Metformin inhibition of mitochondrial ATP and DNA synthesis abrogates NLRP3 inflammasome activation and pulmonary inflammation.

Acute respiratory distress syndrome (ARDS), an inflammatory condition with high mortality rates, is common in severe COVID-19, whose risk is reduced by metformin rather than other anti-diabetic medications. Detecting of inflammasome assembly in post-mortem COVID-19 lungs, we asked whether and how metformin inhibits inflammasome activation while exerting its anti-inflammatory effect. We show that metformin inhibited NLRP3 inflammasome activation and interleukin (IL)-1ß production in cultured and alveolar macrophages along with inflammasome-independent IL-6 secretion, thus attenuating lipopolysaccharide (LPS)- and SARS-CoV-2-induced ARDS. By targeting electron transport chain complex 1 and independently of AMP-activated protein kinase (AMPK) or NF-κB, metformin blocked LPS-induced and ATP-dependent mitochondrial (mt) DNA synthesis and generation of oxidized mtDNA, an NLRP3 ligand. Myeloid-specific ablation of LPS-induced cytidine monophosphate kinase 2 (CMPK2), which is rate limiting for mtDNA synthesis, reduced ARDS severity without a direct effect on IL-6. Thus, inhibition of ATP and mtDNA synthesis is sufficient for ARDS amelioration.

Possible shift in controls of the tropical Pacific surface warming pattern.

Changes in the sea surface temperature (SST) pattern in the tropical Pacific modulate radiative feedbacks to greenhouse gas forcing, the pace of global warming and regional climate impacts. Therefore, elucidating the drivers of the pattern is critically important for reducing uncertainties in future projections. However, the causes of observed changes over recent decades, an enhancement of the zonal SST contrast coupled with a strengthening of the Walker circulation, are still debated. Here we focus on the role of external forcing and review existing mechanisms of the forced response categorized as either an energy perspective that adopts global and hemispheric energy budget constraints or a dynamical perspective that examines the atmosphere-ocean coupled processes. We then discuss their collective and relative contributions to the past and future SST pattern changes and propose a narrative that reconciles them. Although definitive evidence is not yet available, our assessment suggests that the zonal SST contrast has been dominated by strengthening mechanisms in the past, but will shift towards being dominated by weakening mechanisms in the future. Finally, we present opportunities to resolve the model-observations discrepancy regarding the recent trends.

Atmosphere teleconnections from abatement of China aerosol emissions exacerbate Northeast Pacific warm blob events.

During 2010 to 2020, Northeast Pacific (NEP) sea surface temperature (SST) experienced the warmest decade ever recorded, manifested in several extreme marine heatwaves, referred to as "warm blob" events, which severely affect marine ecosystems and extreme weather along the west coast of North America. While year-to-year internal climate variability has been suggested as a cause of individual events, the causes of the continuous dramatic NEP SST warming remain elusive. Here, we show that other than the greenhouse gas (GHG) forcing, rapid aerosol abatement in China over the period likely plays an important role. Anomalous tropospheric warming induced by declining aerosols in China generated atmospheric teleconnections from East Asia to the NEP, featuring an intensified and southward-shifted Aleutian Low. The associated atmospheric circulation anomaly weakens the climatological westerlies in the NEP and warms the SST there by suppressing the evaporative cooling. The aerosol-induced mean warming of the NEP SST, along with internal climate variability and the GHG-induced warming, made the warm blob events more frequent and intense during 2010 to 2020. As anthropogenic aerosol emissions continue to decrease, there is likely to be an increase in NEP warm blob events, disproportionately large beyond the direct radiative effects.

Global impacts of recent Southern Ocean cooling.

Since the beginning of the satellite era, Southern Ocean sea surface temperatures (SSTs) have cooled, despite global warming. While observed Southern Ocean cooling has previously been reported to have minimal impact on the tropical Pacific, the efficiency of this teleconnection has recently shown to be mediated by subtropical cloud feedbacks that are highly model-dependent. Here, we conduct a coupled model intercomparison of paired ensemble simulations under historical radiative forcing: one with freely evolving SSTs and the other with Southern Ocean SST anomalies constrained to follow observations. We reveal a global impact of observed Southern Ocean cooling in the model with stronger (and more realistic) cloud feedbacks, including Antarctic sea-ice expansion, southeastern tropical Pacific cooling, northward-shifted Hadley circulation, Aleutian low weakening, and North Pacific warming. Our results therefore suggest that observed Southern Ocean SST decrease might have contributed to cooler conditions in the eastern tropical Pacific in recent decades.

