Genome sequence of pan drug-resistant enteroaggregative Escherichia coli belonging to ST38 clone from India, an emerging EAEC/UPEC hybrid pathotype.

Here, we report the genomic characterization of a pan drug-resistant (PDR) enteroaggregative Escherichia coli (EAEC) isolated from an immunocompromised infant who had diarrhea. The isolate belonged to the sequence type (ST) 38, which is a known enteroaggregative Escherichia coli (EAEC)/uropathogenic Escherichia coli (UPEC) hybrid strain having multi-drug resistance (MDR). The strain carried genes encoding multiple resistances to carbapenems, third-generation cephalosporins, polymyxin, fluoroquinolones, aminoglycosides, fosfomycin, nitrofurantoin, sulphonamides, and multiple efflux pump genes. Interspecies horizontal transfer, inter-strain, and clonal spread of these resistances to commensals and pathogens will be worrisome. We are concerned about the spread of such PDR strains. The genomic characterization of such strains will be useful in understanding the genetic makeup of EAEC/UPEC hybrid strains and developing new vaccines/diagnostics and therapeutics.

Elevating the Standard of Care for Patients with Axial Spondyloarthritis: 'Calls to Action' from Rheumacensus, a Multistakeholder Pan-European Initiative.

INTRODUCTION: Several barriers to optimal care in axial spondyloarthritis (axSpA) exist, which is detrimental to patient outcomes. The Rheumacensus programme aimed to identify how the standard of care (SoC) and treatment ambition for patients with axSpA could be elevated, from the unique perspective of three key stakeholders from across Europe: patients, healthcare professionals (HCPs) and payors. METHODS: Rheumacensus followed three phases: an insights-gathering workshop to identify current unmet needs in axSpA and an area of focus, a modified Delphi process to gain consensus on improvements within the agreed area of focus, and a Consensus Council (CC) meeting to generate 'Calls to Action' (CTA) to highlight the changes needed to elevate the SoC for patients with axSpA. RESULTS: The Rheumacensus CC consisted of four patient representatives, four HCPs and four payors. All 12 members completed all three Delphi e-consultations. The shared area of focus that informed the Delphi process was patient empowerment through education on the disease and treatment options available, to enable patient involvement in management and ultimately increase treatment adherence. Four key themes emerged from the Delphi process: patient empowerment, patient knowledge, patient-HCP consultations and optimal initial treatment. These themes informed 11 overarching CTA, which demonstrate the need for a multistakeholder approach to implement a paradigm shift towards patient-centred care to elevate health outcomes in patients with axSpA. CONCLUSION: Rheumacensus identified CTA to help bridge the disparities observed in axSpA care. It is now imperative for all stakeholders to take practical steps towards addressing these CTA to elevate the SoC and treatment ambition in patients with axSpA.

Axial spondyloarthritis (axSpA) is a long-term inflammatory disease involving the spine and other joints of the body as well as where tendons and ligaments attach to bone. AxSpA is associated with a significant burden to patients which can be worsened by delays in diagnosis and poor disease management. This report is about a programme called Rheumacensus which has the overall aim of improving the standard of care (SoC) for patients with axSpA. Rheumacensus brings together the points of view of three key groups involved in the care of people with axSpA: patients, payors and healthcare professionals (HCPs) from across Europe. Together, these three groups agreed to focus on patient empowerment through education on the disease and treatment options to effectively enhance treatment adherence, as a way to raise the SoC. Through a series of exercises­to agree on the current SoC and what needs to be improved­and group discussions, four themes were established which were used by the groups to help them suggest 'Calls to action' (CTA). The CTAs were ideas of how improvements could be made or what needs to be done to improve the care patients receive. The four themes were (1) patient empowerment, (2) patient knowledge, (3) patient­HCP consultation and (4) optimal initial treatment. In total, 11 CTAs were developed across these themes that provide direction and practical next steps which patients, payors and HCPs could take to drive change and make a real difference to patients by improving their care.

Drought and heat stress: insights into tolerance mechanisms and breeding strategies for pigeonpea improvement.

