Poor sleep quality is a common problem and has profound physical and mental effects on older adults. Loneliness, another common and harmful condition for older adults, is associated with heightened levels of vigilance and feeling unsafe, which may contribute to poor sleep. Although some studies show that trait loneliness is related to compromised sleep, there are few studies examining whether and how day-to-day variations in loneliness relate to sleep quality. The current study aimed to examine within- and between-person associations of loneliness and daily self-rated sleep quality using ecological momentary assessment (EMA) approach. Community-dwelling participants , 56% white) reported loneliness and self-rated sleep quality during a 14-day EMA study via mobile phones. Trait loneliness was measured once prior to EMA. Unexpectedly, multilevel modeling showed that the amount of loneliness experienced on a given day did not predict sleep quality, however lower levels of prior night sleep quality predicted elevated levels of loneliness (p < .01). Regarding the between-person association, individual differences in trait loneliness were not related to sleep quality, but differences in average levels of EMA loneliness were related to sleep quality, such that people who felt higher levels of loneliness on average during the 14 days reported worse quality of sleep during that time period than others (p < .0001). These results suggest that worse sleep quality may be a factor that increases loneliness, and may not be a consequence of loneliness. Potential benefits of using EMA loneliness in research of daily sleep quality in older adults will be discussed.


Aging is an inexorable event occurring universally for all organisms characterized by the progressive loss of cell function. However, less is known about the key events occurring inside the nucleus in the process of aging. The advent of chromosome capture techniques and extensive modern sequencing technologies have illuminated a rather dynamic structure of chromatin inside the nucleus. As cells advance along their life cycle, chromatin condensation states alter which leads to a different epigenetic landscape, correlated with modified gene expression. The exact factors mediating these changes in the chromatin structure and function remain elusive in the context of aging cells. The accumulation of DNA damage, reactive oxygen species and loss of genomic integrity as cells cease to divide can contribute to a tumor stimulating environment. In this review, we focus on genomic and epigenomic changes occurring in an aged cell which can contribute to age-related tumor formation. The mystery of who we are, why we are here, why we age, and die has intrigued the human intellect, spanning art, literature, music, religion, and even the earliest experimental science. For instance, in ancient Egypt, incantations from funerary scrolls of the Book of the Dead dating around 2,323 B.C.E–2,291 B.C.E. were typically painted on the ceiling of tombs with the hope that it would protect and resurrect the deceased in a vividly imagined afterlife. In ancient Mayan culture, the Popul Vuh, one of the last codices to survive the erstwhile Spanish invasion of Mexico, details a cycle of life, death, and eventual resurrection. In the modern scientific era, however, a long-sought-after goal has been to retard or even reverse human aging, by trying to decipher its molecular basis and use chemicals to block or reverse phenotypes associated with aging. This is no trivial feat, as aging is now understood to be a multifactorial process manifested by the gradual decline of physiological functions from the organ all the way down to the cellular, possibly even the molecular level. The phenomenon of functional loss is seen in almost all living organisms ranging from unicellular to multicellular organisms . To gainLifespan varies tremendously among species ranging from a few hours (bacteria) to thousands of years (sea sponges)  Figure . This obE. coli, the budding yeast Saccharomyces cerevisiae or the Caulobacter crescentus which undergo asymmetric cell division demonstrate a progressive decline in reproductive potential  resulting in a c-terminal truncated version of the prelamin A called the progerin (lamin A gene found in HGPS (G608G) activates a cryptic RNA splice donor site, causing an internal deletion of 50 amino acids from prelamin A. This truncated, farnesylated prelamin A variant (progerin) fails to undergo cleavage resulting in accumulation in HGPS patients  indicate reduction in Stem Loop Binding Protein (SLBP), which is an important factor regulating histone mRNA stability . Genes eDespite several studies supporting the general hypothesis of canonical histone degradation over age, there are some contradicting reports that merit closer examination. A recent study in mice tissues obtained from different time points of the mouse lifespan reanalyzed histone H3 occupancy genome wide . Their rCollectively, these studies signify the chromatin regulation through histone variants or their post translational modifications. Are these genomic sites specific, or do they vary in a cell type or tissue specific manner? How does this replacement affect the chromatin structure at the localized sites? Does replacement of canonical histones with their corresponding variants have implications in mediating long range interactions across the genome? It is interesting to consider how an eroding chromatin landscape is rewired in an aged cell, and whether this impacts gene expression.Striking nuclear structures associated with aging are senescence