Subtropical clouds key to Southern Ocean teleconnections to the tropical Pacific.

Excessive precipitation over the southeastern tropical Pacific is a major common bias that persists through generations of global climate models. While recent studies suggest an overly warm Southern Ocean as the cause, models disagree on the quantitative importance of this remote mechanism in light of ocean circulation feedback. Here, using a multimodel experiment in which the Southern Ocean is radiatively cooled, we show a teleconnection from the Southern Ocean to the tropical Pacific that is mediated by a shortwave subtropical cloud feedback. Cooling the Southern Ocean preferentially cools the southeastern tropical Pacific, thereby shifting the eastern tropical Pacific rainbelt northward with the reduced precipitation bias. Regional cloud locking experiments confirm that the teleconnection efficiency depends on subtropical stratocumulus cloud feedback. This subtropical cloud feedback is too weak in most climate models, suggesting that teleconnections from the Southern Ocean to the tropical Pacific are stronger than widely thought.

Practices Among Local Public Health Agencies to Support Evidence-Based Decision Making: A Qualitative Study.

OBJECTIVES: Evidence-based decision making (EBDM) capacity in local public health departments is foundational to meeting both organizational and individual competencies and fulfilling expanded roles. In addition to on-the-job training, organizational supports are needed to prepare staff; yet, less is known in this area. This qualitative study explores supportive management practices instituted as part of a training and technical assistance intervention. DESIGN: This qualitative study used a semistructured interview guide to elicit participants' descriptions and perceptions via key informant interviews. Verbatim transcripts were coded and thematic analyses were conducted. SETTING: Local public health departments in a US Midwestern state participated in the project. PARTICIPANTS: Seventeen middle managers and staff from 4 local health departments participated in remote, audio-recorded interviews. INTERVENTION: Following delivery of a 3½-day in-person training, the study team met with health department leadership teams for department selection of supportive agency policies and procedures to revise or newly create. Periodic remote meetings included collaborative problem-solving, sharing of informational resources, and encouragement. MAIN OUTCOME MEASURES: Included management practices instituted to support EBDM and impact on day-to-day work as described by the interview participants. RESULTS: Leadership and middle management practices deemed most helpful included dedicating staff; creating specific guidelines; setting expectations; and providing trainings, resources, and guidance. Health departments with a preexisting supportive organizational culture and climat e were able to move more quickly and fully to integrate supportive management practices. Workforce development included creation of locally tailored overviews for all staff members and onboarding of new staff. Staff wanted additional hands-on skill-building trainings. Several worked with partners to incorporate evidence-based processes into community health improvement plans. CONCLUSIONS: Ongoing on-the-job experiential learning is needed to integrate EBDM principles into day-to-day public health practice. Management practices established by leadership teams and middle managers can create supportive work environments for EBDM integration.

The impact of parametrized convection on cloud feedback.

We investigate the sensitivity of cloud feedbacks to the use of convective parametrizations by repeating the CMIP5/CFMIP-2 AMIP/AMIP + 4K uniform sea surface temperature perturbation experiments with 10 climate models which have had their convective parametrizations turned off. Previous studies have suggested that differences between parametrized convection schemes are a leading source of inter-model spread in cloud feedbacks. We find however that 'ConvOff' models with convection switched off have a similar overall range of cloud feedbacks compared with the standard configurations. Furthermore, applying a simple bias correction method to allow for differences in present-day global cloud radiative effects substantially reduces the differences between the cloud feedbacks with and without parametrized convection in the individual models. We conclude that, while parametrized convection influences the strength of the cloud feedbacks substantially in some models, other processes must also contribute substantially to the overall inter-model spread. The positive shortwave cloud feedbacks seen in the models in subtropical regimes associated with shallow clouds are still present in the ConvOff experiments. Inter-model spread in shortwave cloud feedback increases slightly in regimes associated with trade cumulus in the ConvOff experiments but is quite similar in the most stable subtropical regimes associated with stratocumulus clouds. Inter-model spread in longwave cloud feedbacks in strongly precipitating regions of the tropics is substantially reduced in the ConvOff experiments however, indicating a considerable local contribution from differences in the details of convective parametrizations. In both standard and ConvOff experiments, models with less mid-level cloud and less moist static energy near the top of the boundary layer tend to have more positive tropical cloud feedbacks. The role of non-convective processes in contributing to inter-model spread in cloud feedback is discussed.

