Globally, men have a higher epidemiologic burden of tuberculosis  than women do, possibly due to differences in disease incidence, treatment initiation, self-cure, and/or untreated-tuberculosis mortality rates. Using a simple, sex-stratified compartmental model, we employed a Bayesian approach to explore which factors most likely explain men’s higher burden. We applied the model to smear-positive pulmonary tuberculosis in Vietnam (2006–2007) and Malawi (2013–2014). Posterior estimates were consistent with sex-specific prevalence and notifications in both countries. Results supported higher incidence in men and showed that both sexes faced longer durations of untreated disease than estimated by self-reports. Prior untreated disease durations were revised upward 8- to 24-fold, to 2.2  years for men in Vietnam and 2.8  years for men in Malawi, approximately a year longer than for women in each country. Results imply that substantial sex differences in tuberculosis burden are almost solely attributable to men’s disadvantages in disease incidence and untreated disease duration. The latter, for which self-reports provide a poor proxy, implies inadequate coverage of case-finding strategies. These results highlight an urgent need for better understanding of gender-related barriers faced by men and support the systematic targeting of men for screening. Substantial sex disparity exists in the burden of tuberculosis, as indicated by incidence, prevalence, and mortality estimates. Each year, more tuberculosis cases are reported among men than among women globally and in most countries . PrevaleSex disparities in the epidemiologic burden of tuberculosis could be explained by sex differences in 4 factors: disease incidence, treatment initiation, self-cure, and/or untreated-tuberculosis mortality rates. Individuals are added to the pool of prevalent cases upon development of incident disease, and disease incidence rates could differ between men and women due to sex differences in exposure to infection and/or susceptibility to disease. Diseased individuals are then removed from the prevalent pool by successfully initiating treatment, naturally clearing themselves of disease (“self-cure”), or dying , rates oUsing a simple compartmental model  of tuberWe performed analyses for smear-positive pulmonary tuberculosis in 2 settings: Vietnam, where the male-to-female ratio in smear-positive tuberculosis prevalence is one of the highest in the world at 5.1:1 , and MalSex-specific tuberculosis incidence rates were based on 2015 World Health Organization (WHO) estimates of incident cases (age ≥15 years)  and popuSex-specific prevalence data for smear-positive tuberculosis were collated from national prevalence surveys conducted in Vietnam in 2006–2007  and in MFull details of prior specification and data are provided in the Mycobacterium tuberculosis, progression to tuberculosis disease, and death following infection—notably tobacco smoking in Vietnam and human immunodeficiency virus in Malawi—were not explicitly modeled, instead being captured as part of overall sex differences in disease incidence and untreated-tuberculosis mortality rates.We developed a simple sex-stratified  model of disease incidence, prevalence, and case notification rates for adult (age ≥15 years) smear-positive tuberculosis, as shown in Figure g, prevg, was calculated as prevg= incg÷(tig+ sc + mu) where incg is the disease incidence rate in sex g, tig is the treatment initiation rate in sex g, sc is the self-cure rate, and mu is the untreated-tuberculosis mortality rate. The expected case notification rate for smear-positive tuberculosis in sex g, notg, was calculated as notg= prevg× tig. Male-to-female ratios in expected prevalence-to-notification ratios were calculated.The expected prevalence of smear-positive tuberculosis in sex The evidence described above was used to specify model priors for disease incidence, treatment initiation, self-cure, and untreated-tuberculosis mortality for each sex in each country Tables . PosteriPosterior model estimates were calculated using Markov chain Monte Carlo algorithm in WinBUGS  via R R accordinWe conducted extensive sensitivity analyses, which are described in detail in Prior model estimates accurately represented evidence on disease incidence, treatment initiation, self-cure rate, and untreated-tuberculosis mortality rates.Posterior model estimates were consistent with empirical data on sex-specific prevalence and case notification rates, as well as male-to-female ratios in prevalence-to-notification ratios, in both countries Tables  and 2.In both countries, posterior incidence rate estimates were consistent with empirical data. In Vietnam, incidence was estimated as (posterior median) 258  per 100,000 men and 67  per 100,000 women. In Malawi, incidence was estimated as (posterior median) 295  per 100,000 men and 161  per 100,000 women.Posterior estimates for treatment initiation rate showed that both men and women faced a much longer time between onset of disease and initiation of treatment than estimated from self-reports of symptom duration prior to treatment Figure . Prior uIn both countries, sensitivity analyses around model structure  supporteSensitivity analyses were also conducted using incidence estimates from IHME rather than WHO . PosteriFinal sensitivity analyses assumed self-reports of symptom duration prior to treatment accurately described untreated disease duration and examined the impact of this assumption on disease burden estimates. Posterior prevalence estimates from these analyses were only 4% to 12% of those reported in recent prevalence surveys  per 100,000 men in Vietnam) and male-to-female ratios in prevalence-to-notification ratios significantly less than 1 . These rOur results imply that the substantial sex differences in the epidemiologic burden of tuberculosis are almost solely attributable to sex differences in disease incidence and treatment initiation rates, both of which disadvantage men. Although differences between self-reported symptom duration prior to treatment and our model posteriors indicate that both men and women face long periods of undiagnosed tuberculosis disease prior to treatment, men face substantially longer durations of untreated disease. Improved access to tuberculosis diagnostic and treatment services is needed for all individuals, but with more pressing need to better understand and address men’s barriers to care.Our model confirms sex differences in tuberculosis incidence that have already been acknowledged to some extent in estimates from WHO  and IHMEWe also found that prevalence and case notification data are simply not consistent with a longer untreated disease duration in women than in men, despite the widespread recognition of women as a key population with need for improved access to tuberculosis services –8. Our rTimely access to tuberculosis care is essential for successful patient outcomes and for the prevention of transmission, yet current evidence points to considerable delays between the onset of disease and treatment initiation –52. Our There are several limitations to the results presented here. The model chosen for this analysis was deliberately simple in order to clearly define and examine the overall impact of each parameter within the model. As such, results provided here describe median untreated disease duration and do not take into account heterogeneity within the populations of interest. Furthermore, we cannot assess the relative contribution of specific biological and sociocultural factors to increased disease incidence and untreated disease duration among men. In addition, we have not included any consideration of smear-negative and extrapulmonary tuberculosis disease, for which untreated disease duration is likely even longer than described here, although it seems unlikely that the sex differences found here would disappear when other disease types are considered.Our results imply that the substantial sex differences in the epidemiologic burden of tuberculosis are almost solely attributable to sex differences in disease incidence and treatment initiation rates, both of which disadvantage men. Our results add weight to the growing body of evidence that men have a higher incidence of tuberculosis disease , 31 and Despite male disadvantage in accessing care and strong evidence that men have a higher epidemiologic burden of disease, discussions of gender and tuberculosis tend to focus on and prioritize the needs of women. There is little consideration that men face substantial gender-related barriers of their own when accessing tuberculosis diagnosis and treatment. National and international tuberculosis programs need to reconsider gender disparity as a barrier to achieving the ambitious elimination goals set for tuberculosis under the End Tuberculosis Strategy  and the Acknowledging men as a disadvantaged group with limited access to timely diagnosis and treatment is only a first step. The long duration of untreated disease estimated here, particularly among men, implies inadequate coverage of current case-finding strategies. Action is needed to ensure that men are not being unduly disadvantaged by the prominent focus on maternal and child health that characterizes primary care in many countries. Steps must be taken to acknowledge and address the ways in which constructions of masculinity add to and interact with health system barriers that affect men’s health-seeking behaviors. Systematic screening offers an opportunity to expedite diagnosis with less reliance on severe symptoms . The conWeb MaterialClick here for additional data file.