associated heterochromatin foci (SAHF) . SeveralOne could speculate that SAHF might be enriched with histone variants. It is indeed found that macroH2A is associated with the facultative heterochromatin region (H3K9me2) of SAHF  indicatiin vitro  are the largest source of sequence variation in a DNA sequence among individuals. SNPs act as chromosomal tags and can be used for variations that may be involved in a human disease or disorder. SNP profiling of an individual’s genome helps to study the mechanisms of the aging process as well. Nevertheless, studies showed that mitochondrial DNA (mtDNA) SNPs of individuals reaching a long life, such as the centenarians, are different from that at a younger age . A longeThus, it is evident that accumulation of mutational events that increase in age could be strongly correlated with gender, ethnicity and ancestorial background. As senescence sets in, the system’s capacity to remove cells carrying altered genotypes is hampered resulting in pathophysiological conditions. Genetic mosaicism arises when balanced or imbalanced chromosomal aberrations such as deletion or duplication occur as cells divide . These aWhy do aged cells accumulate mutations? One approach to address this seemingly straightforward question is to compare closely related short- and long-lived animals. A study comparing long-lived and short-lived bats revealed that two genes involved in mismatch repair (MSH2 and MLH1) were significantly reduced in short-lived bats compared to the long-lived ones . This inApart from the DNA lesions and variations, cellular senescence can be triggered through other mechanisms. An important factor is telomere attrition which is evolutionarily conserved . TelomerThe progressive decline of physiological functions during aging results in various pathological conditions including cancer . AlthougThe progressive buildup of DNA damage and mutations are prime drivers of both cancer and aging . ExtensiAdult stem cells after acquiring enough mutations, epigenetic alterations, depart from the proliferative pool  Figure . This phChemically induced senescence can be promoted by anti-cancer drugs such as aphidicolin, bleomycin, cisplatin, doxorubicin, etoposide, mitoxantrone, retinols, hydroxyurea, carboplatin combined with docetaxel, and many others . This cavia autocrine and paracrine pathways , characterized by an overproduction of a variety of chemokines, growth factors , cytokines along with several extracellular matrix constituents and remodeling proteins . Apart from causing major chronic inflammation, SASP also act pathways . This enpathways , MMP-1 hpathways . Replicapathways . Aged hupathways    but lackWe posit that analyzing the biophysical and mechanical nature of aged chromatin polymer in different cell types might provide clues to its natural decay and dysfunction. Despite current technological challenges, even elucidating the half-life or turnover of chromatin factors, including post-translational modifications of nucleosomes, repair factors, chromatin remodelers could be an important start. Knowing these parameters, we can better understand and potentially model how the nuclear landscape changes as cells age. How do these different half-lives impact protein-complex composition and functional stability of transcriptionally active and inactive regions of the genome? Genomic regions which exhibit distinct functions such as promoter, enhancers, and constitutive heterochromatin are marked by the presence of histone PTMs . Ideally, established histone PTMs are maintained to continue the faithful expression of tissue-specific genes. Rare and unconventional PTMs, such as glypiation, neddylation, siderophorylation, AMPylation, and cholesterolysation, are expected to accumulate in senescent cells, purely by change, or chance, acting as driver epi-mutations. These PTMs influence protein structure and function . DNA dam“Four things do not come back: the spoken word, the sped arrow, the past life, and the neglected opportunity.” Billionaire Trekkie space pioneers compete with each other, to boldly go where no human has gone before, in the hopes of terraforming distant planets. Examining how human lifespan and aging impacts our potential for exploration is now no longer in the arena of futuristic sci-fi, but an opportunity for nano-exploration rooted firmly to our species’ survival on this planet.Finally, the study of aging needs to be expanded from murine/human cells to that of long-lived whales, termites or even plants which live for hundreds of years. These species may provide unanticipated and novel mechanisms of aging and rejuvenation  that hav


Editorial on the Research TopicOptimization strategies for pain management with neuromodulationChronic pain is a high-priority global health issue due to its high prevalence, impact on quality of life, and cost . In mostNeuromodulatory interventions are promising management options that target maladaptive neuroplasticity, which has been associated with chronic pain conditions . TechniqUnder this scenario, one potential solution is to systematically optimize these interventions, including treatment protocols, biomarkers, and delivery models, inducing a shift from a pathway of “sustaining innovation” to “disruptive innovation” . AccordiThis research topic aimed to gather original research and reviews illustrating the recent advances in this optimization pathway. To provide a broader context for the studies, we propose a framework for “disruptive pain neuromodulation” , where wDaSilva et al. proposed and developed a new approach for excitatory stimulation targeting