Increased Asian aerosols drive a slowdown of Atlantic Meridional Overturning Circulation.

Observational evidence and climate model experiments suggest a slowdown of the Atlantic Meridional Overturning Circulation (AMOC) since the mid-1990s. Increased greenhouse gases and the declined anthropogenic aerosols (AAs) over North America and Europe are believed to contribute to the AMOC slowdown. Asian AAs continue to increase but the associated impact has been unclear. Using ensembles of climate simulations, here we show that the radiative cooling resulting from increased Asian AAs drives an AMOC reduction. The increased AAs over Asia generate circumglobal stationary Rossby waves in the northern midlatitudes, which shift the westerly jet stream southward and weaken the subpolar North Atlantic westerlies. Consequently, reduced transport of cold air from North America hinders water mass transformation in the Labrador Sea and thus contributes to the AMOC slowdown. The link between increased Asian AAs and an AMOC slowdown is supported by different models with different configurations. Thus, reducing emissions of Asian AAs will not only lower local air pollution, but also help stabilize the AMOC.

Disentangling the mechanisms of equatorial Pacific climate change.

Most state-of-art models project a reduced equatorial Pacific east-west temperature gradient and a weakened Walker circulation under global warming. However, the causes of this robust projection remain elusive. Here, we devise a series of slab ocean model experiments to diagnostically decompose the global warming response into the contributions from the direct carbon dioxide (CO2) forcing, sea ice changes, and regional ocean heat uptake. The CO2 forcing dominates the Walker circulation slowdown through enhancing the tropical tropospheric stability. Antarctic sea ice changes and local ocean heat release are the dominant drivers for reduced zonal temperature gradient over the equatorial Pacific, while the Southern Ocean heat uptake opposes this change. Corroborating our model experiments, multimodel analysis shows that the models with greater Southern Ocean heat uptake exhibit less reduction in the temperature gradient and less weakening of the Walker circulation. Therefore, constraining the tropical Pacific projection requires a better insight into Southern Ocean processes.

Type 2 Diabetes Polygenic Score Predicts the Risk of Glucocorticoid-Induced Hyperglycemia in Patients Without Diabetes.

OBJECTIVE: To assess whether increased genetic risk of type 2 diabetes (T2D) is associated with the development of hyperglycemia after glucocorticoid treatment. RESEARCH DESIGN AND METHODS: We performed a retrospective analysis of individuals with no diagnosis of diabetes who received a glucocorticoid dose of ≥10 mg prednisone. We analyzed the association between hyperglycemia and a T2D global extended polygenic score, which was constructed through a meta-analysis of two published genome-wide association studies. RESULTS: Of 546 individuals who received glucocorticoids, 210 developed hyperglycemia and 336 did not. T2D polygenic score was significantly associated with glucocorticoid-induced hyperglycemia (odds ratio 1.4 per SD of polygenic score; P = 0.038). CONCLUSIONS: Individuals with increased genetic risk of T2D have a higher risk of glucocorticoid-induced hyperglycemia. This finding offers a mechanism for risk stratification as part of a precision approach to medical treatment.

Role of mitochondria-bound HK2 in rheumatoid arthritis fibroblast-like synoviocytes.