Although many cardioprotective strategies have demonstrated benefits in animal models of myocardial infarction, they have failed to demonstrate cardioprotection in the clinical setting highlighting that new therapeutic target and treatment strategies aimed at reducing infarct size are urgently needed. Completion of the Human Genome Project in 2001 fostered the post-genomic research era with the consequent development of high-throughput “omics” platforms including transcriptomics, proteomics, and metabolomics. Implementation of these holistic approaches within the field of cardioprotection has enlarged our understanding of ischemia/reperfusion injury with each approach capturing a different angle of the global picture of the disease. It has also contributed to identify potential prognostic/diagnostic biomarkers and discover novel molecular therapeutic targets. In this latter regard, “omic” data analysis in the setting of ischemic conditioning has allowed depicting potential therapeutic candidates, including non-coding RNAs and molecular chaperones, amenable to pharmacological development. Such discoveries must be tested and validated in a relevant and reliable myocardial infarction animal model before moving towards the clinical setting. Moreover, efforts should also focus on integrating all “omic” datasets rather than working exclusively on a single “omic” approach. In the following manuscript, we will discuss the power of implementing “omic” approaches in preclinical animal models to identify novel molecular targets for cardioprotection of interest for drug development. The Human Genome Project started in 1990 with the aim of determining the sequence of the human genome and improving disease diagnosis and genetic susceptibility to particular diseases  marked tIn this review, we will focus on the use of “omic” technologies in animal models with high translatability with the aim to discover new cardioprotective targets with potential for drug development.Ischemic heart disease, including myocardial infarction, is the leading cause of mortality worldwide, being myocardial infarct size the main determinant of long-term mortality and chronic heart failure . ReperfuThe discovery, 30 years ago, of the ischemic conditioning phenomena, has amplified our knowledge of the molecular basis of cell injury and survival mechanisms during myocardial ischemia and reperfusion . IschemiThe discovery of these endogenous cardioprotective mechanisms has encouraged the exploration of new ways to protect the ischemic/reperfused heart. In this regard, “omic” analysis in the setting of ischemic conditioning has provided us with novel targets for cardioprotection amenable to pharmacological development.There is no ideal animal model able to recapitulate the complexity that characterizes the clinical scenario of STEMI patients undergoing pPCI. Patients undergoing revascularization present a certain gene predisposition, are often middle-advanced age with various risk factors/co-morbidities and co-medications and with the presence of a culprit coronary atherosclerotic lesion that triggers thrombotic total coronary occlusion. However, despite the differences between the human clinical condition and animal models, experimentally induced myocardial-infarction (MI) models offer valuable tools for understanding the MI pathophysiology, discover novel molecular targets and assess novel therapeutic strategies.Interestingly, consensus statements and recommendations have just been released for the measurement of cardiac physiology in mice and pigs . InformaIn the past, dogs were extensively used as animal models to study myocardial ischemia. However, canines demonstrate significant variations in the coronary circulation pattern between breeds (mongrels or purebreds) and have an extensive collateral circulation able to supply as much as 40% of the blood flow after coronary occlusion, markedly limiting myocardial damage . MoreoveIn addition to the existing differences between animal models, there are important factors that must be considered when performing pre-clinical studies because they can certainly impact the “omic”-related findings. These are detailed in Overall, for identification of valid drug targets, the effect of cardiovascular risk factors, co-morbidities, and co-medications of ischemic heart disease should be taken into account , and theThe past 15 years have witnessed an enormous rise in the development of high-throughput porcine transcriptomic data. Porcine expressed sequence tags, serial analysis of gene expression  and geneRegarding lncRNAs, although most of the transcripts are linear, a circular type of lncRNA has been identified . In cardAny cell expresses all genes simultaneously; yet, there is selective gene transcription depending on the cell type and the stimuli to which it is exposed. Proteomics allows the characterization of those proteins responsible for a cell function at a given moment. Elmadhun and colleagues examined, by proteomic analysis, the effects of daily moderate alcohol consumption in the pericardium and myocardium in a swine model of chronic myocardial ischemia . The autPost-translational modifications can regulate the myocardial proteome. Various proteins and signaling pathways orchestrating cardioprotection are mainly regulated by phosphorylation and to a lesser extent by O-GlcNAcylation .Phosphoproteomics identifies proteins containing a phosphate group as a post-translational modification whose activation or inhibition regulates cell survival, apoptosis, calcium homeostasis, and reactive oxygen species . Please Research into the role of GlcNAcylation in post-translational modifications is relatively new. The O-linked attachment of β-N acetylglucosamine (O-GlcNAc) has shown to regulate cardioprotective proteins involved in calcium homeostasis and reducing apoptosis . Recent So far, few studies have addressed the metabolomic and lipidomic changes associated with cardioprotection. The metabolic profile provides readout of the metabolic state of a specific physiological/pathogenic situation . An inteFinally, cardioprotection research has also to integrate epigenetics. Epigenetics refers to the alteration of gene expression without modifying the DNA sequence. In this sense, genes may suffer modifications of their DNA (and histones) through methylation or acetylation eventually modulating gene activity. Methylation involves adding a methyl group in the DNA thereby preserving DNA positive charge and pronouncing its curvature leading to diminished gene transcription. In contrast, the addition of an acetyl group (acetylation) neutralizes DNA charge and lessens DNA bending and further transcription. The addition of an acetyl group is carried out by histone acetyltransferases whereas its removal by histone deacetylases (HDACs). So far, only one study in swine hearts has revealed modifications in the methylation of myosin light chain isoforms in the left ventricle as compared to the atria paving the way for a better understanding of their functional roles in cardiac physiology and pathophysiology . On the It is clear that genomic information alone, although crucial, is not sufficient to explain the complexity that surrounds ischemic heart disease. The development of post-genomic approaches has allowed widening our understanding of MI-injury with each approach capturing a different angle of the global picture of disease. Transcriptomics has revealed changes in non-coding RNA in the setting of I/R thereby identifying new players in the modulation of cardiac injury; proteomics has determined alterations in protein expression and post-translational modifications upon implementing an endogenous form of cardioprotection called ischemic conditioning, thereby providing us with therapeutic candidates amenable to pharmacological exploitation; and, metabolomics and lipidomics are emerging as important tools to depict changes in both global and cardiac-specific metabolic profiles that occur in ischemic heart disease. However, still much work needs to be done to make sense out of all the available “omic” data to take the next step in overcoming pharmacological deficits to protect the heart from MI. Indeed, the discovery of potential therapeutic targets for cardioprotection requires insight into transcript/protein/metabolite interaction. Accordingly, efforts should focus on integrating all “omic” datasets rather than working exclusively on a single “omic” approach . Integra


Purpose: To compare chronic health and mental health conditions between mid-to-older deaf lesbian, gay, bisexual, transgender, and queer (LGBTQ) and mid-to-older non-LGBTQ adults who are 45 years or older.Methods: Medical conditions and mental health disorders data were gathered from 981 mid-to-older deaf adults (178 LGBTQ and 803 non-LGBTQ) who took the Health Information National Trends Survey in American Sign Language between 2015 and 2019. Modified Poisson regression with robust standard errors was used to calculate relative risk estimates and 95% confidence intervals for all medical conditions and mental health disorders with self-reported LGBTQ status as the main predictor, adjusting for known health correlates.Results: Consistent with the LGBTQ health disparity in the general population, our study findings indicated health disparities for certain medical conditions  and mental health disorders  among mid-to-older deaf LGBTQ compared with non-LGBTQ deaf adults.Conclusion: Like the LGBTQ counterparts in the general population, deaf LGBTQ adults may require more frequent and comprehensive health care services. Culturally and linguistically competent care by providers may be invaluable in reducing such health inequities, particularly when provider education and training is undertaken through an intersectional framework that considers the interaction and context of multiple patient and provider social identities. Healthy People initiative includes plans to reduce health disparities among lesbian, gay, bisexual, transgender, and queer (LGBTQ) individuals by the end of 2030.4–7 Nonconcordant patient–physician communication, inaccessible health information, and few qualified sign language interpreters in health care settings are among the barriers encountered by this medically underserved group. In a national study of over 1500 Deaf adults, the prevalence of self-reported hypertension diagnosis was similar for age and gender compared with the general population whereas this differed for race between Deaf and hearing populations.8 The authors attributed this racial disparity to the underdiagnosis of hypertension in African American Deaf patients due to possible nonconcordant patient–physician communication and mistrust between such patients and their providers.Many Deaf adults who use American Sign Language (ASL) experience barriers to accessing health information and health care, which places them at health knowledge disparity compared with the predominantly hearing, primarily English-speaking population.10 In a 2017 smoking and lung disease study of 188 Deaf adults aged 55 to 80 years, Deaf patients who did not experience accessible communication with their doctors were significantly less likely to ask about lung cancer screening testing compared with Deaf patients who used ASL or other sign language interpreters to communicate with their health care providers.6 However, in another national study of nearly 300 LGBTQ-identified Deaf adults, the presence of a sign language interpreter in the room did not appear to increase patients' disclosure of their marginalized sexual orientation and/or gender