% (38/39 target vessels) of cases (P = 0.3). In-hospital mortality was significantly higher after CG-EVAR (3.3% vs. 16.1%; P = 0.03). Incidence of acute kidney injury and CKD did not differ significantly between both groups. At 12 and 24 months, overall survival was 91.4% after F-EVAR vs. 82.1% and 81.8% vs. 69.0% (P = 0.4), estimated freedom from aneurysm related reintervention was 93.3% vs. 82.1% and 84.9% vs. 82.1% (P = 0.6), and target vessel's primary patency rate was 97.5% vs. 89.9% (P = 0.06), respectively. Freedom from type I EL's survival was significantly higher after F-EVAR at 12 and 24 months (100% vs. 89.0% and 97.7% vs. 89.0%; P = 0.01), but aneurysm maximum transverse diameter decrease did not differ significantly. CONCLUSIONS: There are potential advantages to CG-EVAR with off-the-shelf availability, versatility, and low-profile devices. In this series, patients treated by CG-EVAR showed promising and durable midterm results compared with F-EVAR. CG-EVAR and F-EVAR should not be apprehended as opposed strategies but more as complementary ones, while the best indications for CG-EVAR are clarified.

Nuclear matrix metalloproteinase-2 in the cardiomyocyte and the ischemic-reperfused heart.

Matrix metalloproteinases (MMPs) are zinc-dependent proteases involved in intra- and extra-cellular matrix remodeling resulting from oxidative stress injury to the heart. MMP-2 was the first MMP to be localized to the nucleus; however, its biological functions there are unclear. We hypothesized that MMP-2 is present in the nucleus under normal physiological conditions but increases during myocardial ischemia-reperfusion (I/R) injury-induced oxidative stress, proteolyzing nuclear structural proteins. Lamins are intermediate filament proteins that provide structural support to the nucleus and are putative targets of MMP-2. To identify lamin susceptibility to MMP-2 proteolysis, purified lamin A or B was incubated with MMP-2 in vitro. Lamin A, but not lamin B, was proteolysed by MMP-2 into an approximately 50kDa fragment, which was also predicted by in silico cleavage site analysis. Immunofluorescent confocal microscopy and subcellular fractionation showed MMP-2 both in the cytosol and nuclei of neonatal rat ventricular myocytes. Rat hearts were isolated and perfused by the Langendorff method aerobically, or subjected to I/R injury in the presence or absence of o-phenanthroline, an MMP inhibitor. Nuclear fractions extracted from I/R hearts showed increased MMP-2 activity, but not protein level. The level of troponin I, a known sarcomeric target of MMP-2, was rescued in I/R hearts treated with o-phenanthroline, demonstrating the efficacy of MMP inhibition. However, lamin A or B levels remained unchanged in I/R hearts. MMP-2 has a widespread subcellular distribution in cardiomyocytes, including a significant presence in the nucleus. The increase in nuclear MMP-2 activity seen during stunning injury here, indicates yet unknown biological actions, other than lamin proteolysis, which may require more severe ischemia to effect.

Chlamydia trachomatis Inclusion Disrupts Host Cell Cytokinesis to Enhance Its Growth in Multinuclear Cells.

Chlamydia trachomatis, the leading cause of bacterial sexually transmitted infections, disrupts cytokinesis and causes significant multinucleation in host cells. Here, we demonstrate that multinuclear cells that result from unsuccessful cell division contain significantly higher Golgi content, an important source of lipids for chlamydiae. Using immunofluorescence and fluorescent live cell imaging, we show that C. trachomatis in multinuclear cells indeed intercept Golgi-derived lipid faster than in mononuclear cells. Moreover, multinuclear cells enhance C. trachomatis inclusion growth and infectious particle formation. Together, these results indicate that C. trachomatis robustly position inclusions to the cell equator to disrupt host cell division in order to acquire host Golgi-derived lipids more quickly in multinucleated progeny cells.

Measuring Haitian children's exposure to chikungunya, dengue and malaria.

OBJECTIVE: To differentiate exposure to the newly introduced chikungunya virus from exposure to endemic dengue virus and other pathogens in Haiti. METHODS: We used a multiplex bead assay to detect immunoglobulin G (IgG) responses to a recombinant chikungunya virus antigen, two dengue virus-like particles and three recombinant Plasmodium falciparum antigens. Most (217) of the blood samples investigated were collected longitudinally, from each of 61 children, between 2011 and 2014 but another 127 were collected from a cross-sectional sample of children in 2014. FINDINGS: Of the samples from the longitudinal cohort, none of the 153 collected between 2011 and 2013 but 78.7% (48/61) of those collected in 2014 were positive for IgG responses to the chikungunya virus antigen. In the cross-sectional sample, such responses were detected in 96 (75.6%) of the children and occurred at similar prevalence across all age groups. In the same sample, responses to malarial antigen were only detected in eight children (6.3%) but the prevalence of IgG responses to dengue virus antigens was 60.6% (77/127) overall and increased steadily with age. Spatial analysis indicated that the prevalence of IgG responses to the chikungunya virus and one of the dengue virus-like particles decreased as the sampling site moved away from the city of Léogâne and towards the ocean. CONCLUSION: Serological evidence indicates that there had been a rapid and intense dissemination of chikungunya virus in Haiti. The multiplex bead assay appears to be an appropriate serological platform to monitor the seroprevalence of multiple pathogens simultaneously.