Background: Glucose metabolism, specifically, hexokinase 2 (HK2), has a critical role in rheumatoid arthritis (RA) fibroblast-like synoviocyte (FLS) phenotype. HK2 localizes not only in the cytosol but also in the mitochondria, where it protects mitochondria against stress. We hypothesize that mitochondria-bound HK2 is a key regulator of RA FLS phenotype. Methods: HK2 localization was evaluated by confocal microscopy after FLS stimulation. RA FLSs were infected with Green fluorescent protein (GFP), full-length (FL)-HK2, or HK2 lacking its mitochondrial binding motif (HK2ΔN) expressing adenovirus (Ad). RA FLS was also incubated with methyl jasmonate (MJ; 2.5 mM), tofacitinib (1 µM), or methotrexate (1 µM). RA FLS was tested for migration and invasion and gene expression. Gene associations with HK2 expression were identified by examining single-cell RNA sequencing (scRNA-seq) data from murine models of arthritis. Mice were injected with K/BxN serum and given MJ. Ad-FLHK2 or Ad-HK2ΔN was injected into the knee of wild-type mice. Results: Cobalt chloride (CoCl2) and platelet-derived growth factor (PDGF) stimulation induced HK2 mitochondrial translocation. Overexpression of the HK2 mutant and MJ incubation reversed the invasive and migrative phenotype induced by FL-HK2 after PDGF stimulation, and MJ also decreased the expression of C-X-C Motif Chemokine Ligand 1 (CXCL1) and Collagen Type I Alpha 1 Chain (COL1A1). Of interest, tofacitinib but not methotrexate had an effect on HK2 dissociation from the mitochondria. In murine models, MJ treatment significantly decreased arthritis severity, whereas HK2FL was able to induce synovial hypertrophy as opposed to HK2ΔN. Conclusion: Our results suggest that mitochondrial HK2 regulates the aggressive phenotype of RA FLS. New therapeutic approaches to dissociate HK2 from mitochondria offer a safer approach than global glycolysis inhibition.

How to "Start Small and Just Keep Moving Forward": Mixed Methods Results From a Stepped-Wedge Trial to Support Evidence-Based Processes in Local Health Departments.

Background: Local health departments (LHDs) in the United States are charged with preventing disease and promoting health in their respective communities. Understanding and addressing what supports LHD's need to foster a climate and culture supportive of evidence-based decision making (EBDM) processes can enhance delivery of effective practices and services. Methods: We employed a stepped-wedge trial design to test staggered delivery of implementation supports in 12 LHDs (Missouri, USA) to expand capacity for EBDM processes. The intervention was an in-person training in EBDM and continued support by the research team over 24 months (March 2018-February 2020). We used a mixed-methods approach to evaluate: (1) individuals' EBDM skills, (2) organizational supports for EBDM, and (3) administered evidence-based interventions. LHD staff completed a quantitative survey at 4 time points measuring their EBDM skills, organizational supports, and evidence-based interventions. We selected 4 LHDs with high contact and engagement during the intervention period to interview staff (n = 17) about facilitators and barriers to EBDM. We used mixed-effects linear regression to examine quantitative survey outcomes. Interviews were transcribed verbatim and coded through a dual independent process. Results: Overall, 519 LHD staff were eligible and invited to complete quantitative surveys during control periods and 593 during intervention (365 unique individuals). A total of 434 completed during control and 492 during intervention (83.6 and 83.0% response, respectively). In both trial modes, half the participants had at least a master's degree (49.7-51.7%) and most were female (82.1-83.8%). No significant intervention effects were found in EBDM skills or in implementing evidence-based interventions. Two organizational supports scores decreased in intervention vs. control periods: awareness (-0.14, 95% CI -0.26 to -0.01, p < 0.05) and climate cultivation (-0.14, 95% CI -0.27 to -0.02, p < 0.05) but improved over time among all participants. Interviewees noted staff turnover, limited time, resources and momentum as challenges to continue EBDM work. Setting expectations, programmatic reviews, and pre-existing practices were seen as facilitators. Conclusions: Challenges (e.g., turnover, resources) may disrupt LHDs' abilities to fully embed organizational processes which support EBDM. This study and related literature provides understanding on how best to support LHDs in building capacity to use and sustain evidence-based practices.

Zonal mean and shift modes of historical climate response to evolving aerosol distribution.