identities (SOGIs) to health care providers.11 Instead, this study found that Deaf LGBTQ patients' willingness or hesitation to disclose SOGI was significantly associated with their perceptions of providers' patient–centered communication behavior. This finding suggests that societal stigmas associated with LGBTQ identities may be particularly impactful or salient among LGBTQ Deaf adult patients. Given this, together with extensive discussion about minority stress faced by LGBTQ adults and older adults,13 it may be that mid-to-older LGBTQ Deaf adults may have poorer health outcomes compared with their Deaf non-LGBTQ  counterparts.Providers who lack or rate low in cultural competence in working with Deaf patients may further perpetuate community and individual histories of inadequate care and poor treatment adherence.2 Adults over 50 years who self-identified as transgender, lesbian, or as bisexual women were more likely to report indicators of poorer physical health such as obesity and lower rates of physical activity compared with their non-LGBTQ counterparts.14–16 Additionally, chronic conditions were more frequently identified among transgender adults compared with cisgender counterparts, including in particular asthma, chronic obstructive pulmonary disease, depression, and HIV.Among mid-to-older hearing LGBTQ populations, compared with hearing, non-LGBTQ same-age populations, LGBTQ individuals experienced health disparity in terms of physical health. Lesbian, gay, and bisexual adults aged 50 years or older were significantly more likely to report chronic medical conditions than their heterosexual counterparts; similarly, gay and bisexual older men were more likely to report having angina pectoris or cancer than heterosexual older men.2 while older transgender adults reported significantly higher depression symptomatology than that reported by their similar-aged cisgender counterparts.14 Clearly, significant health-related disparities exist for LGBTQ individuals in the general population and in Deaf individuals; however, not much is known about the health disparity experienced by Deaf individuals who self-identify as LGBTQ.Similar disparity has been reported relative to mental health. Self-reported percentages of disability and mental distress were higher among lesbian, gay, and bisexual older adults,5 As older hearing LGBTQ adults are found to be at greater risk for chronic diseases, depression, and worse physical health than non-LGBTQ counterparts, a similar disparity may exist between Deaf LGBTQ older adults and their Deaf non-LGBTQ same-aged counterparts. Thus, this article aims to explore whether within-group disparity exists for medical conditions among Deaf LGBTQ older adults in comparison to their Deaf non-LGBTQ counterparts.To date, no available literature has examined Deaf LGBTQ health factors. The little research available on the Deaf older adult population is that those individuals who predominantly use ASL and have lower English literacy typically have gaps in their health-related knowledge along with insufficient health literacy.hints.cancer.gov) is a survey focused on collecting information about the American public's use of cancer-related information and health communication. HINTS was culturally adapted and translated into ASL. Items were translated and back-translated by Deaf bilingual professionals. The translated measure was then tested for clarity and understanding through cognitive interviews with Deaf people who had a high school education or less schooling. The finalized translation was then filmed and included in an online survey that was administered to a U.S. sample of Deaf adults who used ASL.Health Information National Trends Survey  and LGBTQ (n=178), all who were between 45 and 95 years and had answered the medical condition questions, whether they had medical conditions or not. Comorbidity status was assigned if the respondent reported that they had two or more medical conditions as diagnosed by their health care providers. Modified Poisson regression with robust standard errors was used to calculate relative risk estimates and 95% confidence intervals for all medical conditions with self-reported LGBTQ status as the main predictor, adjusting for known correlates of medical conditions . The modified Poisson approach is recommended for models with binomial outcomes, and the application of robust standard errors helps rectify the overestimation for the relative risk of having a medical condition.17 The adjusted risk ratios were used to estimate the likelihood of having had a medical condition as diagnosed by a health care provider or health professional compared with not having a medical condition (reference category). Data analyses were conducted using SPSS version 25.Using age-weighted data, descriptive statistics were used to summarize the sample characteristics of mid-to-older Deaf ASL users identifying as non-LGBTQ 23; and targeted marketing by tobacco companies that often sponsor large-scale LGBTQ-friendly events, programs, and festivals. Because such events frequently retain ASL interpreters and provide accessible opportunities for social networking, Deaf LGBTQ consumers may be likely to attend.The higher prevalence of chronic lung-related health issues reported by Deaf LGBTQ participants compared with Deaf non-LGBTQ participants is consistent with similarly higher rates of lung and chronic obstructive lung diseases found among the national LGBT adult population.24–26 Due to scarcity of mental health research among Deaf LGBTQ populations, additional studies are needed to examine affiliation with, and social support received through, Deaf and signing communities as a potential resiliency factor mitigating depression and anxiety risk.Among the general population of lesbian, gay, and bisexual adults with depression or anxiety, associated contributing factors may include experiences of victimization, internalized stigma, financial barriers to health care, and poor physical health.27; subpar provider treatment, ill-equipped and inadequate facilities, and exclusionary office climates.28 Deaf LGBTQ patients may face similar challenges. However, when seeking help for mental health-related concerns, Deaf LGBTQ patients may be required to manage additionally complex processes of determining relative safety around disclosure of SOGI information to health care providers, potentially as providers may be unfamiliar both with communication needs of Deaf individuals and culturally competent practices for working with LGBTQ patients. Further, mental health disparity between Deaf LGBTQ and non-LGBTQ patients may be perpetuated through systemic inequities and considerable challenges to accessing adequate, timely, and culturally informed mental health education and care, rendering help-seeking an especially precipitous task for Deaf LGBTQ patients.Of note, barriers to psychological help-seeking among hearing LGBTQ patients may include societal stigmas, adverse coping behaviors, challenges in accessing insurance, and gaps in culturally specific knowledge related to mental health and illness. For many, obstacles may include outright discrimination and lack of provider sensitivity29 Additionally, a 2017 study of 536 older adults found that marginalization and stigma were associated with higher rates of cancer reported among sexual minority older men compared with heterosexual older men.30 Interestingly, among Deaf LGBTQ adults, those who self-identified as female were significantly less likely to disclose SOGI-related information to their health care providers compared with those who self-identified as male.11 The authors propose that these disparate rates may be due to missed cancer diagnoses. That is, as LGBTQ patients frequently experience increased stigma related to SOGI, preventive and first-line health care may be even further postponed among Deaf individuals considering communication barriers. This may have a particular downstream impact on Deaf LGBTQ female patients uncomfortable with disclosing sexual orientation and/or transgender identities to their providers, possibly contributing to underreported symptoms and delayed or missed diagnoses.32 Future research is needed to replicate the results in other samples to clarify the aspects and influences of intersectional identities for cancer health disparities within the Deaf population.The results of the current study suggest that heterosexual patients self-report higher rates of cancer; however, this is in contrast to a previous study.33 The review of the literature in this National Health, Aging, and Sexuality/Gender Study study also found that the LGBTQ group, compared with non-LGBTQ hearing adults, were also more likely to report poor general health, mental distress, and smoking habits. Arthritic conditions may involve multiple organs resulting in varied and widespread symptoms, and as such may be linked to metabolic, genetic, infectious, traumatic, and immunological factors. Among those with arthritis, the challenges of managing multiple medications and resulting drug interactions, impacts on cognitive function, and limitations on mobility and activities of daily living may exacerbate mood-related symptoms and overall constrict access to social and economic supports. Older LGBTQ adults, particularly those who are Deaf or hard of hearing, may be less apt to follow through on routine health care appointments or engage in preventive self-care behaviors due to communication barriers and challenges to health literacy.The higher relative risks for arthritis and comorbidity among Deaf LGBTQ individuals compared with Deaf non-LGBTQ individuals are consistent with the general literature indicating similar risks in hearing lesbian, gay, or bisexual adults aged 50 years or older.A major strength of this study is its inclusion of the largest U.S. sample of mid-to-older deaf, ASL-using LGBTQ-identified adults to date. A limitation is that the study did not assess risk factors in relation to intersectional identities due to insufficient number of responses when broken down by medical conditions, ethnic/racial group, and LGBTQ status; such analysis could have provided further research insights into disparities particularly unique to subgroups of Deaf LGBTQ older adults.The mental and physical health disparities experienced by Deaf LGBTQ communities may be better understood in the context of stressors impacting physical and mental health, systemic and individually encountered barriers to health knowledge, and societal stigmas associated with these psychosocial and sociocultural identities. Providers working with Deaf LGBTQ patients—who as a population increasingly comprise older adults—should strive to provide equitable, culturally competent, and linguistically accessible services with particular attention to patient risk factors that may be associated with physical and mental health-related conditions.Like their hearing LGBTQ counterparts, Deaf LGBTQ mid-to-older adults may require more frequent, comprehensive, or uniquely tailored health care services and social support. Need for such services and support may be particularly demanded given risk factors related to and arising from anti-LGBTQ stigma and low rates of provider cultural and linguistic competency. Culturally and linguistically competent care by health care providers at all levels is invaluable in promoting health equity, particularly when provider education and training is undergirded by an intersectional framework that examines and treats based on the interaction and context of multiple patient and provider social identities.


