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.

Social epidemiology of urban COVID-19 inequalities in Latin America and Canada.

BACKGROUND: The COVID-19 pandemic has spread through pre-existing fault lines in societies, deepening structural barriers faced by precarious workers, low-income populations, and racialized communities in lower income sub-city units. Many studies have quantified the magnitude of inequalities in COVID-19 distribution within cities, but few have taken an international comparative approach to draw inferences on the ways urban epidemics are shaped by social determinants of health. METHODS: Guided by critical epidemiology, this study quantifies sub-city unit-level COVID-19 inequalities across eight of the largest metropolitan areas of Latin America and Canada. Leveraging new open-data sources, we use concentration indices to quantify income- and vulnerability-related inequalities in incidence, test positivity, and deaths over the first 125 weeks of the pandemic between January 2020 and May 2022. RESULTS: Our findings demonstrate that incidence, deaths, and test positivity are all less concentrated in low-income sub-city units than would be expected, with incidence ranging concentration in lower income neighbourhoods in Toronto (CI = -0.07) to concentration in higher income neighbourhoods in Mexico City (CI = 0.33). Drawing on relevant studies and evaluations of data reliability, we conclude that the best available public surveillance data for the largest cities in Latin America are likely not reliable measures of the true COVID-19 disease burden. We also identify recurring trends in the evolution of inequalities across most cities, concluding that higher income sub-city units were frequent early epicentres of COVID-19 transmission across the Latin America and Canada. CONCLUSIONS: Just as critical epidemiology points to individuals biologically embodying the material and social conditions in which we live, it may be just as useful to think of cities reifying their material and social inequities in the form of sub-city unit-level infectious disease inequities. By shifting away from a typical vulnerability-based social determinants of health frame, policymakers could act to redress and reduce externalities stemming from sub-city unit-level income inequality through redistributive and equity-promoting policies to shift the centre of gravity of urban health inequalities before the next infectious disease epidemic occurs.

1-10-100: Unifying goals to mobilize global action on antimicrobial resistance.

The Bellagio Group for Accelerating AMR Action met in April 2024 to develop the ambitious but achievable 1-10-100 unifying goals to galvanize global policy change and investments for antimicrobial resistance mitigation: 1 Health; 10 million lives saved; and 100% sustainable access to effective antimicrobials. High profile political goals such as the Paris Agreement's objective to keep global warming well below 2° Celsius compared to pre-industrial levels, UNAIDS' 90-90-90 goal, and the Sustainable Development Goals challenge global norms, direct attention towards relevant activities, and serve an energizing function to motivate action over an extended period of time. The 1-10-100 unifying goals propose to unite the world through a One Health approach to safeguard human health, animal welfare, agrifood systems, and the environment from the emergence and spread of drug-resistant microbes and infections; save over 10 million lives by 2040 through concerted efforts to prevent and appropriately treat infections while preserving the vital systems and services that depend on sustained antimicrobial effectiveness; and commit to ensuring that antimicrobials are available and affordable for all, used prudently, and secured for the future through innovation. Compared to existing technical targets, these unifying goals offer advantages of focusing on prevention, encouraging multisectoral action and collaboration, promoting health equity, recognizing the need for innovation, and integrating with Sustainable Development Goals. By committing to 1 Health, 10 million lives saved, and 100% sustainable access to effective antimicrobials, we can protect lives and livelihoods today and safeguard options for tomorrow.

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.

Learning from the Montreal Protocol to improve the global governance of antimicrobial resistance.

The Montreal Protocol has played a critical role in promoting global collective action to phase out the use of ozone-depleting substances, ultimately preventing millions of cases of skin cancer, cataracts and other health issues related to ultraviolet radiation exposure. This success entails transferable lessons for coordinated action required to improve the global governance of other challenges. Like ozone depletion, antimicrobial resistance (AMR) is a challenge of the global commons, requiring coordinated actions across human, animal and environmental sectors. We identify equity, flexibility and accountability as three core governance principles that underlie the success of the protocol and employ the 3-i framework to understand how interests, ideas and institutions contributed to the protocol's success. Equity-promoting strategies consisted of an inclusive negotiation process, supporting developing countries with multilateral funding and a progressive compliance model. Flexibility was built into the protocol through the development of country-specific strategies, reorienting incentive structures for industry and facilitating regular amendments in response to emerging scientific evidence. Accountability was promoted by mobilising public advocacy, establishing targets and enforcement mechanisms and conducting independent scientific and technical assessments. Applying our proposed principles presents an opportunity to improve the global governance of AMR. Finally, we acknowledge limitations to our analysis, including our focus on a single environmental treaty, significantly greater funding requirements and multifacetted stakeholder involvement in the case of AMR, differing market and incentives structures in antibiotic development and distribution, and ethical concerns with using trade restrictions as a policy tool.