Anthropogenic aerosols are effective radiative forcing agents that perturb the Earth's climate. Major emission sources shifted from the western to eastern hemisphere around the 1980s. An ensemble of single-forcing simulations with an Earth System Model reveals two stages of aerosol-induced climate change in response to the global aerosol increase for 1940-1980 and the zonal shift of aerosol forcing for 1980-2020, respectively. Here, using idealized experiments with hierarchical models, we show that the aerosol increase and shift modes of aerosol-forced climate change are dynamically distinct, governed by the inter-hemispheric energy transport and basin-wide ocean-atmosphere interactions, respectively. The aerosol increase mode dominates in the motionless slab ocean model but is damped by ocean dynamics. Free of zonal-mean energy perturbation, characterized by an anomalous North Atlantic warming and North Pacific cooling, the zonal shift mode is amplified by interactive ocean dynamics through Bjerknes feedback. Both modes contribute to a La Niña-like pattern over the equatorial Pacific. We suggest that a global perspective that accommodates the evolving geographical distribution of aerosol emissions is vital for understanding the aerosol-forced historical climate change.

An Evaluation of Postmarketing Reports of Serious Idiosyncratic Liver Injury Associated with Ulipristal Acetate for the Treatment of Uterine Fibroids.

INTRODUCTION: Ulipristal acetate (ulipristal) is a selective progesterone receptor modulator that has been marketed for daily use in Europe and Canada to reduce symptoms caused by uterine fibroids. Long-term use of some other members of this class of 19-norprogesterone-derived agents has been associated with idiosyncratic hepatotoxicity. OBJECTIVE: We analyzed postmarketing reports of suspected drug-induced liver injury associated with the daily use of 5 mg of ulipristal to treat symptoms of uterine fibroids. METHODS: We searched for reports of serious liver injury associated with ulipristal, submitted to the US Food and Drug Administration through 31 January, 2020. Cases of liver injury temporally associated with long-term ulipristal exposure that reported combined increases of serum aminotransferases and bilirubin were individually assessed using a five-tier categorical scale of likelihood for a causal association with the drug by individuals with expertise in drug-induced liver injury evaluation. Individual cases that did not culminate in liver failure, death, or liver transplantation were also assessed for their causal association with ulipristal by the Roussel Uclaf Causality Assessment Method. RESULTS: We identified nine non-US cases that met the criteria for inclusion in our search for cases of serious liver injury associated with ulipristal. Five cases reported clinical outcomes of liver transplantation and/or death and all were assessed to have a probable causal association with ulipristal acetate. Evaluation of the other four cases reporting resolution of liver injury after treatment discontinuation revealed a possible or probable causal relationship with ulipristal. CONCLUSIONS: We identified postmarketing cases of serious acute drug-induced liver injury causally associated with ulipristal used to treat uterine fibroids, some with outcomes of liver transplant and/or death. The presence of common structural features identified with certain selective progesterone receptor modulators in the treatment of chronic conditions may indicate a liability for idiosyncratic drug-induced liver injury.

Walker circulation response to extratropical radiative forcing.

Walker circulation variability and associated zonal shifts in the heating of the tropical atmosphere have far-reaching global impacts well into high latitudes. Yet the reversed high latitude-to-Walker circulation teleconnection is not fully understood. Here, we reveal the dynamical pathways of this teleconnection across different components of the climate system using a hierarchy of climate model simulations. In the fully coupled system with ocean circulation adjustments, the Walker circulation strengthens in response to extratropical radiative cooling of either hemisphere, associated with the upwelling of colder subsurface water in the eastern equatorial Pacific. By contrast, in the absence of ocean circulation adjustments, the Walker circulation response is sensitive to the forcing hemisphere, due to the blocking effect of the northward-displaced climatological intertropical convergence zone and shortwave cloud radiative effects. Our study implies that energy biases in the extratropics can cause pronounced changes of tropical climate patterns.

Fixational Eye Movement Waveforms in Amblyopia: Characteristics of Fast and Slow Eye Movements.

