Store-and-forward (SAF) teledermatology uses electronically stored information, including patient photographs and demographic information, for clinical decision-making asynchronous to the patient encounter. The integration of SAF teledermatology into clinical practice has been increasing in recent years, especially during the COVID-19 pandemic. Despite this growth, data regarding the outcomes of SAF teledermatology are limited. A key distinction among current literature involves comparing the quality and utility of images obtained by patients and trained clinicians, as these metrics may vary by the clinical expertise of the photographer.This narrative literature review aimed to characterize the outcomes of SAF teledermatology through the lens of patient- versus clinician-initiated photography and highlight important future directions for and challenges of the field.patient-initiated, patient-submitted, clinician-initiated, clinician-submitted, store-and-forward, asynchronous, remote, image, photograph, and teledermatology. Only studies published after 2001 in English were included. In total, 47 studies were identified from the PubMed electronic database and Google Scholar after omitting duplicate articles.A literature search of peer-reviewed research was performed between February and April 2021. Key search terms included Image quality and diagnostic concordance are generally lower and more variable with patient-submitted images, which may impact their decision-making utility. SAF teledermatology can improve the efficiency of and access to care when photographs are taken by either clinicians or patients. The clinical outcomes of clinician-submitted images are comparable to those of in-person visits in the few studies that have investigated these outcomes. Coinciding with the onset of the COVID-19 pandemic, asynchronous teledermatology helped minimize unnecessary in-person visits in the outpatient setting, as many uncomplicated conditions could be adequately managed remotely via images captured by patients and referring clinicians. For the inpatient setting, SAF teledermatology minimized unnecessary contact during dermatology consultations, although current studies are limited by the heterogeneity of their outcomes.In general, photographs taken by trained clinicians are higher quality and have better and more relevant diagnostic and clinical outcomes. SAF teledermatology helped clinicians avoid unnecessary physical contact with patients in the outpatient and inpatient settings during the COVID-19 pandemic. Asynchronous teledermatology will likely play a greater role in the future as SAF images become integrated into synchronous teledermatology workflows. However, the obstacles summarized in this review should be addressed before its widespread implementation into clinical practice. The role of telecommunications in clinical dermatology (teledermatology) is continually expanding as technology becomes an inextricable component of medical practice. The COVID-19 pandemic has driven it to the forefront of many dermatology practices around the world, often with rapid implementation spurred more by necessity than methodology. Teledermatology can be classified by the temporal relationship between the clinician’s decision-making and the patient encounter. Synchronous teledermatology takes the form of web-based, real-time patient visits and is outside the scope of this review. Asynchronous, or store-and-forward (SAF), teledermatology uses electronically stored information, such as patient photographs and demographic information, for medical decision-making.Data on SAF teledermatology vary considerably depending on how studies are structured. A key element of experimental setup is whether the SAF images are acquired by a trained clinician or the patient. Intuitively, variation in the quality and utility of patient-submitted images is to be expected. These characteristics may depend on whether a patient possesses a high-quality camera, their understanding of clinical photography, and their access to assistance with taking photographs—elements that are more readily available in the clinical setting. Characterizing the differences in SAF images submitted by clinicians versus patients is crucial as more health care systems integrate teledermatology consultation programs into clinical practice. Given the lack of comprehensive articles regarding this distinction, this review will explore the outcomes, consider the impacts of COVID-19, and highlight the future directions of asynchronous teledermatology based on whether photographs are taken by clinicians or patients.patient-initiated, patient-submitted, clinician-initiated, clinician-submitted, store-and-forward, asynchronous, remote, image, photograph, and teledermatology. The study designs of the identified literature included a meta-analysis, systematic reviews, randomized controlled trials, and observational studies.A narrative review of peer-reviewed literature was performed between February and April 2021 to identify articles pertaining to SAF teledermatology with clinician- and patient-initiated images. Key search terms included Only studies published after 2001 were included in the search criteria, although a substantial number of articles related to SAF teledermatology were published in the past decade. In total, 47 studies were selected from the PubMed electronic database and Google Scholar after omitting duplicate articles. Inclusion criteria consisted of articles that primarily examined the clinical aspects of SAF teledermatology, such as diagnosis, waiting intervals, change in management, clinical outcomes, and image quality. Survey studies and observational reports were also included if they primarily focused on the use of SAF teledermatology in patient care. Studies that investigated synchronous but not asynchronous teledermatology, focused on SAF teledermatology outside of patient care , and were not available in English were excluded. In total, 2 independent researchers with knowledge of study interpretation and literature review performed separate screenings of the literature and validated their search results. Several studies in this review met the exclusion criteria but were included as discussion points rather than for result interpretation.The evaluation of a photographed skin condition can be heavily influenced by its image quality. Several studies that assessed images taken by trained clinicians found that those deemed of low or poor quality ranged from approximately 5% to 20% -4. In coInterrater agreement refers to the degree to which the responses of 2 or more raters are similar . When reRecent evidence suggests that the diagnostic utility of SAF images depends on lesion type. Warshaw et al  found thCompared to clinician-initiated images, patient-initiated images have diagnostic concordance rates that are lower and more variable. Several studies indicate that diagnostic concordance rates between dermatologists evaluating patient-generated SAF images and dermatologists evaluating patients at a FTF visit range from approximately 40% to 80% ,8,16,17 Diagnoses based on SAF teledermatology images can also be compared to histopathological reports, referred to here as diagnostic accuracy. A recent study found that the diagnostic accuracy of clinician-initiated images was higher for malignant diagnoses such as melanomas and nonmelanoma skin cancers than benign diagnoses . HoweverIn summary, the rates of diagnostic concordance between SAF teledermatology and FTF clinic visits are higher and less variable when skin conditions are photographed by clinicians. Agreement can be impacted by several factors, including the practice type of the referring clinician, type of lesion being photographed, and image quality. Studies that evaluate the diagnostic outcomes of patient-initiated SAF images in a real-life setting are needed.Aside from diagnostic concordance, other outcomes that are relevant to SAF teledermatology may include change in a skin condition and waiting interval between consultation and appointment, among several others. For images taken by clinicians, outcomes appear to be generally similar between SAF teledermatology and FTF visits . A prospSeveral studies investigated the waiting intervals between initial consultation and subsequent clinic visit for clinician-initiated SAF teledermatology and traditional referral systems. They all found that SAF teledermatology significantly reduced the time between referral and clinic visit -24. One The clinical outcomes of patient-submitted images are mostly descriptive in nature. Hubiche et al  found thIn summary, outcomes such as change in condition and the quality of life between clinician-initiated SAF teledermatology and FTF care are not significantly different. However, there are a limited number of studies that examine clinically relevant outcomes, and more research is needed. Waiting intervals between SAF referral and FTF appointment are significantly decreased compared to conventional referral systems. Patient-initiated images could supplement decision-making but lack comparable outcomes to other forms of dermatologic care.One practical advantage of asynchronous teledermatology is the potential to expand health care access to underserved populations . SeveralThe COVID-19 pandemic necessitated many clinics to temporarily adopt teledermatology for all patient encounters. Although most teledermatology visits were synchronous, asynchronous visits drastically increased from prior years -35. For Several important considerations arose following the widespread adoption of teledermatology. For patients who communicated directly with their dermatologists, it was important to explore whether the circumstances that used their self-acquired SAF images were appropriate. Das et al  used patFor clinicians referring patients to dermatology, additional considerations included the triage of patients based on their skin condition and the outcomes of triage. A group in England conducted a pilot study for skin cancer referrals in which patients were triaged based on clinician-taken photographs . They foUnlike the outpatient setting, research on SAF teledermatology in the inpatient setting is limited to clinician-initiated images. Prior to the COVID-19 pandemic, data regarding asynchronous teledermatology for inpatient consultations were scarce. Barbieri et al  found thDuring the COVID-19 pandemic, the integration of asynchronous teledermatology into inpatient consultations substantially increased as dermatology departments sought to maximize patient safety by minimizing unnecessary clinical exposures . ConsequSAF teledermatology uses electronically stored information, including patient photographs and demographic information, for clinical decision-making asynchronous to the patient encounter. The integration of SAF teledermatology into clinical practice has been increasing in recent years, especially during the COVID-19 pandemic. This narrative literature review explored 47 articles by a key element of study design—whether the images were acquired by a trained clinician or the patient, as the quality and utility of the images may vary by the clinical expertise of the photographer. In general, photographs taken by trained clinicians rather than patients are higher quality and have better and more relevant diagnostic and clinical outcomes. SAF teledermatology helped clinicians avoid unnecessary physical contact with patients in the outpatient and inpatient settings during the COVID-19 pandemic.The growth and increased use of SAF teledermatology following the COVID-19 pandemic is evident. However, it remains unclear how SAF teledermatology will continue to be integrated into dermatologic practice. A cross-sectional study surveying the Association of Professors of Dermatology observed that most respondents  found the implementation of SAF images alongside video or phone calls the most feasible for teledermatology visits . Of thosSubstantial barriers must be overcome before SAF teledermatology can be implemented into standard dermatologic care across multiple systems of practice . AdherenSecure apps that combine SAF images with patient communication could streamline the delivery of teledermatology care. Such apps currently exist but may be difficult to use, lack EHR integration, or incur substantial out-of-pocket costs to patients . Kim et Furthermore, increased clinician workload and the lack of a definitive reimbursement model cause asynchronous teledermatology to be a substantial burden or gamble for many practices -56. CurrThis narrative literature review was limited by the sole inclusion of studies published in English that were available in PubMed and Google Scholar, which may have excluded other important studies not available in English or not indexed in these databases. Our review included both qualitative and quantitative studies; although both study types are valuable for learning about SAF teledermatology, quantitative outcomes may be more relevant and prognostic for health care systems considering the implementation of new SAF programs. Furthermore, many prospective studies included in this review involved motivated patient cohorts or referring clinicians who were equipped with thorough instructions. These conditions are often not representative of actual clinical practice and could have limited applicability to a real-life setting. Finally, many studies included in this review used patient cohorts with relatively small sample sizes (<100 subjects) and consequently reported descriptive outcomes or had wide variability in their data. More quantitative studies on the outcomes of SAF teledermatology with larger cohorts are needed.SAF teledermatology has a growing role in dermatology with increasingly promising diagnostic utility and clinical outcomes over the past 2 decades. Assessing SAF teledermatology by whether images are submitted by patients or clinicians can illuminate key differences in outcomes. For instance, image quality and diagnostic concordance are generally lower and more variable with patient-submitted images, which may impact their decision-making utility. SAF teledermatology can improve the efficiency of and access to care when photographs are taken by either clinicians or patients. Only the long-term clinical outcomes of clinician-submitted images have been studied, albeit to a limited extent. Amid the COVID-19 pandemic, the use and role of SAF teledermatology rapidly expanded in the inpatient and outpatient settings. For the outpatient setting, asynchronous teledermatology helped avoid FTF visits unless necessary, as many uncomplicated conditions could be managed remotely via images captured by patients and referring clinicians. For the inpatient setting, SAF teledermatology minimized unnecessary contact during dermatology consultations, although current studies are limited by the heterogeneity of their outcomes. Asynchronous teledermatology will likely play a greater role in the future, becoming incorporated into hybrid SAF and video teledermatology models. However, the obstacles summarized in this review should be addressed before its widespread implementation into clinical practice.