MAIN CONCLUSION: Pigeonpea has potential to foster sustainable agriculture and resilience in evolving climate change; understanding bio-physiological and molecular mechanisms of heat and drought stress tolerance is imperative to developing resilience cultivars. Pigeonpea is an important legume crop that has potential resilience in the face of evolving climate scenarios. However, compared to other legumes, there has been limited research on abiotic stress tolerance in pigeonpea, particularly towards drought stress (DS) and heat stress (HS). To address this gap, this review delves into the genetic, physiological, and molecular mechanisms that govern pigeonpea's response to DS and HS. It emphasizes the need to understand how this crop combats these stresses and exhibits different types of tolerance and adaptation mechanisms through component traits. The current article provides a comprehensive overview of the complex interplay of factors contributing to the resilience of pigeonpea under adverse environmental conditions. Furthermore, the review synthesizes information on major breeding techniques, encompassing both conventional methods and modern molecular omics-assisted tools and techniques. It highlights the potential of genomics and phenomics tools and their pivotal role in enhancing adaptability and resilience in pigeonpea. Despite the progress made in genomics, phenomics and big data analytics, the complexity of drought and heat tolerance in pigeonpea necessitate continuous exploration at multi-omic levels. High-throughput phenotyping (HTP) is crucial for gaining insights into perplexed interactions among genotype, environment, and management practices (GxExM). Thus, integration of advanced technologies in breeding programs is critical for developing pigeonpea varieties that can withstand the challenges posed by climate change. This review is expected to serve as a valuable resource for researchers, providing a deeper understanding of the mechanisms underlying abiotic stress tolerance in pigeonpea and offering insights into modern breeding strategies that can contribute to the development of resilient varieties suited for changing environmental conditions.

Differential cardiopulmonary haemodynamic phenotypes in PASC-related exercise intolerance.

Background: Post-acute sequelae of COVID-19 (PASC) affect a significant proportion of patients who have previously contracted SARS-CoV-2, with exertional intolerance being a prominent symptom. This study aimed to characterise the invasive haemodynamic abnormalities of PASC-related exertional intolerance using invasive cardiopulmonary exercise testing (iCPET). Study design and intervention: 55 patients were recruited from the Yale Post-COVID-19 Recovery Program, with most experiencing mild acute illness. Supine right heart catheterisation and iCPET were performed on all participants. Main results: The majority (75%) of PASC patients exhibited impaired peak systemic oxygen extraction (pEO2) during iCPET in conjunction with supranormal cardiac output (CO) (i.e., PASC alone group). On average, the PASC alone group exhibited a "normal" peak exercise capacity, V'O2 (89±18% predicted). ∼25% of patients had evidence of central cardiopulmonary pathology (i.e., 12 with resting and exercise heart failure with preserved ejection fraction (HFpEF) and two with exercise pulmonary hypertension (PH)). PASC patients with HFpEF (i.e., PASC HFpEF group) exhibited similarly impaired pEO2 with well compensated PH (i.e., peak V'O2 and CO >80% respectively) despite aberrant central cardiopulmonary exercise haemodynamics. PASC patients with HFpEF also exhibited increased body mass index of 39±7 kg·m-2. To examine the relative contribution of obesity to exertional impairment in PASC HFpEF, a control group comprising obese non-PASC group (n=61) derived from a historical iCPET cohort was used. The non-PASC obese patients with preserved peak V'O2 (>80% predicted) exhibited a normal peak pulmonary artery wedge pressure (17±14 versus 25±6 mmHg; p=0.03) with similar maximal voluntary ventilation (90±12 versus 86±10% predicted; p=0.53) compared to PASC HFpEF patients. Impaired pEO2 was not significantly different between PASC patients who underwent supervised rehabilitation and those who did not (p=0.19). Conclusions: This study highlights the importance of considering impaired pEO2 in PASC patients with persistent exertional intolerance unexplained by conventional investigative testing. Results of the current study also highlight the prevalence of a distinct high output HFpEF phenotype in PASC with a primary peripheral limitation to exercise.