Cardiac amyloidosis is an acquired heart disease secondary to the deposition of β-pleated amyloid proteins in heart tissue. Amyloid light chain (AL) amyloidosis is usually secondary to multiple myeloma and can rapidly deteriorate cardiac function, with high mortality. Up to 50% of AL patients have cardiac involvement presenting as heart failure, conduction abnormalities, and cardiomyopathies. One of the rare presentations is the likely simulation of disease with hypertrophic cardiomyopathies like left ventricular outflow tract (LVOT) obstruction due to the systolic anterior motion of the mitral valve and irregular septal hypertrophy secondary to amyloid deposits. We present a case of cardiac amyloidosis secondary to multiple myeloma who presented with dynamic LVOT obstruction resembling hypertrophic obstructive cardiomyopathy and complicated by acute pulmonary edema. These complicated cases can be initially treated for pulmonary edema with an elevation of the head of the bed, furosemide, and nitroglycerin intravenously. For multiple myeloma, chemotherapy was continued. Beta-blockers, calcium channel blockers and angiotensin-converting enzyme inhibitors, and aldosterone receptor blocker were avoided due to poor tolerability. After symptomatic control, the patient can likely be scheduled for septal myotomy and the placement of a pacemaker or implantable cardiac defibrillator to prevent any arrhythmias causing sudden cardiac death in these subsets of patients. Cardiac amyloidosis is an acquired heart disease secondary to the deposition of β-pleated amyloid proteins. The classification and prognosis of amyloidosis depend on the type of amyloid deposits, such as amyloid light chain (AL) amyloidosis, transthyretin amyloidosis, and amyloid-A amyloidosis. AL amyloidosis is usually secondary to multiple myeloma and can rapidly deteriorate cardiac function with high mortality . Up to 5A 67-year-old man with a past medical history of multiple myeloma, hyperlipidemia, and hypertension presented to the emergency department with two days of chest pain, shortness of breath, and orthopnea progressing to a single episode of loss of consciousness on exertion. He reported having similar symptoms over the past two weeks, but it has progressed in severity and had accompanied an episode of syncope in the last two days. Syncope is not preceded by any prodromal symptoms like dizziness, sweating, or autonomic symptoms. The patient denied fever, chills, nausea, vomiting, and abdominal pain.On physical examination, he appeared alert and in no acute distress. His heart rate was 84 beats per minute; blood pressure was 120/70 mmHg; respiration rate was 28 breaths per minute, and peripheral capillary oxygen saturation was 98%. Cardiac examination showed elevated jugular venous pressure, a systolic ejection murmur at the apex and left of the sternal border. The respiratory exam showed a bilateral inspiratory crackle. The other findings of his examination were unremarkable.Initial laboratory investigations showed normal white blood cell count, normal hemoglobin, and normal electrolytes. His pro-brain natriuretic peptide (BNP) was 1425 pg/mL . Chest radiography showed pulmonary edema in the lower lung field of both lungs with some Kerley-B lines, as shown in Figure EKG showed a right bundle branch block with low voltage in the limb leads and no ST-T ischemic change, as shown in Figure Echocardiogram showed a markedly increased left ventricular (LV) wall thickness, hyperdynamic function with an ejection fraction of 75%, paradoxical motion of the interventricular septum with LVOT obstruction due to systolic anterior motion (SAM) of the mitral valve, and moderate mitral and tricuspid regurgitation, as shown in Figure A constellation of findings on laboratory, EKG, echocardiogram, and magnetic resonance imaging (MRI) in the setting of the history of multiple myeloma led us to a presumptive diagnosis of acute decompensated diastolic heart failure with LVOT obstruction secondary to cardiac amyloidosis. Initial symptomatic treatment started by an elevation of the head of the bed and one dose of furosemide 40 mg and nitroglycerin 200 mcg/minute intravenously. For multiple myeloma, we continued treatment with cyclophosphamide, thalidomide, and dexamethasone. Beta-blockers, calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II receptor blockers (ARB) were avoided due to concerns of symptomatic deterioration with these medications. After symptomatic control, the patient was scheduled for septal myotomy that helped in symptomatic improvement, and we placed an implantable cardiac defibrillator (ICD) to prevent any arrhythmias causing sudden cardiac death.Cardiac amyloidosis refers to heart disease secondary to the deposition of amyloid fibrils in the heart. Amyloid deposition can present as restrictive cardiomyopathy, heart failure, and rhythm abnormalities due to conduction blocks and valvular involvement. Cardiac amyloidosis can present as both systolic and diastolic heart failure . One of The treatment of cases of cardiac amyloidosis with LVOT obstruction complicated by acute pulmonary edema involves the propped-up position, diuresis, nitrates, and spironolactone. Beta-blockers and calcium channel blockers are poorly tolerable in CA patients. ACE/ARBs can be used with caution due to symptomatic deterioration. Myomectomy can be considered in severe septal hypertrophy cases causing obstruction due to SAM. These patients have a high risk of developing life-threatening arrhythmias, so adding a pacemaker/ICD add a great prognostic benefit. Definitive treatment is cardiac transplantation for carefully selected candidates . In all Cardiac amyloidosis is a rare entity secondary to multiple myeloma. Cardiovascular symptoms in multiple myeloma can be likely considered as the deposition of amyloid fibrils in the heart. In rare circumstances, cardiac amyloidosis with LVOT obstruction can mimic HOCM. It should be differentiated based on genetic testing, and a disproportion of low voltage on EKG with LVH on echocardiography is unique to cardiac amyloidosis as a cause of septal hypertrophy causing LVOT obstruction. We presented this case report to highlight the different presentation of cardiac amyloidosis and to share our experience in managing this condition both symptomatically and therapeutically for multiple myeloma, as patients have very high mortality.


Flaviviridae family. There are 4 serotypes of DENV thatcause human disease through transmission by mosquito vectors. DENV infection resultsin a broad spectrum of clinical symptoms, ranging from mild fever to denguehemorrhagic fever (DHF), the latter of which can progress to dengue shock syndrome(DSS) and death. Researchers have made unremitting efforts over the lasthalf-century to understand DHF pathogenesis. DHF is probably caused by multiplefactors, such as virus-specific antibodies, viral antigens and host immuneresponses. This review summarizes the current progress of studies on DHFpathogenesis, which may provide important information for achieving effectivecontrol of dengue in the future. Dengue virus (DENV) is a mosquito-borne virus belonging to the


Microbial-based bioformulations that increase plant performance are greatly needed, and in particular bioformulations that exhibit complementary and synergistic effects with mineral fertilization. Such an integrated soil fertility management strategy has been demonstrated through several controlled and non-controlled experiments, but more efforts have to be made in order to thoroughly understand the multiple functions of beneficial microorganisms within the soil microbial community itself and in interaction with plants and mineral resources. In fact, the combined usage of microbial  and mineral resources is an emerging research area that aims to design and develop efficient microbial formulations which are highly compatible with mineral inputs, with positive impacts on both crops and environment. This novel approach is likely to be of a global interest, especially in most N- and P-deficient agro-ecosystems. In this review, we report on the importance of NF bacteria and P solubilizing/mobilizing microbes as well as their interactions with mineral P fertilization in improving crop productivity and fertilizers efficiency. In addition, we shed light on the interactive and synergistic effects that may occur within multi-trophic interactions involving those two microbial groups and positive consequences on plant mineral uptake, crop productivity, and resiliency to environmental constraints. Improving use of mineral nutrients is a must to securing higher yield and productivity in a sustainable manner, therefore continuously designing, developing and testing innovative integrated plant nutrient management systems based on relevant biological resources (crops and microorganisms) is highly required.Tomorrow’s agriculture, challenged by increasing global demand for food, scarcity of arable lands, and resources alongside multiple environment pressures, needs to be managed smartly through sustainable and eco-efficient approaches. Modern agriculture has to be more productive, sustainable, and environmentally friendly. While macronutrients such as nitrogen (N), phosphorus (P), potassium (K), and sulfur (S) supplied by mineral fertilizers are vital to crop production, agriculturally beneficial microorganisms may also contribute directly (i.e., biological N Global food demand is increasing rapidly and so more in developing nations where crop lands and resources hardly contribute to an efficient crop production needed to meet such an urgent demand for food. There is a need to intensify agricultural production in a sustainable manner through use of efficient agro-biosystems which consider the entire agroecosystem bio-chemical diversity and their potential to mitigate the adverse impacts of low soil fertility, abiotic stress, pathogens, and pests . In thisToday, microbial-based biofertilizers are considered to be among key agricultural components that improve crop productivity and contribute to sustainable agro-ecosystems. It is a component that aggregates a variety of microbial-based bio-products whose bioactivities are essential to stimulate and improve biological processes of the intricate plant–microbe–soil continuum . DiffereGenerally, beneficial rhizosphere microorganisms can boost plant growth via multiple regulatory biochemical pathways (categorized as direct and indirect mechanisms) that include manipulating the plant