The change in climatic conditions is the major cause for decline in crop production worldwide. Decreasing crop productivity will further lead to increase in global hunger rate. Climate change results in environmental stress which has negative impact on plant-like deficiencies in growth, crop yield, permanent damage, or death if the plant remains in the stress conditions for prolonged period. Cold stress is one of the main abiotic stresses which have already affected the global crop production. Cold stress adversely affects the plants leading to necrosis, chlorosis, and growth retardation. Various physiological, biochemical, and molecular responses under cold stress have revealed that the cold resistance is more complex than perceived which involves multiple pathways. Like other crops, legumes are also affected by cold stress and therefore, an effective technique to mitigate cold-mediated damage is critical for long-term legume production. Earlier, crop improvement for any stress was challenging for scientific community as conventional breeding approaches like inter-specific or inter-generic hybridization had limited success in crop improvement. The availability of genome sequence, transcriptome, and proteome data provides in-depth sight into different complex mechanisms under cold stress. Identification of QTLs, genes, and proteins responsible for cold stress tolerance will help in improving or developing stress-tolerant legume crop. Cold stress can alter gene expression which further leads to increases in stress protecting metabolites to cope up the plant against the temperature fluctuations. Moreover, genetic engineering can help in development of new cold stress-tolerant varieties of legume crop. This paper provides a general insight into the “omics” approaches for cold stress in legume crops. This technique has advantage over biparental mapping as it involves study of highly diverse germplasm for identification of associated markers or candidate genes. Since last 20 years, GWAS/MTA approach has been used in various plant species to understand the mechanism of acclimatization to different stresses and to look about the genetic basis of desired traits during stress induction. In case of legumes, GWAS/MTA studies related to cold stress tolerance are limited. GWAS was conducted in white clover for identification of cold tolerance-related traits. 53 loci associated with cold tolerance traits were identified from 192 diverse germplasm collected from Patagonia region of South America. 17 of the 53 SNP trait relationships regulated several traits and were stable across many sites, according to the study carried by Inostroza and co-workers. This work was the first one to establish a QTL for cold tolerance-related phenotypes, and it revealed its genetic basis as well as prospective genomic areas for future functional validation investigations . In pea A. thaliana have been undertaken in order to decipher cold responses , and Next-Generation Sequencing (NGS) based RNA-sequencing technology were developed to obtain the transcriptome as well as identifying differentially expressed genes . The risesponses . Some hicia faba , Pisum s sativum , Arachishypogaea , Ammopipngolicus , Glycinecine max , Lotus japonicus , Vigna uipedalis , Vigna serranean , Medicag falcate , Medicago sativa , and Cicrietinum . Transcrrietinum . These crietinum  includinrietinum . TF famirietinum , WRKY , protein–protein interactions, protein accumulation, post-translational modifications (PTMs), and analysis of gene product . The posCold stress has affected soybean production by 47–63% . Differe2+-dependent signal transduction pathways associated proteins and cell division and expansion regulating proteins can be seen in roots of pea and common bean plant affected by cold stress  is a high feed crop commonly grown in different countries where winters are bitterly cold which pose a barrier to regeneration and growth of alfalfa, resulting in significant economic deficits. Enhancing alfalfa’s capacity to withstand the winter has emerged as a critical production concern. A study was performed by employing biochemical and metabolomic assays to compare the resistance against freezing in alfalfa grown under two different soil water regimes to understand how water shortage impacts tolerance against freezing stress. Water-stressed alfalfa had lower semi-lethal temperatures than the well-watered alfalfa. Under water scarce and low-temperature circumstances, the pool proportions of total soluble amino acids, sugars, and proline altered significantly. Metabolomic findings indicated 72 distinct subclasses of differential metabolites viz lipid and lipid-like molecules  and peptides, amino acids, and analogues , were highly expressed in water scarce conditions. Certain flavonoids and carbohydrates, like raffinose and D-maltose, were elevated at low temperatures. Investigations of the Kyoto Encyclopedia of Genes and Genomes indicated the existence of 18 highly enriched pathways implicated in the production and metabolism of amino acids, carbohydrates, glycerophospholipids, and unsaturated fatty acids  in susceptible ones and (29.05 vs. 19.79%) in tolerant genotypes  coding sequence has been reported in recent. Cah expression reduced cyanamide levels in soybean leaf callus and embryogenic cultures as evidenced by cyanamide resistance (Brassica campestris accumulated more methyl jasmonate (MeJA). The NTR1 gene codes a plant regulator called jasmonic acid carboxyl methyl transferase that regulates the expression of various plant defense genes against diverse challenges, such as wounding, dehydration, and infections. The transgenic soybean plants’ greater levels of MeJA provided dehydration tolerance throughout seed germination and seedling growth, as measured by the percentage of fresh weight of seedlings.Traditionally, crop development for cold tolerance by a standard breeding approach has been limited due to stress-tolerant trait complexity, absence of precise phenotyping methods, selection criteria, and little genetic diversity in the respective breeding populations . Advanceiculture . Transgeiculture  and soybiculture  show thiiculture  or that iculture , or LEA iculture , and deticulture . Both Agiculture  and particulture . Commerciculture . The trasistance . AnotherArabidopsis significantly boosted plant survival. GmTCF1a was mainly induced in response to cold stressors, and ectopic expression of GmTCF1a increased cold resistance and levels of COR15a. These findings suggest that GmTCF1a positively influences cold resistance in soybean, which may bring unique insights into cold-tolerant genetic improvements in crops , which is involved in tolerance of plant to low temperatures. Cold stress induces GmTCF1a robustly and precisely. Remarkably, higher expression of GmTCF1a ectopically in in crops . A DREB in crops .Medicago truncatula using transgenic lines overexpressing MtCTLK1 (MtCTLK1-OE). MtCTLK1-OE lines had greater cold resistance than the wild type, but MtCTLK1 lines exhibited lower cold resistance. The decreased tolerance against cold in MtCTLK1 might be compensated for the transgenic expression of MtCTLK1 or its Medicago falcata homolog MfCTLK1. Proline buildup, antioxidant enzyme activity, and transcript levels of related genes were enhanced in response to cold, with greater levels in MtCTLK1-OE lines or reduced levels in mtctlk1 lines relative to wild type  which was proved by an experiment on transgenic chickpea chloroplasts to determine the survival rate during photo inhibitory damage, and it was found that wild-type plants exposed to high light intensity lost a greater level of PS II activity than transgenic chickpea chloroplasts under the same conditions . Researct system . It is it system . Reductit system . During t system . The efft system . These renerated . To dateenerated . It has enerated . Under aenerated . Peanut sistance . Severalsistance .Global climate change has resulted in the emergence of complex stress combinations and their effects on crop yield and overall growth in modern day agriculture. Climate change is a multifaceted issue with long-term consequences in the form of many abiotic pressures. Cold tolerance is among one of those abiotic stresses with a complicated feature that results from multiple molecular interactions in an organism’s genome, transcriptome, proteome, and metabolome. Cold tolerance is stage-specific and appears as a response to cell stability toward external stimuli. Despite the fact that genomic loci influencing cold stress tolerance in plants share a degree of homology across species, the relative expression and location of protein/gene products varies with systems between species, and the context defining cold response may differ entirely. Moreover, the function of “omics” technologies in understanding cold stress tolerance in plant species is of enormous importance and immediate solicitation in elucidating new pathways behind such processes. Plants mainly undergo morphological, biochemical, and molecular changes as a result of cold stress. Although most legumes can withstand these fluctuations at low temperature but extended exposure could cause partial or complete failure of the final product. Multiple changes occur throughout the crop life cycle, from germination to harvesting, as a result of such an environment/climate. Crop plants also show a variety of biochemical and molecular manifestations under cold stress. Cold acclimation in response to the freezing stress has been studied extensively in various plants to understand the molecular and physiological status. Contrary to this a little is known about the responses in legumes for the process of deacclimation and reacclimation. Low temperature alters the gene expression of some important gene products which include the dehydrin, Cor, and CBF genes. Legumes are nutritionally as well as economically important crop species and to understand the process of acclimation during freezing or cold stress a lot of research needs to be carried out. Environmental and genotypic impacts, as well as their interactions, end up making elucidating generic responses difficult. When designing studies and evaluating acclimation, deacclimation and reacclimation reactions affecting cold stress tolerance, plant developmental stages, tissue type, and other characteristics, such as light conditions, must be taken into account. Finally, the function of “omics” technologies in understanding cold stress resistance in plant species is of enormous importance with direct solicitation in drawing out new pathways behind such a mechanism and deciphering the genes providing cold tolerance will help to solve the problem of