Efficacies of S-nitrosoglutathione (GSNO) and GSNO reductase inhibitor in SARS-CoV-2 spike protein induced acute lung disease in mice.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which initially surfaced in late 2019, often triggers severe pulmonary complications, encompassing various disease mechanisms such as intense lung inflammation, vascular dysfunction, and pulmonary embolism. Currently, however, there's no drug addressing all these mechanisms simultaneously. This study explored the multi-targeting potential of S-nitrosoglutathione (GSNO) and N6022, an inhibitor of GSNO reductase (GSNOR) on markers of inflammatory, vascular, and thrombotic diseases related to COVID-19-induced acute lung disease. For this, acute lung disease was induced in C57BL/6 mice through intranasal administration of recombinant SARS-CoV-2 spike protein S1 domain (SP-S1). The mice exhibited fever, body weight loss, and increased blood levels and lung expression of proinflammatory cytokines (e.g., TNF-α and IL-6) as well as increased vascular inflammation mediated by ICAM-1 and VCAM-1 and lung infiltration by immune cells (e.g., neutrophils, monocytes, and activated cytotoxic and helper T cells). Further, the mice exhibited increased lung hyperpermeability (lung Evans blue extravasation) leading to lung edema development as well as elevated blood coagulation factors (e.g., fibrinogen, thrombin, activated platelets, and von Willebrand factor) and lung fibrin deposition. Similar to the patients with COVID-19, male mice showed more severe disease than female mice, along with higher GSNOR expression in the lungs. Optimization of GSNO by treatment with exogenous GSNO or inhibition of GSNOR by N6022 (or GSNO knockout) protects against SP-S1-induced lung diseases in both genders. These findings provide evidence for the potential efficacies of GSNO and GSNOR inhibitors in addressing the multi-mechanistic nature of SARS-CoV-2 SP-associated acute-lung disease.

Right Heart Failure in the Intensive Care Unit: Etiology, Pathogenesis, Diagnosis, and Treatment.

Right heart (RH) failure carries a high rate of morbidity and mortality. Patients who present with RH failure often exhibit complex aberrant cardio-pulmonary physiology with varying presentations. The treatment of RH failure almost always requires care and management from an intensivist. Treatment options for RH failure patients continue to evolve rapidly with multiple options available, including different pharmacotherapies and mechanical circulatory support devices that target various components of the RH circulatory system. An understanding of the normal RH circulatory physiology, treatment, and support options for the RH failure patients is necessary for all intensivists to improve outcomes. The purpose of this review is to provide clinical guidance on the diagnosis and management of RH failure within the intensive care unit setting, and to highlight the different pathophysiological manifestations of RH failure, its hemodynamics, and treatment options available at the disposal of the intensivist.

The Utility of Leadless Atrioventricular Synchronous Pacemaker Implantation as a Novel Alternative to a Traditional Pacemaker During Pregnancy.

The Micra™ leadless pacemaker (Medtronic, Minneapolis, MN, USA) is indicated for the management of symptomatic bradycardia and advanced heart block. However, the safety of this procedure during pregnancy has not been studied. Here, we present a unique case of Micra™ leadless pacemaker implantation (MLP) in a 31 weeks pregnant patient with intermittent complete heart block who presented with multiple syncopal episodes. The patient underwent an MLP implantation with <40 mGy radiation exposure (about 0.6 min of total fluoroscopy time), which is deemed a negligible dose of radiation exposure during pregnancy. Her subsequent hospital course was uneventful, and she was safely discharged home and was able to continue her pregnancy and delivery without further syncopal episodes or incidence of heart block.

Cognitive impairment in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is characterized by progressive pulmonary vascular remodeling with resultant abnormal increase in pulmonary artery pressure and right heart dysfunction. There is evidence that PAH includes cognitive impairment. However, the cognitive impairment syndrome has not been well described, and both the underlying mechanism and the relationship between cardiopulmonary and cognitive dysfunction in PAH are unknown. We performed cognitive evaluations and same day sub-maximum cardiopulmonary exercise testing on adult subjects with PAH. A frontal-subcortical syndrome suggestive of vascular cognitive impairment was found in 26% of subjects and was associated with noninvasive markers of pulmonary vascular remodeling.

Integrating Right Ventricular Pressure Waveform Analysis With Two-Point Volume Measurement for Quantification of Systolic and Diastolic Function: Experimental Validation and Clinical Application.