bilateral primary motor cortices that could potentially expand its therapeutic effect to more global pain relief. The authors reported computational models to compare brain current flow for current laboratory-based unilateral and bilateral motor cortex stimulations with a functional home-based prototype. They discussed the promising concept of bilateral excitatory motor cortex stimulation which can be focal and home-based. Considering our framework, this study is related to three of our proposed domains: the use of digital health framework (home-based treatment), bioengineering development (user-centered design of prototype), and applied data science .Thomas et al. addressed an optimization question of transcutaneous electrical nerve stimulation (TENS) for migraine using computational modeling techniques. The authors developed the first-ever model TENS model for migraine that will support advances, from the exploration of additional electrode designs, considering individual anatomy, and study the extent of variation in current flow. They also found that a extended V-shaped with greater contact separation design has potential advantages but requires further clinical validation.Additionally, Deblieck et al. used computational models in a different scenario, the safety of concomitant use of more than one neuromodulatory technique. In a 54-year-old woman with an implanted spinal cord stimulation (SCS) system for another pain syndrome, high definition tDCS was initiated for refractory neuropathic pain. The authors reported a notable decrease in pain perception, lasting for approximately 5–6 h with no reported adverse events. The stimulation parameters and clinical efficacy of the SCS system remained unchanged. The computational model indicated no meaningful alteration of current flow. These two studies represent the tremendous utility of computational models (the use of applied data science methods in our framework) for parameters optimization and even to confirm the safety of combined protocols.Similarly, Diaz et al. proposed the development of composite pain biomarkers. The authors reviewed current literature on the taxonomy of pain biomarkers and their utilities as pain-related indicators that can help in the diagnosis, treatment, and prognosis of chronic pain. Including physiological non-imaging and imaging biomarkers. Besides, Diaz et al. presented multiple analytic approaches that have been used in the field. The authors highlighted the use of artificial intelligence methods and the integration of multiple types of assessments for the creation of composite biomarkers. This study is an excellent example of the biomarkers optimization for pain neuromodulation using applied data science methods and network-based approaches.Furthermore, Castelo-Branco et al. reported interesting insights on two different protocols of pain temporal summation (phasic and tonic) in fibromyalgia subjects, and the associations between these biomarkers and other clinical variables. The result suggests that phasic and tonic protocols are not correlated and could index different neural responses in FM subjects. The authors recommend further studies with larger sample sizes to clarify their results. Likewise, this is an example on how biomarkers optimization is needed to potentially differentiate specific pain phenotypes.Finally, In summary, we believe our proposed four domains and the articles presented here can guide the ongoing optimization of pain neuromodulation. The next generation of neuromodulation devices should therefore provide neuromodulation therapies that could offer rapid acute relief in an easy-to-use manner, thus increasing user's acceptability. The articles presented in this research topic thus provide valuable information and examples of different developmental pathways for optimizing these techniques and harnessing a potentially disruptive innovation highly needed in chronic pain management.


Headucate: University of East Anglia, a university student-led society, was founded almost 10 years ago by medical students to promote mental health education and raise awareness and funds for mental health causes.Headucate aims to spread mental health awareness and reduce stigma by working with schools, universities, other societies and charities internationally.Headucate delivers workshops for children aged 4-18 in primary and secondary schools, community and youth groups and university students. These sessions were delivered in-person pre-COVID and online as interactive webinars since 2020, to spark discussion around mental health, and provide information about the variety of supports available for young people.In the past decade, Headucate UEA has grown to become one of UEA’s largest student-led groups boasting over 175 members in 2020-2021 from all courses. Within the online world, Headucate’s events have reached worldwide. The initiative has received national recognition, won national student awards and has expanded to set up three further Headucate branches nationwide. Outreach has accelerated and the school workshops reached over 1,000 students in the past year.Headucate has grown from strength to strength and has plans to continue to develop, with passionate student drivers behind the project. Expansion of the project could include a national mental health university directory, bringing together like-minded mental health advocate students around the country and creating new Headucate branches across the country. To further develop, Headucate could expand outreach to the elderly community as discussed by previous committee.No significant relationships.