growing seasons of the legumes and help in growing legumes in different seasons of the year. There is a greater need to investigate and concentrate on the genetic features of legumes that enables to resist cold stress effects and continue to grow and develop normally. It was improved even more by finding a wide range of genetic features and mapping them using various gene mapping approaches like QTL mapping and genome-wide association studies. Apart from that, several other osmolytes (such as glycine betaine) and plant hormones  are currently overlooked and can be more promising at regulating plant responses to cold stress using multi-omic approaches. As a result, adopting integrated multidisciplinary methodologies to investigate these gaps and open up new research vistas is urgently required.KAB, RM, MMP, and UU collected the literature and prepared the first draft. KAB and ZB helped in preparing figures. AAS, AA, and PAS helped in editing the manuscript. BB helped in revising the manuscript. AM finalized figures, tables and helped in revising the manuscript. SMZ conceive the idea, prepared the outline, and helped in finalizing manuscript and its revision. All authors contributed to the article and approved the submitted version.RM and SMZ acknowledge the support of funding agency DST KIRAN WOS-B, New Delhi, India (Vide Project Sanction Order No. DST/WOS-B/2018/832). SMZ acknowledges the support of funding agency NMHS GBPNIHESD, Almora, Uttrakhand, India (Vide Project Sanction Order No. GBPNI/NMHS17-18/SG24/622). AM was funded by the Italian Ministry for University and Research’s “Progetti di Ricerca di Rilevante Interesse Nazionale” . SMZ and AM acknowledge European Union for funding Erasmus Programme (2018–2020 and 2020–2023) that helped in interaction among the authors for preparing 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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Escherichia coli compared to benzylpenicillin. It is not known, however, how the primary amine may affect interaction with other cell envelope components. This study applied TraDIS to identify genes that affect E. coli fitness in the presence of equivalent subinhibitory concentrations of ampicillin and benzylpenicillin, with a focus on the cell envelope. Insertions that compromised the outer membrane, particularly the lipopolysaccharide layer, were found to decrease fitness under benzylpenicillin exposure, but had less effect on fitness under ampicillin treatment. These results align with expectations if benzylpenicillin is poorly able to pass through porins. Disruption of genes encoding the AcrAB-TolC efflux system were detrimental to survival under both antibiotics, but particularly ampicillin. Indeed, insertions in these genes and regulators of acrAB-tolC expression were differentially selected under ampicillin treatment to a greater extent than insertions in ompF. These results suggest that maintaining ampicillin efflux may be more significant to E. coli survival than full inhibition of OmpF-mediated uptake.Gram-negative bacteria are problematic for antibiotic development due to the low permeability of their cell envelopes. To rationally design new antibiotics capable of breaching this barrier, more information is required about the specific components of the cell envelope that prevent the passage of compounds with different physiochemical properties. Ampicillin and benzylpenicillin are β-lactam antibiotics with identical chemical structures except for a clever synthetic addition of a primary amine group in ampicillin, which promotes its accumulation in Gram-negatives. Previous work showed that ampicillin is better able to pass through the outer membrane porin OmpF in IMPORTANCE Due to the growing antibiotic resistance crisis, there is a critical need to develop new antibiotics, particularly compounds capable of targeting high-priority antibiotic-resistant Gram-negative pathogens. In order to develop new compounds capable of overcoming resistance a greater understanding of how Gram-negative bacteria are able to prevent the uptake and accumulation of many antibiotics is required. This study used a novel genome wide approach to investigate the significance of a primary amine group as a chemical feature that promotes the uptake and accumulation of compounds in the Gram-negative model organism Escherichia coli. The results support previous biochemical observations that the primary amine promotes passage through the outer membrane porin OmpF, but also highlight active efflux as a major resistance factor. Escherichia coli using a nontargeted genomic approach.Gram-negative pathogens are naturally resistant to many compounds that effectively inhibit Gram-positive bacteria due to the low intrinsic permeability of their cell envelopes, making them a high priority for new antibiotic development . The GraE. coli (Ampicillin (AMP) and benzylpenicillin (PEN) are identical except for the presence of a primary amine group in AMP that is absent in PEN , 3. The E. coli , 6. HoweE. coli K-12 strain BW25113 , constructed using a custom EzTn5 transposome according to previously described protocols , a potential target of PEN, and bamB, encoding part of the β-barrel assembly machinery (BAM) complex, highlighting the importance of β-barrel proteins in the outer membrane and/or their products for the exclusion of PEN (Genes identified as important during antibiotic exposure were classified as having a +/-≥2-fold change in mutant abundance (as measured by change in relative transposon insertion frequency) between antibiotic-treated cells and untreated controls and q-value < 0.05. There were 111 such genes following 1 μg/mL AMP treatment, 91 following 6.25 μg/mL PEN treatment, and only 2 following 1 μg/mL PEN treatment . lpoB, encoding an activator of McrB, was among the genes with the greatest decrease in insertions for either treatment. Insertions in several other genes involved in cell envelope production were also selected against by both treatments at similar levels, such as slt, which encodes a lytic transglycosylase thought to be involved in peptidoglycan quality control. Thus, many of the genes whose disruption most greatly decreased fitness under both antibiotics were either PBPs or genes that may compensate for PBP target inhibition, such as slt. The highly similar levels of selection against disruption of these genes supports the equivalence of the AMP and PEN concentrations tested.Insertions in other nonessential PBP genes such as yejM, which is implicated in lipid homeostasis; lpp, which anchors the OM to the cell wall; all genes making up the mla pathway (mlaA-F), which plays a role in maintaining LPS asymmetry; and the LPS core biosynthesis genes waaF and waaB. Although not uniquely affected, waaG and waaP were also both more negatively selected under PEN than AMP treatment. Mutations in both the waa and mla pathways compromise the OM and can significantly increase OM permeability and sensitivity to hydrophobic antibiotics like PEN . GalU is involved in the production of UDP-d-glucose, a central precursor used in the synthesis of several OM components, including LPS, and is also essential in the galactose degradation pathway. Deletion of galU results in a compromised OM, as well as reduced levels of TolC . The expression of marA is controlled by MarR in response to antibiotic and other stresses .Another transcriptional regulator, stresses , 19. Insstresses , albeit E. coli than AMP  and no significant change under PEN treatment. These results are consistent with the greater capacity of AMP to pass through OmpF compared to PEN, but suggest that under the conditions tested maintaining AMP efflux via AcrAB-TolC is more beneficial to cells than disrupting uptake via OmpF. Due to the role of OmpF in mediating the OM passage of other small molecules important to cell fitness, its inactivation may have an overall negative fitness effect. This is supported by the decreased growth rate of BW25113 ΔompF compared to wild-type . However, there is evidence of selection for reduced ompF expression via regulatory mutations, particularly under AMP selection. For example, selection against insertions in cpxR, which encodes the response regulator of the CpxR/CpxA two-component regulatory system, was observed after AMP but not PEN treatment. Phosphorylated CpxR has been shown to repress expression of ompF and so its maintenance could reduce ompF expression levels (cpxA have been shown to increase ompF expression in the presence of acetyl phosphate due to increased levels of phosphorylated CpxR (cpxR was observed under AMP, but not PEN, exposure. Further, insertions in the small RNA micF, which inhibits ompF expression (micF may also be repressed by AcrR and activated by MarA (acrR and against insertions in marA under AMP treatment. Such insertions could lead to reduced ompF expression. Therefore, there may have been stronger selection for reduced expression of ompF, rather than its complete inactivation under AMP selection.The porin OmpF has previously been shown to be important for the uptake of ampicillin into the n levels . Conversted CpxR . Selectipression , 25, wer by MarA , 27. ThiE. coli survival as inhibiting uptake. These results highlight the potential for TraDIS to guide investigations of antibiotic accumulation into Gram-negative bacteria.Previous investigations into the role of the primary amine in ampicillin accumulation in Gram-negatives have primarily focused on how this chemical feature affects compound uptake. The significance of this altered uptake efficiency in improving accumulation is supported by this study. Collectively, these results suggest that unlike PEN, compromising the LPS layer does not appear to have a drastic impact on cell survival in AMP. This is to be expected as AMP is able to enter cells through OmpF-mediated uptake. However, the potential effects of the primary amine on compound efflux and the contribution of this to changes in overall levels of accumulation have been understudied. These findings suggest that maintaining AMP efflux via AcrAB-TolC is of comparable importance to PRJNA875563.TraDIS sequence reads are available on the NCBI Sequence Read Archive and can be accessed using the NCBI BioProject accession