OBJECTIVE: To define in an experimental model the variance, accuracy, precision, and concordance of single-beat measures of right ventricular (RV) contractility and diastolic capacitance relative to conventional reference standards, and apply the methods to a clinical data set. DESIGN: A retrospective, observational analysis of recorded pressure waveforms and RV volume measurements. SETTING: At a university laboratory. PARTICIPANTS: Archived data from previous studies of anesthetized swine and awake patients undergoing clinically-indicated right-heart catheterization. INTERVENTIONS: Recording of RV pressure with simultaneous measurement of RV volume by conductance (swine) or 3-dimensional (3D) echocardiography (humans) during changes in contractility and/or loading conditions. MEASUREMENTS AND MAIN RESULTS: Using experimental data, single-beat measures of RV contractility quantified as end-systolic elastance, and diastolic capacitance quantified as the predicted volume at an end-diastolic pressure of 15 mmHg (V15), were compared to multi-beat, preload- variant, reference standards using correlation, Bland-Altman analysis, and 4-quadrant concordance testing. This analysis indicated that the methods were not directly interchangeable with reference standards, but were sufficiently robust to suggest potential clinical utility. Clinical application supported this potential by demonstrating enhanced assessment of the response to inhaled nitric oxide in patients undergoing diagnostic right-heart catheterization. CONCLUSIONS: Study results supported the possibility of integrating automated RV pressure analysis with RV volume measured by 3D echocardiography to create a comprehensive assessment of RV systolic and diastolic function at the bedside.

High-Risk Pulmonary Embolism: Management for the Intensivist.

High-risk pulmonary embolism (PE) also known as massive PE carries a high rate of morbidity and mortality. The incidence of high-risk PE continues to increase, yet the outcomes of high-risk PE continue to remain poor. Patients with high-risk PE are often critically ill, with complex underlying physiology, and treatment for the high-risk PE patient almost always requires care and management from an intensivist. Treatment options for high-risk PE continue to evolve rapidly with multiple options for definitive reperfusion therapy and supportive care. A thorough understanding of the physiology, risk stratification, treatment, and support options for the high-risk PE patient is necessary for all intensivists in order to improve outcomes. This article aims to provide a review from an intensivist's perspective highlighting the physiological consequences, risk stratification, and treatment options for these patients as well as providing a proposed algorithm to the risk stratification and acute management of high-risk PE.

Proteomic profiling demonstrates inflammatory and endotheliopathy signatures associated with impaired cardiopulmonary exercise hemodynamic profile in Post Acute Sequelae of SARS-CoV-2 infection (PASC) syndrome.

Approximately 50% of patients who recover from the acute SARS-CoV-2 experience Post Acute Sequelae of SARS-CoV-2 infection (PASC) syndrome. The pathophysiological hallmark of PASC is characterized by impaired system oxygen extraction (EO2) on invasive cardiopulmonary exercise test (iCPET). However, the mechanistic insights into impaired EO2 remain unclear. We studied 21 consecutive iCPET in PASC patients with unexplained exertional intolerance. PASC patients were dichotomized into mildly reduced (EO2peak-mild) and severely reduced (EO2peak-severe) EO2 groups according to the median peak EO2 value. Proteomic profiling was performed on mixed venous blood plasma obtained at peak exercise during iCPET. PASC patients as a group exhibited depressed peak exercise aerobic capacity (peak VO2; 85 ± 18 vs. 131 ± 45% predicted; p = 0.0002) with normal systemic oxygen delivery, DO2 (37 ± 9 vs. 42 ± 15 mL/kg/min; p = 0.43) and reduced EO2 (0.4 ± 0.1 vs. 0.8 ± 0.1; p < 0.0001). PASC patients with EO2peak-mild exhibited greater DO2 compared to those with EO2peak-severe [42.9 (34.2-41.2) vs. 32.1 (26.8-38.0) mL/kg/min; p = 0.01]. The proteins with increased expression in the EO2peak-severe group were involved in inflammatory and fibrotic processes. In the EO2peak-mild group, proteins associated with oxidative phosphorylation and glycogen metabolism were elevated. In PASC patients with impaired EO2, there exist a spectrum of PASC phenotype related to differential aberrant protein expression and cardio-pulmonary physiologic response. PASC patients with EO2peak-severe exhibit a maladaptive physiologic and proteomic signature consistent with persistent inflammatory state and endothelial dysfunction, while in the EO2peak-mild group, there is enhanced expression of proteins involved in oxidative phosphorylation-mediated ATP synthesis along with an enhanced cardiopulmonary physiological response.