hormonal signaling, preventing pathogenic microbial strains and increasing the bioavailability of soil-borne nutrients . Direct Penicillium spp. and AM fungi induced positive and synergistic effects  in cereals and legumes , but also to several nutrients  . Moreove legumes . Such poicillium , rhizobiicillium , Rhizobibacteria , or eveng fungus . Multifug fungus .Sinorhizobium meliloti RMP and Pseudomonas aeruginosa GRC2 improved growth and yield of Brassica juncea supplied with urea and diammonium phosphate (DAP) fertilizers  significantly improved yield of multiple agriculturally important crops including legumes  that address soil fertility issues, crop nutrient needs and sustainable eco-intensification. Indeed, while mineral fertilizers provide high amounts of nutrients to plants, biological resources  are key components of such IPNMS wherein both resources may synergistically co-interact to improve nutrient compositions and biological functions that plants need to grow stronger. In this regards, a limited number of studies have focused on the positive and complementary combinatory effect of using beneficial microbes for increasing the efficiency in use of mineral fertilizers . For instilizers . Likewis legumes .2-fixers segments, respectively  and P solubilizing/mobilizing microorganisms have increasingly been used as biofertilizers, and now account for more than 75% of globally marketed microbial-based biostimulants. These segments are expected to grow by 20 and 13% for the P-solubilizers and Nectively . Given tFigures 1, 2. The significant involvement of those two microbial groups as key drivers of N and P dynamics in soils as well as their use efficiency by plants are presumably to provide clear evidence of two inseparable microbial–rhizosphere processes as described in Figure 2.Microbial biotechnology through the exploitation of microbial resources has proved in the last 30 years to be one of the most powerful and potent tool that could provide palpable answers to address nutrient limitations (notably N and P) in most agricultural soils. Today, beneficial microbes are extensively used  to promote plant growth and to act as biological control agents. In this paper, the importance of the beneficial microorganisms belonging to NF and P-solubilizing/mobilizing groups is illustrated in Pisum sativum which were believed to be induced by soil bacteria  and Bacillus megaterium (PSB) were used in Russia and East European countries. For 1958, it was reported that about 10 million ha in Russia were treated with those microbial preparations  was successfully used in Russia. Further studies however did not show the same efficiency in soils in the United States, thus concluding that there were no enough indications clearly demonstrating beneficial effects on field crops  in the presence of nitrogenase. Such an enzymatic conversion is found in a wide diversity of NF organisms called diazotrophs. Some diazotrophs can fix N2 in the free-living state, while others perform it in association with plants including endophytic (inside plant tissues) and symbiotic bacteria involving structural and physiological modifications of both microbe and plant roots in specialized structures namely nodules  that can use root nodules to sequester atmospheric nitrogen as ammonia, a form of N that can then be incorporated into organic components including proteins and nucleic acids (Frankia) with a variety of angiosperms like Alnus and Casuarina  with the ability to proliferate owing to energy and nutrients derived from plant roots (2 fixation) does not involve a direct controlled exchange of N and C between bacteria and plant hosts.In non-legumes such as grasses, the ability to fix Nhe paper . Among tnt roots . It is w2 fixation are also a major component of this challenge  from some studies  of soil content of which only a small fraction is bioavailable for plants . In soilPseudomonas, Bacillus, Azotobacter, and Bradyrhizobium), fungi , actinomycetes , and algae are all capable of solubilizing P-metal complex to release bioavailable P in the form of orthophosphate through specific mechanisms implying mainly organic acids, siderophore production, and phosphatase enzymes playing a key role in hydrolyzing organic P forms. Overall, PSM could contribute in promoting plant growth through enhancing P use efficiency directly through exudation of organic acids and P-hydrolyzing phosphatase enzymes and thus enhancing the bioavailable P pool, or indirectly through the production of phytohormones, antifungal compounds, toxin-resistance compounds, and other high value bioactive molecules which could help building robust shoot/rooting system, specially under biotic and abiotic constraints .A number of genera among bacteria , found that both strains exhibit equal solubilization potential, although T. flavus produced four times less organic acids than P. purpurogenum. This finding, which is in line with a study by Despite the variety of mechanisms involved in P solubilization, organic acids are the main contributors . Secreti+ and Ca2+  with 2-ketogluconic acid and gluconic acid are the most common ones in gram negative bacteria . Organicand Ca2+ . Neverthand Ca2+ .In addition to microbial solubilization of mineral P, organic P mineralization through the action of microorganisms plays also a vital role in P cycling, giving that organic P content in soil (mostly in the form of inositol polyphosphates) can represent between 30 and 50% of the total P . The minAdditionally to PSM, AMF are also key microbial component of agro-systems giving they are the most widespread symbiosis on earth  which is defined by a symbiotic relationship involving a bidirectional exchange of nutrients between the two organisms . Their cBacillus sp., Bacillus thuringiensis, and Paenibacillus rhizospherae) from Gigaspora margarita spores that exhibited multiple PGP properties including P solubilization, ethylene production, nitrogenase activity, and antagonism toward soil-borne pathogens. Dual positive effects of AMF and their associative endobacteria with regards to facilitation of P uptake under P-limiting conditions were evidenced by However, until now, and even if the ability of fungal hyphae to exudate acid phosphatase enzymes and organic acids has been confirmed , the magGigasporaceae are habitats of several endophtytic bacteria. For example, the endophtytic bacteria Glomeribacter gigasporarum which was previously assigned to the Burkholderia genus according to 16S rRNA sequencing, lives inside the mycorrhizal spores and cannot complete their life cycle otherwise  legumes than in non-symbiotic plants whose growth rely on mineral N sources , photosynthesis, root development, root hair formation, nodulation, BNF, and particularly as an energy source for the latter biological process . Plant NFigure 2). Regarding P, these traits may substantially contribute in alleviating the sensitivity of NF plants to low P availability through ensuring large amount of P-dependent carbon and energy turnover required during the NF process (Bacillus) and NF (Bradyrhizobium) strains improved symbiotic traits related to growth of nodules and roots, aboveground biomass, total N and grain yield  and this leads to great variation in terms of growth, nodulation, and thus Nme crops . Under sme crops , and thaR. leguminosarum association whose N requirement might be secured up to 80% through symbiotic NF according to The Saskatchewan Pulses Growers (Pulses Crop Development Board). Coincident with the efficient use of adequate amounts of P fertilizers required for optimal plant productivity, aboveground N requirement may then be promoted by using effective NF strains and relevant crop–microbe biosystems that are efficient in contributing to sustainable intensification of agriculture. Although not fully exploited, some inoculants can substantially improve plant uptake of essential nutrients and thereby increase use efficiency of applied mineral and organic fertilizers . However, and despites P has been demonstrated to be essential for the rhizobial symbiosis establishment and functioning, there are so far fewer reports on the effects of combined use of P fertilizers and rhizobial inoculation that could produce additional benefits to the symbiosis performance and host feedback responses. Recently, a study by Bradyrhizobium symbiosis agronomic efficiency compared to either inoculant or P applied alone. In addition to a positive influence that P may have on the rhizobia efficiency (higher N content in shoots and seeds) and yield component (grain yield and plant biomass), application of this nutrient was also been demonstrated to boost the effectiveness and efficiency of the indigenous rhizobia population (-1), which is in line with previous studies that succeeded to physiologically explain advantageous mutualistic benefits in response to P supply and rhizobia inoculants (Ensifer meliloti and Ensifer medicae) from a fertilized-field soil conferred higher mutualistic benefits with Medicago lupulina. The combined-micronutrients plant fertilizer was generally beneficial for rhizobia growth compared to isolates from unfertilized field soil. Several reports revealed that rhizobial inoculation of many legume crops  supplemented with P fertilizer improved the uptake of N, P, K, Mg, Ca, and Na . Likewispulation . Those moculants . Moreoveoculants . These aWith regards to P application and BNF, 2 fixation, and uptake in cowpea crop.Moreover, combinatory use of the rhizobial symbiosis and P fertilization has been shown to help ensure yield stability under stressful conditions such as salinity owing, among other factors, to stimulating plant–defense mechanisms coupled with adequate nodulation, plant biomass, protein content, grain yield, and other growth variables . In thisPoaceae family do not naturally form symbiotic NF associations, but they can derive a substantial part of their N through non-symbiotic associations with free, associative and endophytic NF bacteria. In non-leguminous crops like cereals, the optimization of NF ability has long been a major goal of plant scientists not only to make cereals self-sufficient in N nutrition  whose impacts on growth and yield of B. juncea were positive when co-applied with DAP and urea fertilizers. Co-inoculation with the latter NF and P-solubilizing strains were found to be effective on Brassica crop in terms of growth performances under half dose of N and P fertilizers (Sinorhizobium and Burkholderia sp. enhanced growth of pigeon pea. This