Non-obstructive coronary artery disease (CAD), which is defined as coronary stenosis <50%, has been increasingly recognized as an emerging entity in clinical practice. Vasomotion abnormality and coronary microvascular dysfunction are two major mechanisms contributing to the occur of angina with non-obstructive CAD. Although routine coronary functional assessment is limited due to several disadvantages, functional evaluation can help to understand the pathophysiological mechanism and/or to exclude specific etiologies. In this review, we summarized the potential mechanisms involved in ischemia with non-obstructive coronary arteries (INOCA) and myocardial infarction with non-obstructive coronary arteries (MINOCA), the two major form of non-obstructive CAD. Additionally, we reviewed currently available functional assessment indices and their use in non-obstructive CAD. Furthermore, we speculated that novel technique combined anatomic and physiologic parameters might provide more individualized therapeutic choice for patients with non-obstructive CAD. Angina with non-obstructive coronary artery (defined as lesions with <50% stenosis) has been recognized as a frequent problem encountered in clinical practice , 2. It iAlthough increasing attention have been paid to non-obstructive CAD, the mechanisms are largely unknown, and the diagnosis might be underestimated in the real world. Therefore, it is crucial to identify non-obstructive CAD to provide appropriate management strategies. Coronary functional assessment has emerged as the “golden standard” to optimize the treatment of CAD . BesidesMINOCA is a syndrome characterized by clinical signs of myocardial infarction with no remarkable stenosis (≥50%) of coronary artery on angiography. According to the latest scientific statement published by the AHA, the diagnosis of MINOCA should meet the following criteria: (1) AMI meeting the “Fourth Universal Definition of Myocardial Infarction” criteria; (2) no artery stenosis ≥50% on coronary angiography in any major epicardial vessel; (3) no specific alternate diagnosis for the acute clinical presentation .INOCA is a condition defined as cardiac ischemia in the absence of obvious obstruction of epicardial coronary artery diameter reduction ≥50%) by coronary angiography. Accordingly, ACC published a uniform definition of INOCA as follows: (1) persistent  symptoms suggesting ischemic heart disease; (2) objective evidence of myocardial ischemia from ECG or other cardiac imaging test, such as echocardiography, magnetic resonance imaging, nuclear imaging, or spectroscopy; (3) absence of flow-limiting obstruction by coronary angiography as defined by epicardial coronary artery stenosis ≥50% or fractional flow reserve <0.8 0% by cor.The potential underlying pathophysiological mechanisms for MINOCA include: (1) atherosclerotic causes of myocardial necrosis, including plaque rupture, plaque erosion, and calcific nodules, collectively referred to as plaque disruption; (2) non-atherosclerotic causes, such as epicardial coronary vasospasm, coronary microvascular dysfunction, coronary embolism/thrombosis, and spontaneous coronary artery dissection , 15.Generally, plaque disruption cannot be accurately determined or distinguished by coronary angiography, it can only be definitively diagnosed with optical coherence tomography (OCT) or, to a lesser extent, with intravascular ultrasound (IVUS) –18. NowaCoronary artery spasm refers to intense constriction (>90%) of an epicardial coronary artery and/or microvascular, leading to limited myocardial blood flow . CoronarMicrovascular dysfunction is defined as coronary microvascular (vessels <0.5 mm diameter) structural remodeling or functional dysregulation with reduced myocardial perfusion, which is characterize by impaired coronary flow reserve and abnormal coronary microvascular resistance indices . StructuCoronary embolism/thrombosis is defined as coronary artery obstruction caused by embolus and/or thrombus, which interrupt the oxygen supply to myocardial and cause myocardial infarction , 35. In Spontaneous coronary artery dissection is a non-atherosclerotic, non-traumatic cause of acute coronary event with the development of hematoma within the tunica media . It has Recently, myocardial bridging, a congenital coronary anomaly, has also been investigated and is emerging as an important player in determining MINOCA . In patiDespite many causes of MINOCA have been investigated, the exact mechanisms of MINOCA is largely unknown. We speculate that inflammation plays a vital role during MINOCA. As we known, inflammation is a major trigger of plaque rupture , inflammINOCA shares some similar pathophysiologic mechanisms with MINOCA. The most common mechanisms of INOCA are microvascular dysfunction and epicardial coronary artery spasm . The comNumerous techniques for the assessment of coronary physiologic function have been developed. Fractional flow reserve (FFR) is most widely accepted index for the physiological function evaluation of coronary disease, which is defined as the ratio between mean distal pressure and mean aortic pressure at the stage of maximal hyperemia typically stimulated by adenosine. Regadenoson, a selective A2a receptor agonist, has also been demonstrated as a viable alternative to intravenous adenosine for measuring FFR –50. FFR Nevertheless, prolonged procedural time, extra cost and inevitable wire-related complications remain big challenges to the routine use of these resting functional assessments. Therefore, quantitative flow ratio (QFR) was discovered and almost perfect successfully settled these limitations. QFR is a novel, wireless, vasodilator-free coronary functional assessment method based on computational modeling of 3-dimensional (3D) quantitative coronary angiography (QCA) and Thrombolysis in Myocardial Infarction (TIMI) frame counts . A plentangio), another method to calculate FFR just depends on angiogram with no coronary pressure wire of hyperemic agent, has also been shown to have a high diagnostic performance compared with conventional FFR , a non-invasive evaluation of CAD that provides a combined anatomic and physiologic assessment, has emerged as an alternative method to FFR for decision-making and identification of targets for revascularization in patients with extensive CAD , also known as provocation test. A positive provocation test should include three criteria: angina symptoms, ischemic ECG changes and severe vasoconstriction (>90%) of the epicardial vessel  to correctly assess the function of microvascular. IMR is calculated as the product of distal coronary pressure at maximal hyperemia multiplied by the hyperemic mean transit time . IMR ≥ 2Regardless, some disadvantages exist in both methods, such as prolonged procedural time, extra medical cost, stable injection technology needed and hyperemic medicine required, which are similar to traditionally epicardial coronary physiology evaluation devices. As a result, continuous intracoronary thermodilution and angiography-derived index of microcirculatory resistance (angio-IMR) have been discovered to overcome these limitations. Continuous intracoronary thermodilution is a novel technique to quantify absolute coronary flow (Q) and resistance (R) with a continuous infusion of saline to instead adenosine . Brieflyhyp× [L/(κ × Vdiastole)], Pdhyp is the mean pressure at the distal position when maximal hyperemia, L represents the length from the inlet to the distal position, Vdiastole is the mean flow velocity at the distal position at diastole. Recently, angio-IMR has been investigated in CAD  , myocardFor patients with persistent angina but angiographically normal or moderate stenosis with preserved iFR/FFR, guidewire-based CFR and/or IMR measurements is recommended as IIa indication to detect microvascular angina. Intracoronary provocation test is also a class IIa recommendation to identify coronary spasm in patients with non-obstructive lesions on coronary arteriography. Additionally, intracoronary injection of acetylcholine may also be considered to assess microvascular vasospasm .post-hoc analysis of patients without significant angiographically stenosis, QFR value ≤ 0.80 was showed to be strongly associated with major adverse cardiovascular and cerebrovascular events in long-term follow-up  was a strong predictor of clinical outcome among patients with MONICA, and high caIMR (>43) was an independent predictor of MACE . NonetheCMR is one of the widely used technique to assess myocardial perfusion . It alloTraditionally, provocation test is not routinely used in the context of MI due to multiple safety concerns, such as malign arrhythmias. However, prolonged vasospastic episodes can result in MINOCA and patients with coronary spasm-induced MINOCA might have a higher risk of cardiac death, recurrence of ACS and worse angina . ActuallIn fact, different pathophysiologic mechanisms might concurrently exist in the process of MINOCA, therefore, techniques simultaneously provide anatomical and functional information are of great promising. Fortunately, we now have the technique of OFR and UFR, which allow us to get the information of flow reserve, stenosis degree and plaque property at the same time. To the best of our knowledge, no studies have investigated the role of OFR or UFR in MINOCA, it might be a breakthrough to use OFR or UFR to concurrently detect the underline causes and guide the therapy of MINOCA. Furthermore, with the development of technology, the combination of QCT/IVUS with IMR or CFR might also realize in the near future. We believe that more precise therapeutic strategy would be established and applied in MINOCA with the help of more advanced coronary functional assess devices.CT), can identify truly non-obstructive CAD among those mild to moderate angiographically stenosis . Secondly, functionally assessment, including wire-based , non-wire-based (Angio-IMR and caIMR) and imaging-based  can evaluate the microcirculatory function, which is regarded as a major mechanism for non-obstructive CAD. Thirdly, with the help of provocation test, vasospastic angina can be identified and treatment targeting coronary spasm will be established. Lastly, anatomically and physiologically combined technologies (OFR and UFR) allow us to simultaneously acquire the information of lumen structure, plaque property, and flow reserve, consequently help us to further understand the underling mechanisms of non-obstructive CAD  and to develop specific therapeutic strategies.Numerous studies have demonstrated physiological indices-guided coronary intervention is superior to angiography-based strategy in patients with obstructive CAD , 111–113CT, QFR and Angio-IMR, might provide more promising and attractive utility in clinical practice. Furthermore, in the near future, the microcirculatory resistance perhaps can be assessed by CT, truly realizing the possibility of non-invasive-measured IMR. Nevertheless, it is worth to note that these  techniques are largely dependent on the imaging quality of invasive coronary angiography or computed tomography angiography (CTA). More clinical trials with larger samples and long-term follow-up are needed to investigate the validity of these novel techniques in patients with non-obstructive CAD.Despite the current guidelines recommend the use of FFR/iFR to identify non-obstructive CAD with moderate stenosis, besides, the diagnosis of INOCA is depend on the measurement of CFR, IMR, HMR and vasoreactivity test , 14. SevIn conclusion, a comprehensive functional assessment is important to identify the underlying mechanism of myocardial ischemia and consequently provide an individualized and appropriate treatment strategy.CZ and HF drafted the manuscript. YC revised the manuscript. YZ searched the literature. LS designed the study and edited the manuscript. All authors have read and approved the content of the manuscript.This research was funded by the Key Medicine Disciplines Co-construction Project of Jiaxing Municipal (Grant No. 2019-ss-xxgbx), Jiaxing Science and Technology Program (Grant No. 2021AD30060), Pioneer Innovation Team of Jiaxing Institute of Atherosclerotic Diseases (Grant No. XFCX-DMYH), and Jiaxing Key Laboratory of arteriosclerotic Diseases (Grant No. 2020-dmzdsys).