Systematic comparison of household income, consumption, and assets to measure health inequalities in low- and middle-income countries.

There has been no systematic comparison of how the three most common measures to quantify household SES-income, consumption, and asset indices-could impact the magnitude of health inequalities. Microdata from 22 Living Standards Measurement Study surveys were compiled and concentration indices, relative indices of inequality, and slope indices of inequality were calculated for underweight, stunting, and child deaths using income, consumption, asset indices, and hybrid predicted income. Meta-analyses of survey year subgroups (pre-1995, 1995-2004, and post-2004), outcomes (child deaths, stunting, and underweight), and World Bank country-income status (low, low-middle, and upper-middle) were then conducted. Asset indices and the related hybrid income proxy result in the largest magnitudes of health inequalities for all 12 overall outcomes, as well as most country-income and survey year subgroupings. There is no clear trend of health inequality magnitudes changing over time, but magnitudes of health inequality may increase as country-income levels increase. There is no significant difference between relative and absolute inequality measures, but the hybrid predicted income measure behaves more similarly to asset indices than the household income it is supposed to model. Health inequality magnitudes may be affected by the choice of household SES measure and should be studied in further detail.

Quasi-experimental evaluation of national border closures on COVID-19 transmission.

With over 200 pandemic threats emerging every year, the efficacy of closing national borders to control the transmission of disease in the first months of a pandemic remains a critically important question. Previous studies offer conflicting evidence for the potential effects of these closures on COVID-19 transmission and no study has yet empirically evaluated the global impact of border closures using quasi-experimental methods and real-world data. We triangulate results from interrupted time-series analysis, meta-regression, coarsened exact matching, and an extensive series of robustness checks to evaluate the effect of 166 countries' national border closures on the global transmission of COVID-19. Total border closures banning non-essential travel from all countries and (to a lesser extent) targeted border closures banning travel from specific countries had some effect on temporarily slowing COVID-19 transmission in those countries that implemented them. In contrast to these country-level impacts, the global sum of targeted border closures implemented by February 5, 2020 was not sufficient to slow global COVID-19 transmission, but the sum of total border closures implemented by March 19, 2020 did achieve this effect. Country-level results were highly heterogeneous, with early implementation and border closures so broadly targeted that they resemble total border closures improving the likelihood of slowing the pandemic's spread. Governments that can make productive use of extra preparation time and cannot feasibly implement less restrictive alternatives might consider enacting border closures. However, given their moderate and uncertain impacts and their significant harms, border closures are unlikely to be the best policy response for most countries and should only be deployed in rare circumstances and with great caution. All countries would benefit from global mechanisms to coordinate national decisions on border closures during pandemics.

Informality, Social Citizenship, and Wellbeing among Migrant Workers in Costa Rica in the Context of COVID-19.

Costa Rica is home to 557,000 migrants, whose disproportionate exposure to precarious, dangerous, and informal work has resulted in persistent inequities in health and wellbeing in the midst of the COVID-19 pandemic. We used a novel multimodal grounded approach synthesizing documentary film, experiential education, and academic research to explore socioecological wellbeing among Nicaraguan migrant workers in Costa Rica. Participants pointed to the COVID-19 pandemic as exacerbating the underlying conditions of vulnerability, such as precarity and informality, dangerous working conditions, social and systemic discrimination, and additional burdens faced by women. However, the narrative that emerged most consistently in shaping migrants' experience of marginalization were challenges in obtaining documentation-both in the form of legal residency and health insurance coverage. Our results demonstrate that, in spite of Costa Rica's acclaimed social welfare policies, migrant workers continue to face exclusion due to administrative, social, and financial barriers. These findings paint a rich picture of how multiple intersections of precarious, informal, and dangerous working conditions; social and systemic discrimination; gendered occupational challenges; and access to legal residency and health insurance coverage combine to prevent the full achievement of a shared minimum standard of social and economic security for migrant workers in Costa Rica.

Adopting a Global AMR Target within the Pandemic Instrument Will Act as a Catalyst for Action.

Ensuring that life-saving antimicrobials remain available as effective treatment options in the face of rapidly rising levels of antimicrobial resistance will require a massive and coordinated global effort. Setting a collective direction for progress is the first step towards aligning global efforts on AMR. This process would be greatly accelerated by adopting a unifying global target - a well-defined global target that unites all countries and sectors. The proposed pandemic instrument - with its focus on prevention, preparedness and response - represents an ideal opportunity to develop and adopt a unifying global target that catalyzes global action on AMR. We propose three key characteristics of a unifying global target for AMR that - if embedded within the pandemic preparedness instrument - could rally public support, funding, and political commitment commensurate with the scale of the AMR challenge.