is in accordance with a study by Bacillus sp. strain (KAP6) (slurry of strain and compost) enhanced growth, yield, photosynthetic rate, and nutrient use efficiency of wheat supplied with N-containing fertilizers such as urea and DAP  that have the potency to supplement significant amounts of N would be a wiser alternative , supplied with sufficient amount of P [triple superphosphate (TSP)] fertilizer and deficient amount of N . An increased plant biomass and chlorophyll content  may be attributed to an effective absorption of nutrients (mainly N as attested by higher protein content), but also by the capacity of this strain to synthesize indole acetic acid that could positively impact secondary roots proliferation  into major crops like corn, sorghum, and wheat  enhanced use of nutrients [especially P (30%) compared to N (11%) and K (17%)], biomass and leaf parameters compared to plants supplied with NPK fertilizer alone  in barely plants inoculated with a NF and P-solubilizing Pseudomonas bacterium (strain Az1) compared to other tested strains. This important P uptake would have relied upon plant-induced changes, especially root growth whose nutrient absorptive capacity could be augmented owing to associated non-symbiotic NF bacteria  with multifunctional abilities other than only improving both N and P nutrition  correlated with a specific plant P translocation pattern (higher intracellular P in shoots as compared to that in roots) and the higher ability of the latter strain to solubilize tri-calcium P. Organic acids, among other factors, may enable roots to access readily available P owing to intense acidification at the root vicinity such as in wheat and tomato seedlings supplied with insoluble calcium phosphate and inoculated with a NF bacterium  along with adequate P nutrition  and numerous P solubilizing bacteria (Azotobacter and Azospirillium species) on grain yield, protein, fatty acids, and oil contents of sunflower crop. This integrated fertilization system improved sunflower productivity and seed oil quality and corroborates with other studies on root N absorption from chemical fertilizers that could be increased under application of both biological and manures fertilizers  improved plants biomass and enhanced germination index in rice and cowpea bean owing to stimulation of specific enzyme biosynthesis such as amylase in seeds. Moreover, a recent study by Pseudomonas putida (prepared by coating DAP (20 g/kg) with a mixture of organic material containing compost, molasses, and the P. putida bacterial strain). This study demonstrated the benefit of the combined DAP and PSB co-application as it improved maize dry matter (12%) yield and P uptake (33%) in addition to significant agronomic efficiency in terms of produced biomass that increased by 62% compared to unfertilized soil. Such a P fertilizer-bacteria alliance approach is peculiarly interesting in soil where P management is demanding.Combinatory use of PSM and P has been practiced and a number of studies evidenced improved agronomic efficiency of rock phosphate and P fertilizers such as, DAP, NPK, and TSP . For insFigures 5, 6 reported an improvement of maize growth under combined treatment consisting of mineral P fertilizers  and an efficient PSB strain. Those integrated treatments enhanced used of phosphate and TSP fertilization and improved maize plant agro-physiological performance including shoot P content, chlorophyll content, biomass of root and shoot. This is in agreement with findings by 2O5/ha) and inoculation with two PSB strains induced high growth and yield performances  in wheat and maize. In addition, a recent study by Pseudomonas, Pantoea, Mycobacterium, Bacillus, Burkholderia, Arthrobacter, and Enterobacter) supplied with mineral (single super phosphate and rock phosphate) and organic (poultry and farm yard manures) P fertilizers.Other findings illustrated in Rhizophagus clarus and NPK mineral fertilizer (200 and 100 kg/ha). The co-application “AMF/fertilizer” increased P uptake by 24% compared to the mineral fertilizer alone and that the mycorrhizal colonization remained unchanged in response to NPK application. This is in agreement with findings in Figure 4 showing the impact of tow Moroccan native AMF strains (Funneliformis mosseae and Rhizophagus intraradices) on maize yield and symbiotic performance under mineral P  fertilization. Increased P uptake and dry weight of shoots and roots was obtained in response to combined use of TSP and both AMF, and in particular with F. mosseae that exhibited higher arbuscular mycorrhizal colonization in the presence of TSP . Penicillium oxalicum and rock phosphate co-application on wheat and maize under alkaline conditions where plant P content and yield (70%) of maize were higher over the control. These results are consistent with findings by P. oxalicum and Aspergillus niger) isolated from calcareous soil, enhanced P availability and effectively colonized maize roots which positively influenced aboveground biomass. Those responses were associated with higher biosynthesis of organic acids  when rock phosphate was added. More evidences through field and greenhouse experiments on the beneficial effects attributed to combinatory use of both PSM and P-based mineral fertilizers are highlighted in Table 1.The positive impact of combining both AMF and P fertilizers on plant growth, development and P uptake has been studied. For instance, SSU rRNA revealed AMF to be more diverse in P-based fertilization systems than previously described . Giving all knowledge provided above regarding the positive impacts that single inoculation may have on plant growth, productivity and nutrient use, it is also evidenced that adopting polymicrobial approach  could produce additional improvements as well as much more resiliency to contrasting conditions , NF bacteria (A. chroococcum), and AMF (Glomus fasciculatum) . In legumes, during formation and functioning of nodules, PSB may enhance P availability through the production of organic acids which provides evidence on synergism with the rhizobial symbiosis and so more when P mineral fertilizers are applied  . Moreove applied . SimilarF. mosseae) and Rhizobium (SH212) control N transfer in the soybean/maize intercropping system. Findings of the latter study provided evidences for a beneficial effect owing to a dual inoculation (AMF and Rhizobium) on enhanced nodule number, N uptake and transfer from soybean to maize, and improved maize biomass. Multiple positive responses were attributed to the role of AMF in N uptake, rhizosphere-induced changes (acidification by legume exudates) and enhanced competition toward deleterious microbes , are likely attributed to AMF involvement in mobilizing resources and alleviation of the adverse effects induced by alkaline stress . Notewormicrobes . Obviousmicrobes . For exaR. leguminosarum and a mixture of AMF strains  under four level of alkalinity  resulted in improved nodulation (higher number and biomass) compared to single-inoculated plants that were substantially inhibited by the alkaline conditions. The concept of microbial consortia could also prove beneficial with regards to other constraints such as salinity, one of the major issue faced by today’s agriculture knowing that virtually 20% of irrigated croplands are concerned  and a salt-tolerant (B. subtilis) significantly promoted plant growth when subjected to salinity constraint. This salt-tolerant tripartite symbiosis enhanced nodulation, dry biomass, P content, leghemoglobine, and protein content of A. gerrardii compared to untreated and mono-inoculated plants. B. subtilis which indirectly promoted nutrient acquisition via a better AMF colonization. Similarly, inoculation of two salt-treated maize varieties with two PGPR (Rhizobium sp. and Pseudomonas sp.) led to a higher proline production and a lower osmotic potential concurrently with enhancing P uptake and dulling detrimental effects induced by salinity  and polymeric compounds  in plant nutrition, soil fertility and stress tolerance, new routes and perspectives based on multi-disciplinary approaches should be considered in order to advance testing efficacious microbiological resources within profitable integrated plant nutrient agro-systems.Indeed, continuous designing, developing and testing microbial-based formulations to be used as a component in efficient IPNMS has gained worldwide interest in recent decades and so more under the ever-increasing global demand for food production. Diverse microbial groups, with focus on NF and P-supplying microbes detailed in this review paper, are agriculturally beneficial and their contribution in agriculture does not aim only to improve specific biological functions (either directly or indirectly), but most importantly to increase availability and plant uptake efficiency of major soil pool nutrients and ultimately increase the eco-efficiency in use of mineral fertilizers. One of the most promising mean is to strengthening research on innovative IPNMS which include a variety of multi-functionally biotic and abiotic resources, particularly highly efficient PGPM in combination with mineral fertilizers. The right combination of resources , right rate of resources, right application time, right plant host, adequacy to soil and climatic conditions, and positive legacy effects are highly essential for decisions on relevant nutrient formula, cropping systems as well as best management practices that will lead to enhance crop productivity and soil fertility.Furthermore, in order to achieve those goals with particular emphasis on P fertilizers as described in the paper, a good understanding of the tripartite interaction between microbial inoculants, mineral fertilizers, and crop species is a prerequisite. In fact, research is making recently great progress in that department through advances in several plant–microbe-related research areas including genomics, metabolomics and phenomics. In this context, high throughput technologies would provide necessary data enabling a better understanding of the intricate interactions within the holobiome, more particularly to unravel behavior responses of beneficial microbes in agroecosystems. Taking altogether, it is evident that current advances in terms of plant-, microbe-, and soil-focused research have led to developing crops with specific traits and fine-tuned for higher nutrient uptake and tolerance to multiple constraints. Likewise, these traits have also been targeted in microbes and biotechnological