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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Considerable advances in the investigation and management of oesophagogastric cancer have occurred over the last few decades. While the historically dismal prognosis associated with these diseases has improved, outcomes remain very poor. Cancer cachexia is an often neglected, yet critical, factor for this patient group. There is a persuasive argument that a lack of assessment and treatment of cachexia has limited progress in oesophagogastric cancer care. In the curative setting, the stage of the host , alongside tumour stage, has the potential to influence treatment efficacy. Phenotypical features of cachexia may decrease the survival benefit of (peri-operative) chemoradiotherapy, immunotherapy, or surgical resection in patients with potentially curative malignancy. Most patients with oesophagogastric cancer unfortunately present with disease which is not amenable, or is unlikely to respond, to these treatments. In the palliative setting, host factors can similarly impair results from systemic anti-cancer therapies, cause adverse symptoms, and reduce quality of life. To optimise treatment pathways and enhance patient outcomes, we must utilise this information during clinical decision-making. As our understanding of the genesis of cancer cachexia improves and more therapeutic options, ranging from basic (e.g. exercise and nutrition) to targeted (e.g. anti-IL1 α and anti-GDF-15), become available, there can be grounds for optimism. Cachexia can change from a hitherto neglected condition to an integral part of the oesophagogastric cancer treatment pathway. Helicobacter pylori infection are two key factors that may account for this disparity. These, and other behavioural risk factors, make it one of the most preventable major cancers worldwide. Similarly, notable differences have been observed in the geographic distribution of oesophageal cancer. While squamous cell carcinoma remains the most common histological subtype worldwide, rates of oesophageal adenocarcinoma are rising and it has now transitioned to become the predominant subtype in North America, Oceania and much of Europe [Over 1.5 million new cases of gastric and oesophageal cancer are diagnosed globally each year [f Europe .During the last 20 years, there have been significant developments in the management of patients with oesophagogastric (OG) cancer. The use of neoadjuvant therapies for patients with locally advanced disease , 4 alongCachexia is a syndrome seen in the terminal course of many chronic diseases, such as cardiac or renal failure and chronic obstructive pulmonary disease. It is, however, most frequently associated with advanced malignancy. The 2011 consensus definition described cancer cachexia as a “multifactorial syndrome characterised by an ongoing loss of skeletal muscle mass (with or without loss of fat mass) that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment” . It is aIn OG cancer, cachexia is likely to be a critical factor across pre-surgical assessment, post-surgery recovery, and in those where treatment is with non-curative intent. It can influence the efficacy of systemic anti-cancer therapy (SACT), quality of life, and ultimately survival . Herein,Several studies have attempted to quantify the prevalence of cachexia in patients with cancer. Preceding any published definitions, DeWys et al.’s 1980 paper explored weight loss across a range of cancer types in patients planned for chemotherapy, who were recruited to trials as part of the Eastern Cooperative Oncology Group . This coThroughout the world, malnutrition is all too frequently seen secondary to inadequate oral intake. Traditionally, cachexia was simply viewed as a similar nutritional issue; however, it has since become clear that the pathophysiology of disease-associated wasting is far more complex. Systemic inflammation drives malnutrition via hypermetabolism and neuro-endocrine dysfunction. Alongside inadequate oral intake and anorexia, there is elevated resting energy expenditure and increased catabolism of muscle and fat evident in cachectic patients. The resultant phenotypic changes, with depleted body stores and decreased levels of physical function, are often considered irreversible hallmark signs of impending poor clinical outcomes.Systemic inflammation is a central tenet in the cancer cachexia process. Indeed, the Evans’ et al. alternative definition of cachexia  and the The question of the key mediator(s) for cancer cachexia has eluded researchers for decades. Many candidates have been implicated but results have frequently been conflicting, and interventional studies that have targeted individual factors have been often ineffective.Interleukin-6 (IL-6) is likely to be an important marker in cancer cachexia syndrome . NumerouTumour necrosis factor alpha (TNF-α) has been shown to induce anorexia and have direct catabolic effects on both skeletal muscle and adipose tissue . The majActivin-A and Myostatin are members of the transforming growth factor beta (TGF-β) family that have been identified as potential tumour-derived catabolic factors in cachexia. Both Activin-A and Myostatin are negative growth factors for skeletal muscle; thus, their overexpression would be likely to contribute towards atrophy. Indeed, higher concentrations of Activin-A, and a positive correlation with weight loss, has been observed in patients with cancer cachexia . While aMacrophage inhibitory cytokine-1/growth differentiation factor 15 (MIC-1 / GDF15) is produced by macrophages in response to their activation and, as such, is expressed at high concentrations during inflammatory states. It has been identified as a hypothalamic modulator of appetite, thus stimulating the loss of both lean and fat mass in animal models . Plasma High levels of hypogonadism have been observed in male patients with cancer, especially in those with cachexia . It has Activation of the neuro-endocrine stress response is well-known to lead to muscle wasting in presence of systemic inflammation . It simiWhile earlier cachexia research was predominantly focussed on lean body-mass wasting, more importance is now being placed on changes to visceral and subcutaneous adipose tissue. Increased host energy expenditure necessitates the utilisation of fat stores, via lipolysis, in cancer cachexia . ProinflFunctional lipolysis may have further relevance to overall cancer cachexia pathways owing to fat-muscle “crosstalk”. Genetic ablation of adipose triglyceride lipase or hormone-sensitive lipase reduced muscle loss in mouse tumour models, suggesting that fat loss is permissive of muscle wasting . This suAlongside the primary pathophysiological changes associated with cachexia and anorexia in this OG cancer, there are several secondary factors that may further precipitate wasting. Direct mechanical or digestive issues associated with tumour burden are frequently detrimental to appetite and oral intake. By the time of diagnosis, patients will often have modified their oral intake, to mostly semi-solid food or liquids only, likely further contributing towards poor calorific content.Neoadjuvant chemotherapy is thought to have a beneficial effect on dysphagia for most patients with oesophageal cancer . The infThere is an urgent need to screen for features of the cachectic phenotype in patients with OG cancer. In a potentially curative population, the presence of such features may necessitate modification of treatment pathways or interventions to optimise underlying physiology before and after treatment. For patients with incurable disease, identification and mitigation of the cachexia process could help improve the quality and duration of their remaining life.Weight loss is one of the most frequently reported presenting symptoms in patients with OG cancer , 12. PreSarcopenia is a progressive, generalised disease of skeletal muscle. It is commonly described as an age-related loss of muscle mass and strength, with resultant decline in physical function. However, similar changes can also occur in the context of chronic disease and cachexia. Computed tomography (CT) body composition analysis has allowed researchers to assess patients more readily for sarcopenia. Many consider such objective assessments preferential to anthropometric measures owing to their lack of dependence on patient recall. Recent systematic reviews, considering both curative and palliative cohorts, have identified radiologically-evident sarcopenia as an adverse prognostic marker for survival in both gastric  and oesoThe hepatic acute phase response is stimulated by many of the same inflammatory mediators involved in the pathophysiology of cachexia. As such, laboratory measures of acute phase proteins, such as C-reactive protein (CRP) and albumin, have been used as surrogate indices of inflammation-driven catabolism . In contDespite their efficacy, the utilisation of these biomarkers in current clinical decision-making remains limited. It is likely that phenotypical evidence of cachexia could have value when considering more “borderline” treatment decisions. Further research should aim to explore where best such assessment can effectively guide treatment choices.Despite a growing understanding of cancer cachexia’s pathophysiology, there are a paucity of management strategies in current clinical practice. There is no established standard of care for cachectic patients and, apart from in Japan, there are no licenced drug therapies currently available. All too