This rapid review sought to understand the use of telehealth in earlyparenthood programmes sharing similarities with the Family NursePartnership.A rapid review protocol was developed in accordance with Cochrane RapidReviews Methods Guidance. Medline, Cochrane Library, and CINAHL databaseswere searched. Inclusion criteria were developed using population,intervention, comparator, outcome, study design, and timeframe components.Two reviewers searched, screened, and extracted data. AMSTAR was used forcritical appraisal. Results were synthesised narratively.acceptability andaccessibility; therapeutic relationships;flexibility offered by telehealth;participation and engagement; confidentialityand privacy; equipment and technicalconsiderations; and training and support.Searches yielded 18 studies out of 881 for inclusion. Findings wereidentified across seven domains: Telehealth provides unique opportunities to improve access to early yearshealth services for young mothers. However, considerable accessibilitybarriers remain in the form of connectivity issues, access to appropriatetechnology, and the acceptability of remote healthcare delivery. This reviewpresents a timely overview of the opportunities and challenges associatedwith the use of telehealth in early parenthood and family-basedprogrammes. Telehealth refers to the remote provision of healthcare through avariety of telecommunication tools, such as telephones, smartphones, and mobilewireless devices, with or without video.In the context of COVID-19, many changes have been implemented at an unprecedentedpace and scale to ensure the provision of continuous care and essential services.Such an example includes the rapid digital transformation of complex maternal andchild health home visiting programmes, such as the Family Nurse Partnership (FNP),to incorporate the widespread use of telehealth to enable safe and continuousservice provision during the pandemic.13 In comparison,less is known about the long-term impacts of telehealth being incorporated morewidely into specialist home visiting programmes. Following an extensive review,Totten et al.3identified maternal health as one of the three main areas where telehealth use wasdeemed to be appropriate but significantly under represented by research evidence.More recent studies have also noted a trend of limited telehealth evidence for homevisiting programmes and have highlighted a need to demonstrate the use and impact oftelehealth technologies in these contexts.5A rapidly growing evidence base has charted the use of telehealth in relation to avariety of clinical conditions and health outcomes prior to and during the COVID-19pandemic. Most available evidence relates to the use of telehealth in the treatmentand management of conditions such as cardiovascular disease, diabetes, mental healthconditions (e.g. depression and anxiety), smoking cessation and substance abusesupport, physical rehabilitation, post-operative care, and various chronicconditions such as hypertension, chronic-obstructive pulmonary disorder, and kidneyfailure.The purpose of this review was to inform the use of telehealth in FNP servicedelivery in Scotland during COVID-19. In the absence of FNP-specific evidence, thereview draws on relevant findings from intervention types and population groupssharing similarities with key FNP programme components, service user populations,and practitioner characteristics.6The FNP is specifically tailored to provide support during early parenthood toimprove outcomes for young first-time mothers and their children. The programmesupports young mothers to engage in preventative health practices, responsivecaregiving, positive parenting practices, and the development of self-efficacy toform and achieve goals for the future and improve economicself-sufficiency.710 The FNP is an intensive,one-to-one programme delivered by specially trained nurses in a home visiting formatand is designed to support young first-time mothers and their children.11 Following itsinception in the US, the FNP has been trialled and adapted internationally. Theprogramme has been adopted by three of the four UK nations  and isrun at a national level within each of these healthcare systems. FNP shares severalcommonalities with UK-based health visiting services, in that it targets new mothersand pre-school children and upholds the principles of early intervention andprevention.The license-based FNP was originally developed through a body of research that beganin 1977 and incorporated three US-based randomised trials.13 Youngfirst-time mothers are a vulnerable population group with varied and complex needsthat can be wide ranging across domains such as social issues, health, housing, andwelfare.14 Analysis of pre-enrolment data of clients’ experiences prior toenrolment in FNP in Scotland showed that 98% of FNP clients experienced a form oftrauma or adverse experience prior to entering the programme.6 Amongst a rangeof complexities and challenges recorded in clients’ lives, 88% of