Fixational eye movements comprise of fast microsaccades alternating with slow intersaccadic drifts. These physiologic eye movements play an important role in visual perception. Amblyopic patients are known to have fixation instability, particularly of the amblyopic eye. We examined eye movement abnormalities that contribute to this instability. We found that fixation stability is affected by the presence of fusion maldevelopment nystagmus (FMN). However, some amblyopes can have nystagmus without nasally directed slow phases and reversal in direction of the quick phase on ocular occlusion, features seen in FMN. In patients without nystagmus, we found increased amplitude of fixational saccades and inter-saccadic drifts. We categorized amblyopia patients by type (anisometropic, strabismic, or mixed) and eye movement waveform (no nystagmus, nystagmus without FMN, and FMN). We found specific fast and slow eye movement abnormalities of the fellow and amblyopic eye during fellow, amblyopic and both eyes viewing conditions across eye movement waveforms and types of amblyopia. These eye movement abnormalities can serve as biomarkers that can predict the impact of amblyopia as measured by visual acuity and stereopsis. Evaluation of fixational eye movements in amblyopia could be important to diagnose these common eye diseases and predict treatment effectiveness.

Pantropical climate interactions.

The El Niño-Southern Oscillation (ENSO), which originates in the Pacific, is the strongest and most well-known mode of tropical climate variability. Its reach is global, and it can force climate variations of the tropical Atlantic and Indian Oceans by perturbing the global atmospheric circulation. Less appreciated is how the tropical Atlantic and Indian Oceans affect the Pacific. Especially noteworthy is the multidecadal Atlantic warming that began in the late 1990s, because recent research suggests that it has influenced Indo-Pacific climate, the character of the ENSO cycle, and the hiatus in global surface warming. Discovery of these pantropical interactions provides a pathway forward for improving predictions of climate variability in the current climate and for refining projections of future climate under different anthropogenic forcing scenarios.

Vergence and Strabismus in Neurodegenerative Disorders.

Maintaining proper eye alignment is necessary to generate a cohesive visual image. This involves the coordination of complex neural networks, which can become impaired by various neurodegenerative diseases. When the vergence system is affected, this can result in strabismus and disorienting diplopia. While previous studies have detailed the effect of these disorders on other eye movements, such as saccades, relatively little is known about strabismus. Here, we focus on the prevalence, clinical characteristics, and treatment of strabismus and disorders of vergence in Parkinson's disease, spinocerebellar ataxia, Huntington disease, and multiple system atrophy. We find that vergence abnormalities may be more common in these disorders than previously thought. In Parkinson's disease, the evidence suggests that strabismus is related to convergence insufficiency; however, it is responsive to dopamine replacement therapy and can, therefore, fluctuate with medication "on" and "off" periods throughout the day. Diplopia is also established as a side effect of deep brain stimulation and is thought to be related to stimulation of the subthalamic nucleus and extraocular motor nucleus among other structures. In regards to the spinocerebellar ataxias, oculomotor symptoms are common in many subtypes, but diplopia is most common in SCA3 also known as Machado-Joseph disease. Ophthalmoplegia and vergence insufficiency have both been implicated in strabismus in these patients, but cannot fully explain the properties of the strabismus, suggesting the involvement of other structures as well. Strabismus has not been reported as a common finding in Huntington disease or atypical parkinsonian syndromes and more studies are needed to determine how these disorders affect binocular alignment.

Acquired pendular nystagmus.

Acquired pendular nystagmus is comprised of quasi-sinusoidal oscillations of the eyes significantly affecting gaze holding and clarity of vision. The most common causes of acquired pendular nystagmus include demyelinating disorders such as multiple sclerosis and the syndrome of ocular palatal tremor. However, several other deficits, such as pharmacological intoxication, metabolic and genetic disorders, and granulomatous disorders can lead to syndromes mimicking acquired pendular nystagmus. Study of the kinematic features of acquired pendular nystagmus has suggested a putative pathophysiology of an otherwise mysterious neurological disorder. Here we review clinical features of neurological deficits that co-occur with acquired pendular nystagmus. Subsequent discussion of the pathophysiology of individual forms of pendular nystagmus speculates on mechanisms of the underlying disease while providing insights into pharmacotherapy of nystagmus.