Exercise Pathophysiology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Postacute Sequelae of SARS-CoV-2: More in Common Than Not?

TOPIC IMPORTANCE: Postacute sequelae of SARS-CoV-2 (PASC) is a long-term consequence of acute infection from COVID-19. Clinical overlap between PASC and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has been observed, with shared symptoms including intractable fatigue, postexertional malaise, and orthostatic intolerance. The mechanistic underpinnings of such symptoms are poorly understood. REVIEW FINDINGS: Early studies suggest deconditioning as the primary explanation for exertional intolerance in PASC. Cardiopulmonary exercise testing reveals perturbations related to systemic blood flow and ventilatory control associated with acute exercise intolerance in PASC, which are not typical of simple detraining. Hemodynamic and gas exchange derangements in PASC have substantial overlap with those observed with ME/CFS, suggestive of shared mechanisms. SUMMARY: This review illustrates exercise pathophysiologic commonalities between PASC and ME/CFS that will help guide future diagnostics and treatment.

A Case of Fulminant Right Heart Failure Owing to Tumoral Pulmonary Hypertension.

Tumoral pulmonary hypertension is a rare cause of pulmonary hypertension. We report a patient who was thought to have idiopathic pulmonary arterial hypertension, but later developed fulminant right heart failure ultimately leading to death. Autopsy revealed substantial pulmonary tumor embolism burden originating from liver adenocarcinoma. (Level of Difficulty: Advanced.).

Noninvasive determinants of pulmonary hypertension in interstitial lung disease.

Pulmonary hypertension (PH) in interstitial lung disease (ILD) is associated with increased mortality and impaired exertional capacity. Right heart catheterization is the diagnostic standard for PH but is invasive and not readily available. Noninvasive physiologic evaluation may predict PH in ILD. Forty-four patients with PH and ILD (PH-ILD) were compared with 22 with ILD alone (non-PH ILD). Six-min walk distance (6MWD, 223 ± 131 vs. 331 ± 125 m, p = 0.02) and diffusing capacity for carbon monoxide (DLCO, 33 ± 14% vs. 55 ± 21%, p < 0.001) were lower in patients with PH-ILD. PH-ILD patients exhibited a lower gas-exchange derived pulmonary vascular capacitance (GXCAP, 251 ± 132 vs. 465 ± 282 mL × mmHg, p < 0.0001) and extrapolated maximum oxygen uptake (VO2max) (56 ± 32% vs. 84 ± 37%, p = 0.003). Multivariate analysis was performed to determine predictors of VO2 max. GXCAP was the only variable that predicted extrapolated VO2 max among PH-ILD and non-PH ILD patients. Receiver operating characteristic curve analysis assessed the ability of individual noninvasive variables to distinguish between PH-ILD and non-PH ILD patients. GXCAP (area under the curve [AUC] 0.85 ± 0.04, p < 0.0001) and delta ETCO2 (AUC 0.84 ± 0.04, p < 0.0001) were the strongest predictors of PH-ILD. A CART analysis selected GXCAP, estimated right ventricular systolic pressure (eRVSP) by echocardiogram, and FVC/DLCO ratio as predictive variables for PH-ILD. With this analysis, the AUC improved to 0.94 (sensitivity of 0.86 and sensitivity of 0.93). Patients with a GXCAP ≤ 416 mL × mmHg had an 82% probability of PH-ILD. Patients with GXCAP ≤ 416 mL × mmHg and high FVC/DLCO ratio >1.7 had an 80% probability of PH-ILD. Patients with GXCAP ≤ 416 mL × mmHg and an elevated eRVSP by echocardiogram >43 mmHg had 100% probability of PH-ILD. The incorporation of GXCAP with either eRVSP or FVC/DLCO ratio distinguishes between PH-ILD and non-PH-ILD with high probability and may therefore assist in determining the need to proceed with a diagnostic right heart catheterization and potential initiation of pulmonary arterial hypertension-directed therapy in PH-ILD patients.