often, cachexia remains an inevitable and impervious process.A survival benefit is evident for neoadjuvant chemo(radio)therapy in locally advanced OG cancers , 4. ThesThe impact of pre-operative cachexia on patients undergoing surgical resection has been evaluated across several observational studies. Chen et al. noted its adverse prognostic impact on survival following gastrectomy, particularly in younger patient groups  and simiNutritional support is undoubtedly of value in OG cancer care. The symptomatology of the disease puts patients at high risk of poor oral intake even before considering the effects of cachexia. Contemporary guidance stresses the importance of malnutrition screening and dietary counselling in patients with cancer cachexia –74. The Enteral nutritional support is superior to parenteral, where feasible, following OG resection . In patiSeveral trials have evaluated treatments targeting mediators of cachexia. Inhibition of the systemic inflammatory response has been a particular area of interest. Pharmacological trials of TNF-α blockade have shown mixed results. Infliximab has not shown benefit, across selected outcomes, for patients with cachexia secondary to pancreatic  or lung Both Myostatin and Activin-A share a common receptor: activin-type-2-receptor B. Its antagonism represents another potential therapeutic target for cancer cachexia, with reversed muscle wasting and prolonged survival noted in cancer cachexia murine models treated in such a fashion . ResultsEnobosarm, a non-steroidal selective androgen receptor modulator (SARM), has been evaluated for its anabolic effects on muscle and bone. The POWER II randomised-controlled trial revealed significant improvements in lean body mass, function, and quality of life in older men and post-menopausal women across a number of tumour sites . The relWhile low-levels of the appetite-stimulating hormone ghrelin do not appear to be associated with cancer cachexia in human studies , ghrelinOverall, medical therapies for cachexia have shown modest efficacy in human studies. High-quality randomised-controlled-trials are still required to identify effective disease-modifying therapies.Physical exercise has the potential to improve muscle mass and function in patients with cancer cachexia; however, robust evidence is currently lacking , particuTrials of nutritional and exercise-based interventions, in isolation, for patients undergoing resection of upper GI cancer have yielded inconsistent results , 96. As


Globally, the health workforce has long suffered from labour shortages. This has been exacerbated by the workload increase caused by the COVID-19 pandemic. Major collapses in healthcare systems across the world during the peak of the pandemic led to calls for strategies to alleviate the increasing job attrition problem within the healthcare sector. This turnover may worsen given the overwhelming pressures experienced by the health workforce during the pandemic, and proactive measures should be taken to retain healthcare workers. This review aims to examine the factors affecting turnover intention among healthcare workers during the COVID-19 pandemic.A mixed studies systematic review was conducted. The PubMed, Embase, Scopus, CINAHL, Web of Science and PsycINFO databases were searched from January 2020 to March 2022. The Joanna Briggs Institute’s Critical Appraisal Tools and the Mixed Methods Appraisal Tool version 2018 were applied by two independent researchers to critically appraise the methodological quality. Findings were synthesised using a convergent integrated approach and categorised thematically.n = 35) were included in the majority of the studies, while physicians (n = 13), allied health workers (n = 11) and healthcare administrative or management staff (n = 7) were included in a smaller proportion. Five themes emerged from the data synthesis: (1) fear of COVID-19 exposure, (2) psychological responses to stress, (3) socio-demographic characteristics, (4) adverse working conditions, and (5) organisational support.Forty-three studies, including 39 quantitative, two qualitative and two mixed methods studies were included in this review. Eighteen were conducted in the Middle East, ten in the Americas, nine in the Asia–Pacific region and six in Europe. Nurses (A wide range of factors influence healthcare workers’ turnover intention in times of pandemic. Future research should be more focused on specific factors, such as working conditions or burnout, and specific vulnerable groups, including migrant healthcare workers and healthcare profession minorities, to aid policymakers in adopting strategies to support and incentivise them to retain them in their healthcare jobs.The online version contains supplementary material available at 10.1186/s12960-022-00764-7. The coronavirus disease 2019 (COVID-19) pandemic began in late 2019, with an estimated 400 000 000 infections and 6 200 000 deaths caused by the disease as of April 2022 [A major contributing factor to the shortages seen in the health workforce is employee turnover . In the High turnover rates cause difficulty in staffing healthcare facilities adequately, which has several implications on the quality of care delivered to patients. Low nurse staffing is associated with increased patient mortality rates, as low nurse-to-patient ratios result in fewer nursing care hours available for each patient. Other oWhile some factors are known, turnover is caused by multiple factors, and a fuller understanding of these factors must be pursued if employers seek to reduce turnover. A search for systematic reviews published in the last 10 years examining turnover intention among HCWs on PubMed, PROSPERO and Google Scholar produced nine relevant systematic reviews –19; noneThis review was conducted in accordance with the Joanna Briggs Institute (JBI) methodology for mixed methods systematic reviews using a convergent integrated approach .An initial search of PubMed was performed with free-text words addressing the review aims to identify relevant articles. Titles, abstracts, and keywords of these articles were analysed, which informed the development of an extensive search strategy, details of which are provided in Additional file This review included studies that contained HCWs, following the definition by the World Health Organization as an occupation group consisting of doctors, nurses, and other professionals or supporting personnel, such as pharmacists, physiotherapists, and occupational therapists, that provide health services . StudiesFollowing the search, all identified citations were collated and uploaded into EndNote 20 . Two reviewers (RP & PL) first independently screened the titles and abstracts for assessment against the inclusion criteria, followed by full-text articles. Full-text studies that did not meet the inclusion criteria were excluded. Any disagreements that arose between the two reviewers were resolved through discussion, with the assistance of a third reviewer (SL) where necessary.The JBI checklist for analytical cross-sectional studies and the JBI checklist for qualitative research were used to appraise the included quantitative and qualitative studies, respectively . The MixFull-text articles of eligible studies were retrieved and reviewed. To obtain relevant information that assisted in answering the review question, a customised data extraction template that included the origin and year of publication, study methodology and objective, occupations of participants and primary findings was used. Data was extracted independently by two reviewers (RP & PL), and any discrepancies observed were resolved through discussion with the assistance of a third reviewer (SL). Adhering to the JBI approach to mixed methods systematic reviews, a convergent integrated approach was adopted, where both quantitative and qualitative data were combined and synthesised simultaneously . QuantitA total of 1,082 articles were retrieved. After removing 631 duplicates, 451 records were screened, based on titles and abstracts. Irrelevant records were removed, and 71 full-text articles were screened based on eligibility. A total of 43 articles –68 met tn = 35) were included in a vast majority of the studies, while physicians (n = 13), allied health workers (n = 11) and healthcare administrative or management staff (n = 7) were included in a smaller proportion. Quantitative studies measured turnover intention with the Turnover Intention Scale (TIS-6) [Among the 43 included studies, there were 39 quantitative studies, two qualitative studies and two mixed methods studies. Eighteen studies were conducted in the Middle East, ten in the Americas, nine in the Asia–Pacific region and six in Europe. Nurses ( (TIS-6)  or modifians n = 3, alliedData was categorised into five themes that emerged during the extraction process: (1) fear of COVID-19 exposure, (2) psychological responses to stress, (3) socio-demographic characteristics, (4) adverse working conditions, and (5) organisational support.The most prevalent theme was fear of COVID-19 exposure, which had the greatest number of studies reporting about it. A total of 12 studies revealed a positive correlation or association between fear of COVID-19 and turnover intention. Six quantitative studies used the Fear of COVID-19 Scale (FCV-19S) as an instrument to measure the psychological impact of exposure to COVID-19 on HCWs , 42, 49,A variety of psychological responses to stress displayed by HCWs experiencing turnover intention was observed in several studies Two studies from Saudi Arabia and the United States discovered that high levels of psychological stress and anxiety were linked to HCWs exhibiting higher degrees of turnover intention , 34, whiThree studies noted that certain socio-demographic characteristics significantly influenced the likelihood of HCWs experiencing turnover intention , 51, 67.The COVID-19 pandemic placed heavy pressure on healthcare systems, resulting in excessive job demands and tumultuous work environments. Increases in workload were widely found to be positively correlated with turnover intention among HCWs , 55, 56.Several domains of organisational support were examined by studies and were found to impact turnover intention among HCWs in various ways. Organisational trust and perceived organisational support were core factors that protected nurses from increased turnover intention . Other fFindings of this study identified multiple factors influencing turnover intention among HCWs during the COVID-19 pandemic. The five emerged themes encompassed factors ranging from individual, interpersonal, job-related, and organisational determinants, and many of which were known factors prior to