progresses thrived to provide beneficial microbes with proven efficiency. Now, securing sustainable higher yield and productivity in the near future will rely on exploiting all available multidisciplinary progresses in order to design innovative crop–microorganisms biosystems with synergistic and complementary interactions.All authors equally contributed to the preparation of the review, revised the text at different stages of the writing process, and read and approved the current manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Although wildfires are increasing globally, available information on how mammals respond behaviourally and physiologically to fires is scant. Despite a large number of ecological studies, often examining animal diversity and abundance before and after fires, the reasons as to why some species perform better than others remain obscure. We examine how especially small mammals, which generally have high rates of energy expenditure and food requirements, deal with fires and post-fire conditions. We evaluate whether mammalian torpor, characterised by substantial reductions in body temperature, metabolic rate and water loss, plays a functional role in survival of mammals impacted by fires. Importantly, torpor permits small mammals to reduce their activity and foraging, and to survive on limited food. Torpid small mammals  can respond to smoke and arouse from torpor, which provides them with the possibility to evade direct exposure to fire, although their response is often slowed when ambient temperature is low. Post-fire conditions increase expression of torpor with a concomitant decrease in activity for free-ranging echidnas and small forest-dwelling marsupials, in response to reduced cover and reduced availability of terrestrial insects. Presence of charcoal and ash increases torpor use by captive small marsupials beyond food restriction alone, likely in anticipation of detrimental post-fire conditions. Interestingly, although volant bats use torpor on every day after fires, they respond by decreasing torpor duration, and increasing activity, perhaps because of the decrease in clutter and increase in foraging opportunities due to an increase in aerial insects. Our summary shows that torpor is an important tool for post-fire survival and, although the physiological and behavioural responses of small mammals to fire are complex, they seem to reflect energetic requirements and mode of foraging. We make recommendations on the conditions during management burns that are least likely to impact heterothermic mammals. Changes in global weather patterns are predicted to increase the frequency and intensity of severe events such as storms, floods and fires . Severe In Australia and other regions ‘fuel reduction burns’, ‘prescribed fires’ or ‘management burns’, which are usually low-intensity burns, are generally conducted during the cold season in an attempt to reduce the severity of wildfires in the following warm season. The effectiveness of these burns and their impact on ecosystems have been questioned  and thisDespite the acute and direct threat to animal life during both wildfires and management burns, very little is known about how mammals deal with fire, nor how they cope with a denuded post-fire environment where food and shelter are often reduced and predation pressure usually increases (Trichosurus cunninghami) can survive the direct impact of fires (Loxodonta africana), reduced post-fire home range size and increased faecal stress hormones of cows  died during and after a wildfire, but all survived a management burn, near Sydney, Australia (Macropus giganteus) was to a large extent extinguished (Aquila audax) present after the fire suggests plenty of scavenging opportunities. An influx of scavengers post-fire also occurred in the Yellowstone National Park, where bears, eagles and ravens invaded after fires to feed on carcasses . Large mammals typically avoid fires, and generally mortality rates are low for large mammals such as ungulates and bears, being ≤1% of populations during a wildfire in Yellowstone National Park, North America . Even mearcasses . Overallarcasses . Indeed arcasses .Ta). Reduction in cover may increase vulnerability to predation, exacerbated by predators invading the area in response to improved hunting conditions  and enables some species to survive without food for many months , pygmy-possums (Cercartetus nanus) and bats  can respond to smoke, but the response is slowed at low Ta  responded to the sound of fires by moving to protective cover  the response to smoke, measured as an increase in respiration rate, was rapid and occurred within 1 s at Ta 21.4°C (Tb ~22.4°) and 36 s at Ta 11.9°C (Tb ~12.9°C). All bats rapidly (~8–15 min) rewarmed from torpor  in torpor in the same hollow log were impacted by a management burn (Tb. A. stuartii and A. swainsonii) carcases following a severe wildfire in heathland in south-east New South Wales.There are numerous observations of bats flushing from roost sites in response to smoke and noise from a nearby fire (ts arose . HoweverN. gouldi) re-entered torpor, but they never returned to thermo-conforming, steady-state torpor prior to the end of the experimental day at low Ta, although those at warmer Ta did  increased torpor use and torpor duration after a hazard reduction burn by ~2-fold in comparison to the pre-fire controls and controls measured concurrently in an unburnt area nearby. At the same time activity decreased substantially  and a rodent (Rattus fuscipes) from a burnt area after a period of 18 months; they concluded that wildfire can have a catastrophic impact on small mammal populations in the longer-term, even if they persist in the shorter-term. A. stuartii and A. swainsonii, as well as the homeothermic R. fuscipes, after a forest fire, but the heterothermic dunnart (Sminthopsis leucopus) and house mouse (Mus musculus) persisted, and appeared to even benefit from a post-fire landscape. It is unclear if trapping-based studies are as likely to detect heterothermic animals that increase torpor use and reduce activity post-fire as radio-tracking studies, which may explain some discrepancy in results.Forest-dwelling antechinus also increased torpor expression and duration and decreased daily activity in a post-fire environment , which have high mortality rates (Peromyscus maniculatus) remaining in burned areas post-fire, with good physical condition, although their use of torpor during this period was not reported (e.g. Mus musculus) and Pseudomys spp. dominate the post-fire small mammal community  responded differently to post-fire cues compared with small forest-dwelling mammals. When provided with food and exposed to a charcoal/ash substrate, minimum Tb increased and activity decreased. When food was withheld, torpor expression on a charcoal/ash substrate was similar to the control substrate (Desert-dwelling dunnarts (Myotis macropus), an Australian fishing bat, and the long-eared myotis (Myotis evotis), a North American crevice-roosting bat, both of which actively avoid fire-burnt habitat  are less active in burnt areas , a common Australian insectivorous bat, modified patterns of torpor use following an extensive wildfire  also fly away from the fires, but do not appear to leave their general home range (Ta (In the northern hemisphere, where many bat species hibernate over winter in caves or mines rather than in trees, poorly ventilated caves could be problematic in the event of a fire. Unfortunately, there are few data on the effects of smoke and fire on cave-roosting bats, with one study reporting that bats did not respond to smoke intrusion from a winter management burn . Some Noange (Ta , and winOur summary provides further evidence that daily torpor and hibernation provide heterothermic mammals with an adaptive advantage over homeothermic species in changing environments, due to flexible thermal energetics. Heterothermic species do not only use torpor to survive seasonal energetic and thermal challenges, but also to endure the consequences of unpredictable energy bottlenecks or natural disasters and overall this results in lower risk of extinction . As humaEcological studies, especially those using a trap and release approach, often assume that pre- and post-fire trapping are directly comparable and reflect mammal populations in the same way. This approach cannot reveal the basic behaviour and physiology crucial to understanding the mechanisms of mammalian fire ecology. Moreover, many of these studies have produced ambiguous results and often assume that any observed changes reflect actual changes in diversity and abundance. As our summary shows, many small terrestrial mammals increase torpor use and reduce activity in a post-fire landscape, which may substantially affect trap success. Thus, inferences concerning diversity and abundance in post-fire environments based on trapping studies alone, without data on the behaviour and function of mammals, may not realistically represent changes in populations due to fire and therefore may not be suitable for generating reliable predictive models that have a good probability for improving animal conservation.Based on current knowledge of mammalian fire responses reviewed here, we suggest that further research is required to assess the functional responses of mammals, especially small terrestrial mammals, to fire, particularly wildfire. Larger mammals and bats may have an overall net energetic benefit from fires. For small forest-dwelling mammals, heterothermia appears to provide for increased resilience to fire, at least in the short to medium-term, due to reduction in energy requirements and reduced exposure to predation. However, longer-term effects are not well understood, and the immediate threat of fire can have varied impacts for animals in torpor at the time of the fire. More research is required to understand fire responses of small heterothermic mammals from arid habitats, and the potential impacts of burns in their environment. Based on current knowledge, we recommend that fire management protocols consider the extent of heterothermic species comprising small mammal populations, and conduct management burns accordingly. Survival and retention of small heterothermic terrestrial mammals likely will be improved if very cold periods when deep torpor is common are avoided and when control burns are moving at a slow pace at low intensity and create plenty of smoke to provide early warning of the imminent fire.