Drought priming triggers diverse metabolic adjustments and induces chilling tolerance in chickpea (Cicer arietinum L.).

Chickpea (Cicer arietinum L.) suffers from chilling stress at the reproductive stage (<15 °C) which leads to significant yield loss. This study presents a comprehensive plant response to drought priming and its effect on chilling tolerance during the reproductive stage in two chickpea cultivars PBG1 and PBG5. Lipidome profiling (Fatty acid methyl esters analysis), metabolome profiling (GC-MS based untargeted analysis), fatty acid desaturases and antioxidative gene expression (qRT-PCR) were analyzed to monitor physiological and biochemical events after priming during flowering, podding and seed filling stages. Drought priming alleviated membrane damage and chlorophyll degradation by increasing membrane unsaturated fatty acids (18:3) along with up-regulation of various fatty acid desaturases (CaFADs) genes and antioxidative machinery during flowering and improved seed yield in PBG5. PCA, HCA, and KEGG pathway analysis of 87 identified metabolites showed that metabolites were regulated differently in both cultivars under non-primed and primed conditions. The plant response was more apparent at flowering and podding stages which coincided with chilling temperature (<15 °C). Drought priming stimulated many important genes, especially FADs, antioxidative proteins and accumulation of key metabolites (proline and TCA intermediates) required for defense especially in PBG5. This explains that plant's response to drought priming not only depends on developmental stage, and temperature regime (<15 °C) but also on the genotypic-specificity.

Unlocking the hidden variation from wild repository for accelerating genetic gain in legumes.

The fluctuating climates, rising human population, and deteriorating arable lands necessitate sustainable crops to fulfil global food requirements. In the countryside, legumes with intriguing but enigmatic nitrogen-fixing abilities and thriving in harsh climatic conditions promise future food security. However, breaking the yield plateau and achieving higher genetic gain are the unsolved problems of legume improvement. Present study gives emphasis on 15 important legume crops, i.e., chickpea, pigeonpea, soybean, groundnut, lentil, common bean, faba bean, cowpea, lupin, pea, green gram, back gram, horse gram, moth bean, rice bean, and some forage legumes. We have given an overview of the world and India's area, production, and productivity trends for all legume crops from 1961 to 2020. Our review article investigates the importance of gene pools and wild relatives in broadening the genetic base of legumes through pre-breeding and alien gene introgression. We have also discussed the importance of integrating genomics, phenomics, speed breeding, genetic engineering and genome editing tools in legume improvement programmes. Overall, legume breeding may undergo a paradigm shift once genomics and conventional breeding are integrated in the near future.

Phenotypic evaluation of agronomic and root related traits for drought tolerance in recombinant inbred line population derived from a chickpea cultivar (C. arietinum L.) and its wild relative (C. reticulatum).

Drought is a major abiotic stress that drastically reduces chickpea yields. The present study was aimed to identify drought-responsive traits in chickpea by screening a recombinant inbred line population derived from an inter-specific cross between drought cultivar of GPF2 (C. arietinum L.) and drought sensitive accession of ILWC292 (C. reticulatum), at two locations in India. Twenty-one traits, including twelve morphological and physiological traits and nine root-related traits were measured under rainfed (drought-stress) and irrigated conditions (no-stress). High genotypic variation was observed among RILs for yield and root traits indicated that selection in these germplasms would be useful in achieving genetic progress. Both correlation and principal component analysis revealed that plant height, number of pods per plant, biomass, 100-seed weight, harvest index, membrane permeability index, and relative leaf water content were significantly correlated with yield under both irrigated and drought stress environments. Root length had significant positive correlations with all root-related traits except root length density in drought-stressed plants. Path analysis and multiple and stepwise regression analyses showed that number of pods per plant, biomass, and harvest index were major contributors to yield under drought stress conditions. Thus, a holistic approach across these analyses identified number of pods per plant, biomass, harvest index, and root length as key traits for improving chickpea yield through indirect selection for developing drought-tolerant cultivars. Overall, on the basis of yield components morphological and root traits, a total of 15 promising RILs were identified for their use in chickpea breeding programs for developing drought tolerant cultivars. Supplementary Information: The online version contains supplementary material available at 10.1007/s12298-022-01218-z.