the pandemic –19. HoweHCWs’ fear of COVID-19 infection emerged as the most prevalent theme, especially during the initial stage of uncertainty and limited understanding of the virulence, transmission, and health management of COVID-19. Prior to the widespread deployment of vaccines, COVID-19 was potentially a life-threatening infection. Some HCWs were at high risk of exposure while tending infected patients in the face of shortages of fundamental resource, such as PPE . The posThe adverse working conditions as a result of pandemic emergency responses contribute to HCWs’ turnover intention. With the increase in patients requiring ICU care and mass testing services, HCWs faced increased workloads, higher nurse-to-patient ratios and deployment to areas requiring more staffing . In partResilience within HCWs was observed to be a vital protective factor against turnover intention, as it enabled them to better respond to the disruptions that occurred during the pandemic. Staff who exhibit resilience are able to effectively use coping skills that reduce the psychological burden of treating COVID-19 patients . HoweverSeveral studies in this review investigated different domains of organisational support. In essence, any form of organisational support that can be perceived by HCWs will empower them to adapt to the demands of their work and motivate them to perform their duties to the best of their ability . During Interestingly, this review did not identify financial renumeration as a factor contributing to turnover intention in times of the COVID-19 pandemic. Similarly, in another systematic review that identified barriers to manpower retention during health emergencies, poor leadership communication, emotional support and family worries were most commonly reported, while lacking budget in training, salaries and compensation of personnel were least reported . While iThis review also identified that certain socio-demographic characteristics were associated with turnover intention. Married nurses struggled to achieve a work–life balance, especially those with children, as the pandemic caused increased childcare needs as a result of the implementation of virtual learning during lockdowns . The incPrior to the pandemic, many countries were facing healthcare workforce shortages, and the pandemic brought added challenges for healthcare stakeholders in retaining the current workforce. Nonetheless, the pandemic has also stirred sympathy and gratitude toward the plight of HCWs among citizens, providing a crucial opportunity for policymakers to justify and commit the resources required to achieve meaningful healthcare reform . UltimatWhile it would be valuable to healthcare leaders and policymakers for identifying the significant contributing factors impacting HCWs’ turnover intention in times of pandemic crisis, it was not the intent of this review to identify the strength of relationships between them, or the changes in weighting of these factors. Some of these existing factors might have become more important or less important during the COVID-19 pandemic. Future quantitative works could examine this. Future research conducted in times of crises could also focus on specific factors, such as working conditions or burnout, to elucidate the main drivers that influence them and how to better support or incentivise HCWs to stay in their jobs. In addition, specific vulnerable population groups, e.g., migrant HCWs and healthcare profession minorities, could be examined as they may face different and unique challenges in their personal lives and lines of work, respectively. As border controls inevitably ease over time, international travel will likely return to pre-pandemic levels and researchers could also investigate global labour market trends, such as migration, when analysing data related to HCWs turnover. While the fear of COVID-19 is a pandemic-specific factor, the remaining factors identified in this review were already present before the pandemic and were exacerbated by the extreme conditions of the pandemic; it is unclear whether these factors will diminish as the pandemic wanes, and thus future research can also serve to investigate the persistence of these factors.This review captured studies conducted across a wide range of countries with different cultural and social contexts. However, it did not include grey literature and studies published in non-English languages. The methodological quality of the studies included in this review ranged from medium to high, but some studies did not account for confounding factors in their analyses, which would likely influence the reliability of their results. While the included studies focused on turnover intention instead of actual turnover, there is evidence that these are correlated . Due to In this review, we have provided an extensive overview of factors contributing to turnover intention among HCWs during the COVID-19 pandemic. Although it is unclear if some of the pandemic-specific factors identified will diminish over time as the pandemic ebbs, our findings highlighted the importance of acknowledging and addressing these factors to prevent further aggravation of the turnover issue. In the wake of the overwhelming pressures experienced by the health workforce in the past 2 years, this turnover may worsen, and proactive measures should be taken to retain HCWs. Future research should be more focused on specific factors, such as working conditions or burnout, and specific vulnerable groups, including migrant HCWs and healthcare profession minorities, to aid policymakers in adopting strategies to support them and incentivise them to retain them in their healthcare jobs.Additional file 1. Detailed search strategy for all databases.Additional file 2. Quality appraisal of included studies.


The roots of exercise physiology date back into antiquity, when Susruta (about 600 B.C.) in India was likely the first physician to prescribe moderate daily exercise, and Hippocrates (460–370 B.C.) in Greece was the first to provide a written exercise prescription, and Galen (129–210 A.D.) recommended to include regular physical activity in the management of avoiding illness . While pPart of the current scope of research in exercise physiology is represented by 11 papers contributing to the Research Topic “Insights in Exercise Physiology: 2021,” from different areas.It is widely accepted that opportunely dosed exercise has the potential to treat chronic cardiovascular diseases, including coronary artery disease (CAD), heart failure, and hypertension but several open issues remain on the mechanisms underlying the cardiac and vascular benefits, the optimization and individualization of exercise type, intensity, and duration, and the identification of the limiting factors of the exercise tolerance in patients. Overall, studies published in the present Research Topic shed new light onto some important aspects of the field including the vascular response to exercise in the presence of heart failure/CAD and the role of innovative rehabilitation approaches in cardiopathic patients.Mannozzi et al.). The findings indicate that the already challenged orthostatic and exercise tolerance is impaired by the enhanced ventricular-vascular uncoupling during baroreceptor unloading, negatively affecting exercise tolerance and quality of life in heart failure patients .Mannozzi and colleagues examined whether baroreflex dysfunction in heart failure exacerbated ventricular-vascular uncoupling at rest, and during exercise in response to baroreceptor unloading by performing bilateral carotid occlusions in chronically instrumented conscious canines . Simultaneous real-time ultrasound image and blood flow of the carotid artery showed that all exercise intensities across all modalities resulted in turbulent blood flow. However, endothelial shear stress (ESS) was greatest during treadmill at a high intensity, while bench press and biceps curls yielded the least ESS .Montalvo and colleagues evaluated exercise-induced blood flow patterns in the carotid artery during various types of exercise  at 3 different intensities  .Fanget and colleagues proved tele-rehabilitation as effective and safe alternative for cardiac rehabilitation during the COVID-19 period, suggesting this approach also to be used to facilitate the continuity of care for patients unable to participate in center-based cardiac rehabilitation . Additional IMT resulted in a decrease of the apnea-hypopnea index in those patients.Labeix and colleagues demonstrated benefits of a specific inspiratory muscle training (IMT) during cardiac rehabilitation of patients suffering from coronary artery disease with moderate obstructive sleep apnea . Single leg training was performed over 6 weeks. Cross-sectional area of the vastus lateralis muscle was only increased after HV, but HL improved leg extensor strength more than HV . Biochemical assays revealed that integrated non-myofibrillar protein synthesis rates were higher in HV compared to HL.Vann and colleagues studied the effects of higher-load (HL) versus (lower-load) higher-volume (HV) resistance training on skeletal muscle hypertrophy, strength, and muscle-level molecular adaptations in young men . The authors demonstrated some interesting relationships between miRNAs and exercise responses, e.g., baseline miR-23a predicted VO2peak response to training.Witvrouwen and colleagues evaluated changes in plasma-derived miRNAs by acute and chronic exercise in heart failure with reduced ejection fraction (HFrEF) in order to assess whether these can mechanistically be involved in the variability of exercise-induced adaptations . The authors demonstrated (as previously shown for constitutive Cyp-D ablation) that acute Cyp-D ablation also induces a state of increased O2 utilization efficiency, associated with a metabolic switch toward preferential utilization of glucose via AMPK-TBC1D1 signaling nexus .Radhakrishnan and colleagues investigated whether acute cyclophilin-D (Cyp-D) ablation, using tamoxifen-induced ROSA26-Cre-mediated, would downregulate oxygen consumption and trigger an adaptive response that manifests in higher exercise efficiency in conditional knockout mice . The authors discuss existing knowledge on the relationships between female hormones, musculoskeletal properties, neurophysiological changes and the risk to suffer from an injury. They also emphasize that a multitude of questions need to be answered, several contradictions to be solved, and several correlations to be explained (Legerlotz and Nobis).In the present RT, Kirsten Legerlotz and Tina Nobis comprehensively dealt with the complexity regarding effects of fluctuating female hormones on the