Drug delivery to malignant tumors is limited by several factors, including off-target toxicities and suboptimal benefits to cancer patient. Major research efforts have been directed toward developing novel technologies involving nanoparticles (NPs) to overcome these challenges. Major obstacles, however, including, opsonization, transport across cancer cell membranes, multidrug-resistant proteins, and endosomal sequestration of the therapeutic agent continue to limit the efficiency of cancer chemotherapy. Lipoprotein-based drug delivery technology, “nature’s drug delivery system,” while exhibits highly desirable characteristics, it still needs substantial investment from private/government stakeholders to promote its eventual advance to the bedside. Consequently, this review focuses specifically on the synthetic (reconstituted) high-density lipoprotein rHDL NPs, evaluating their potential to overcome specific biological barriers and the challenges of translation toward clinical utilization and commercialization. This highly robust drug transport system provides site-specific, tumor-selective delivery of anti-cancer agents while reducing harmful off-target effects. Utilizing rHDL NPs for anti-cancer therapeutics and tumor imaging revolutionizes the future strategy for the management of a broad range of cancers and other diseases. Our laboratory has been engaged in reconstituted high-density lipoproteins (rHDL) drug delivery research for more than a decade, focusing on formulating and evaluating rHDL drug delivery vehicles for a multitude of anti-cancer agents. Lipoprotein drug transporters have traditionally been used to deliver hydrophobic and amphiphilic drugs. Recently, our laboratory and others have succeeded in the encapsulation of hydrophilic drugs, including doxorubicin . Our hypFigure 1). Although there are several classes of lipoproteins  in the blood of mammals, the present paper focuses only on high-density lipoproteins because of their preferred use in drug delivery research  is a major protein component of HDL which also serves as a ligand for the SR-B1 receptor. Several methods have been used to assemble rHDL NPs. including cholate dialysis, sonication, thermal cycling, and microfluidics . SynthetThe innate immune system (IIS) is the first line of defense against external pathogens or foreign substances, including NPs. The IIS consists of epithelial barriers, phagocytes, dendritic cells, and plasma proteins (complement). The complement system, one of fundamental components of innate immunity is highly organized and designed to remove/clear ‘foreign’ substances . The comBecause the rHDL complex is assembled from essentially the same constituents as endogenous HDL, rHDL also mimics its endogenous counterpart as reflected by its function of delivering drugs to cancer cells via the SR-B1 receptor . ExposurFigure 2). Adsorption or binding of different serum proteins determines the fate of injected NPs. Opsonins such as complement proteins and immunoglobulin adsorption will facilitate nanomaterial removal from the plasma while adsorption of dysopsonins such as bovine serum albumin, apolipoproteins will enhance the circulation time via avoiding the mononuclear phagocyte system. Apart from complement activation, several other plasma proteins can adsorb onto the NP surface and modify its surface properties  receptors to acquire cholesterol from macrophage foam cells in atherosclerotic plaques, considered to be contributing to its anti-atherosclerotic effect, and attributed to the inverse relationship between HDL-C levels and the risk of coronary heart disease . SynthetFigure 3). Two types of rHDL NPs have been reported in the literature; discoidal; and spherical  tend to accumulate in the liver and spleen while smaller ones (<10 nm) tend to get cleared by the kidney . Thus, sNumerous research articles have discussed the potential of NPs for targeted drug delivery to cancer cells and tumors. An ideal nanocarrier is expected to have a small size, the extended residence time in the circulation, biocompatibility, and absence of immunogenicity. Although the drug-containing NP formulations exhibited much better delivery efficiency compared to the free drug formulations, they were not as efficacious in limiting off-target effects . This diin vitro studies indicated a clear distinction between non-specific and specific uptake of the two types of NPs. All 3 NPs  were phagocytosed by macrophages, while the endothelial cells were involved in the uptake of only αvβ3-integrin-specific rHDL-RGD NPs. Furthermore, in-vivo studies using NIR and MR imaging demonstrated that rHDL-RGD was associated with tumor endothelial cells, whereas HDL and rHDL-RAD NPs were mainly found in the interstitial space. Thus, it is possible to re-route the rHDL NPs via active targeting.The drug delivery via NPs usually occurs via extravasation of NPs through the leaky tumor vasculature (passive targeting) or targeted delivery via ligand modified surface of the drug carrier (active targeting) . AlthougIn another study, The potential utility of HDL mimicking NPs as programmable, and biocompatible drug delivery vehicles suitable for the targeted delivery of tumor imaging and anti-cancer agents has now been established. The HDL NPs owing to their small size, close to neutral charge and long circulation time are able to move out of the circulation and accumulate in malignant tissues. Aforementioned studies also demonstrate the ability to reroute rHDL from its natural target to tumor blood vessels and its potential for multimodal imaging of tumor-associated processes. An analysis of NP payload uptake and drug delivery on the microscopic level in small animal studies will be essential to understanding the efficiency of therapeutic effects. Based on clinical studies, rHDL has already been proven safe for human administration .Unlike small molecules which readily diffuse into cells and tissues, drugs, encapsulated in NPs must have facilitated delivery across cell membranes. Cellular internalization and endosomal/lysosomal entrapment are of great concern in NP design. Whether trapped in compartments or subjected to the low pH and enzymatic environment of the lysosome, endosomal escape is necessary for the efficient delivery of the NP drug cargo to the tumor site. Size, charge and surface decoration of NPs determine which endocytic pathway they may enter and their subsequent intracellular fate . ConcernSeveral pathways exist for movement of the NP or its cargo into the cell interior. Endocytosis is a process of forming vesicles and moving them toward intracellular targets usually involving clathrin-coated pits where the specific receptors reside  and the LDL receptor described by Brown and Goldstein . SeveralStrategies for the endosomal escape is a wide-ranging topic that merits a review of its own. However, these strategies could represent key steps in the design, and manufacturing of NP formulations. Rather than designing and preparing complex formulations, direct cytosolic delivery of the therapeutic payload could be achieved with a drug delivery NP platform such as the reconstituted/recombinant high-density lipoproteins (rHDL). The receptor for HDL, Scavenger Receptor Class B, Type 1 (SR-B1) facilitates the endogenous delivery mechanism directly into the cytosol, a process known as selective lipid uptake There are five isoforms of SR-B1 from splice variants encoded by the SCARB1 gene. The first isoform was named as SR-B1 and shown to be the HDL receptor . The recFigure 4). The exact mechanism of how SR-B1 achieves selective lipid uptake is yet to be fully elucidated. It was postulated that SR-B1 forms a hydrophobic channel or pore when docked with HDL to allow passage of cholesteryl esters across the cell membrane  to probe uptake via the SR-B1-mediated pathway . The corIt important to cite the pioneering work done by several researchers in siRNA delivery and SR-B1 involvement. Bijsterbosch et al studied the biodistribution and organ accumulation of phosphorothioate antisense oligo whereby most of it (>90%) was found to be in the liver at 90 min indicating that scavenger receptors were involved , 2000. Rin vivo efficacy in tumor models  leads to relapse and metastasis and thus substantially diminishes the prospects for remission or cure for cancer patients . Consequcytoplasmic delivery of cytotoxic anti-cancer agents could overcome these obstacles has been considered by several investigators (Because the well-described mechanisms of drug resistance  often intigators . These rtigators . Our labtigators . This detigators . Drug retigators . BecauseWhile this mechanism is attractive and our laboratory has now collected additional evidence for the selective delivery of the rHDL drug payload and for the endosomal escape, so far, there is no direct validation available for the hypothesis that rHDL transported therapeutic agents would be able to mediate or limit drug resistance. All indications point to the success of this approach that is likely to have ‘game-changing’ significance in the therapeutics of aggressive tumors and the management of other diseases as well.In summary, rHDL NPs are inherently capable of overcoming several biological barriers to cancer therapy. Their small size, intrinsic targeting ability, endosomal escape, demonstrated safety in animal and human studies makes this platform highly attractive for new as well as traditional chemotherapy drugs which suffer from off-target toxicity issues. Liver toxicity could be a potential concern, however, we have not come across any report showing liver toxicity of rHDL delivered drugs in murine models. Our laboratory did not find any change in liver enzymes with STAT3 targeted siRNA for ovarian cancer therapy . ClearlySR conceived the idea, wrote and coordinated all the sections in the manuscript. LM, NS, AG, AD, and AL have contributed to writing different sections and revising this manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.