Injury risk in women . The authors found a 28% greater Achilles tendon stiffness in physically active twins compared to their inactive twin. Furthermore, they found sport-specific adaptations, i.e., by demonstrating that the stiffness of tendons responded more to exercise activities with an “aerial phase” such as running and jumping .Sichting and colleagues performed an explorative cross-sectional study in 40 identical twin pairs, investigating the effects of regular recreational exercise activities on Achilles tendon mechanical properties  starting from the day before the marathon until 192 h after completing the race. Recovery effects were investigated under 3 different conditions: total rest (REST), continuous running at their ventilatory threshold 1 (VT1) intensity (RUN), and elliptical workout at their VT1 intensity (ELLIPTICAL). Unexpectedly, the ELLIPTICAL group showed a significantly lower glomerular filtration rate compared to the RUN and the REST group.The known changes in climatic and environmental conditions, also related to the extreme diffusion of pollutants and increased average temperature, on the one hand, and the increasing outdoor sports practice on a large scale, on the other, require great attention to the physiological aspects of adaptations to exercise carried out in critical conditions, both in acute and chronic settings. The study of these interactions represents a major research challenge for the future, with fundamental predictable social implications.You et al. explored potential effects on health when physical exercise (PE) is combined with exposure to air pollution (AP), by applying cluster, co-citation, and co-occurrence analysis using CiteSpace and VOSviewer software . The research distribution, major topics, and relevant hotspots of the PE-AP field have been described by the knowledge-map strategy. At least with regard to the respiratory system, the first barrier of the body to defense against air pollutants, the benefits of exercise might be offset under AP conditions. Finally, the authors highlight a couple of research questions that should be considered by future studies .In the present RT, Exercise physiology amazes for the enormous variety of research fields, each of which has a direct potential impact on the human’s quality of life.trait d’union is the intrinsic value of exercise in determining a plethora of physiological adaptations whose impact depend on the actual conditions and objectives.Despite this heterogeneity a From the role of polypill to fundamental determinant of the athletic performance, exercise represents a field of extreme interest, with transversal entanglements in the various scientific disciplines, from engineering to medical fields, and in its multidisciplinary nature is its beauty.This will ensure that research in this area will not find moments of stalemate or reduction of interest on the part of those who dedicate their lives to research.


A broad array of molecular and cellular events is associated with developing resistance to treatment, such as deregulation of the cell cycle, inhibition of DNA damage repair mechanisms, and metabolic alterations. Most cancer therapy-induced responses, including resistance, involve the dysfunction of mitochondria. Mitochondria have acquired numerous functions throughout evolution, controlling energy production, cellular metabolism, cell survival, apoptosis and autophagy within host cells. Tumor cells can develop defects in mitochondrial function, presenting a potential strategy for designing selective anticancer therapies. However, non-specific targeting of mitochondrial functions may have significant unwarranted effects on normal cell growth and survival. Therefore, treatments conjugated with other anticancer therapy are needed to precisely target specific mitochondrial proteins involved in tumor progression and the acquisition of treatment resistance.In the present Research Topic, we have garnered several contributors to provide evidence‐informed insights into the mechanistic and pathogenic role of mitochondrial proteins to support the discovery of novel therapeutic targets for directed mitochondrial treatment and eventually facilitating enablers of knowledge translation. After a rigorous peer-review process, seven articles have been collected, consisting of two comprehensive review and five original research articles. Notably, these articles were contributed by renowned academic institutes from North America, Europe and Asia engaged in mitochondria-based biology and translational research, demonstrating the great interest in this hot area.Ippolito et al. outlined several crucial functions of mitochondrial redox activity in different cancer stages by elaborating effects of mitochondrial ROS (mROS) on tumor initiation, progression, energy metabolism, stemness achievement, metastases and tumor immune environment. They also explored the impact of mROS on treatment response in cancer, such as tumor chemosensitivity. Because mitochondrial redox homeostasis crucially regulates cancer cell behavior and several cancer hallmarks, the authors also attempted to outline the potential redox-based targeted therapeutic strategies, either single or combined modality. It is worth mentioning that two new mROS-targeted treatments, photothermal and photodynamic therapy, have rendered their effectiveness in curing and preventing cancer. Criscuolo et al. reviewed the available literature on the coordinated regulation of mitochondrial and cytosolic mRNA translation, as well as their effects on the integrity of the mitochondrial proteome and functions. The purpose of this review paper is to highlight the importance of mitochondrial protein quality control systems in coordinating mitochondrial and cytosolic protein translation. More than that, this critical review also hints that mitochondrial protein homeostasis dysfunctions are tightly associated with cancer development, and thus the most relevant therapeutics hold great promises as anticancer strategies.Cancer cells exhibit metabolic plasticity that endows them with a selective advantage to face harsh microenvironmental alterations and orchestrate nutrient sensing and upload, signaling, and redox circuits. The finely tuned reactive oxygen species (ROS) generation and scavenging within a certain sub-toxic tumorigenic range are two aspects fundamental to cancer cells as ROS mediate cell signaling to significantly impact a wide range of pathways involved in cancer development and progression. That is the reason why ROS have recently become an attractive target for anticancer therapies. Panina et al.). Among these drug pairs, IACS-010759/vinorelbine impaired ATP level and disrupted mitochondrial respiration and coupling efficiency most profoundly, which also retained high synergy and strong selectivity in primary AML cells. This study supports the potential of mitochondria-based drug cocktails for future therapeutic development and optimization and reinforces the value of this approach.Mitochondrial dependency of leukemia cells and their altered oxidative metabolism have already been explored as a common abnormality existing in acute myeloid leukemia (AML). Accumulating evidence suggests that AML may be particularly sensitive to chemotherapeutics that target mitochondria. To further investigate this sensitivity, a research group at Rice University screened 36 drug combinations randomly paired one of six mitochondria-targeting compounds  with one of six compounds with other activities  in two AML cell lines . Mechanistically, downregulation of MIEF2 impaired mitochondrial stability and suppressed cytochrome C-dependent apoptosis, and eventually enhanced colorectal cancer cell resistance to OXL. These novel findings suggest that MIEF2 represents a predictive biomarker of OXL responsiveness and targeting it could improve chemotherapeutic effectiveness in colorectal cancer. In the same type of cancer, TRIAP1, a chaperone interacting with the Ups/PRELI family proteins, participates in the intramitochondrial transfer of lipids to synthesize cardiolipin and phosphatidylethanolamine. Nedara et al. reported that depletion of TRIAP1 induced extramitochondrial perturbations, leading to remarkable changes in the endoplasmic reticulum-dependent lipid homeostasis and induction of a p53-mediated stress response. This depletion also conferred strong p53-dependent resistance to the metabolic stress mediated by glutamine deprivation. Another original research collected in this Research Topic shows that mitochondrial morphology and dynamics are altered during ovarian cancer progression and upon aggregation . In this study, the researchers utilized the mouse ovarian surface epithelial (MOSE) model for serous ovarian cancer and analyzed the morphological and functional changes that occur during the progression from benign (MOSE-E), to slow (MOSE-L) and fast-developing disease (MOSE-LTICv), and in response to aggregation and hypoxia. The resulting findings gain new insight into how the alterations in mitochondrial morphology contribute to the survival of aggregates in the non-permissive environment of the peritoneal cavity during metastasis.Interestingly, by performing genome-wide CRISPR/Cas9 library knockdown screening, a Chinese research team identified that mitochondrial elongation factor 2 (MIEF2) was among the top candidate genes in oxaliplatin (OXL) resistant cell lines  and constructed a classifier containing 10 mitochondrial-related genes (Mito-RGs) for predicting the prognosis of HCC. The results from bioinformatics reveal cross-talk between metabolic processes governing bile acid and the infiltration of tumors by immune cells, providing an innovative strategy for HCC metabolic therapy based on the modulation of mitochondrial function.Mitochondria are the powerhouse of the cell, while the liver is the center of human metabolism at the whole organism. Thus, identifying mitochondria localized proteins as prognostic biomarkers for hepatocellular carcinoma (HCC) will be interesting. Although mitochondrial oncology has been known for much longer than 20 years, the field has experienced a resurgence of interest in the past decade. We understand that a large proportion of this journal’s readers are basic and clinical cancer researchers and as such wanted to give them a bigger voice in the journal’s content. Beyond cancer, mitochondrial defects are often the underlying cause of other diseases. The articles within our collection add new value to the development of mechanism-informed therapeutic strategies that place the organelle as a promising target.The author confirms being the sole contributor of this work and has approved it for publication.