clients wereestimated to have at least one socioeconomic disadvantage, such as having a lowincome (60%), poor job stability (10%), and not being in education, training oremployment at the time of enrolment (67%). The analysis also showed that 28% ofclients had experienced homelessness and 28% were recorded as living in poor orunsuitable housing upon enrolment. Additionally, family nurses recorded that 75% ofclients had health issues when entering into the programme, with 63% experiencingmental health issues, namely anxiety disorders.Evidence shows that early parenthood is associated with social disadvantage, as wellas poor health and well-being outcomes for both the mother and the child.15 Due to the essential natureof FNP and transformations taking place to ensure the delivery of care in responseto COVID-19 this review sought to gain an understanding of telehealth implementationin this context and any associated impacts.During the onset of the COVID-19 outbreak, guidance published by the ScottishGovernment in April 2020 stated that the FNP programme ‘provides an essentialservice to the clients and children enrolled on the programme. Families willcontinue to need the support of FNP and, in fact, will likely need their connectionto their FNP nurse more than ever’.1619The aim of the rapid review was to summarise a range of evidence relating to theimpacts of telehealth and the implications of this in the context of FNP and othersimilar home visiting programmes. In this review, early years home visitinginterventions refer to specialist programmes designed to support parents and theirchildren with a range of social and health-related needs that primarily feature anin-home delivery format between families and a trained practitioner. Alongside thetargeted FNP model, similar home visiting programmes include universal healthvisiting services delivered across the four UK nations and the large-scale US-basedMaternal, Infant, and Early Childhood Home Visiting programme.20 which defines a rapid review as ‘a form of knowledge synthesisthat accelerates the process of conducting a traditional systematic review throughstreamlining or omitting specific methods to produce evidence for stakeholders in aresource-efficient manner’.21 The review was designed to provide stakeholders anddecision-makers in Scotland with timely results to support changes to FNP servicedelivery in response to the COVID-19 outbreak.The review protocol follows the Cochrane Rapid Reviews Methods Group InterimGuidance,The research question was developed in consultation with key stakeholdersrepresenting the FNP National Clinical Team and policy officers in the ScottishGovernment. The review question, search strategy, and eligibility criteria weresubsequently refined and agreed upon following the input of the abovestakeholders.20 To increase relevance the review team agreed to conduct limitedand targeted searches to include recent primary studies (from 2020 to 2021) and greyliterature holding direct relevance to the intervention of study and/or the emergingcontext of COVID-19.Priority was given to the inclusion of review-based study designs  to provide the highest level of availableevidence.What are the potential impacts of telehealth service delivery in the context ofearly parenthood programmes such as the FNP?Population, intervention, comparator, outcome, study design and timeframe/otherlimits (PICOST) eligibility criteria were established a priori.Healthcare practitioners delivering a programme of care using modes oftelehealth and/or relevant client groups receiving care via telehealth wereeligible. Client population groups relating to young females, mothers,parents of young children, and families were of particular interest. Lessrelevant population groups were excluded, such as older or predominantlymale groups as well as studies focussing primarily on highly specificclinical populations or the treatment of specific chronic conditions .Telehealth interventions delivered by healthcare practitioners to serviceusers/clients that hold contextual relevance to the FNP programme wereincluded. Examples of eligible interventions with relevance to the FNPincluded home visiting programmes, parenting programmes, child andfamily-based health promotion interventions, pre- and post-natal care,sexual and reproductive health interventions, and mental healthinterventions. Interventions had to include at least one telehealthcomponent such as telephone calls, SMS, video-conference calls, use ofspecialist video consultation software (e.g. NearMe and Attend Anywhere),emails, or another online web-based mode (e.g. WhatsApp messaging).Interventions also had to include continuous or ongoing telehealthinteractions and as such, studies with singular or one-off interactions wereexcluded. Service user/client–practitioner and practitioner–practitionerinteractions via telehealth were all eligible for inclusion.Studies with and without comparator groups were eligible for inclusion.Continuity of care and carerImpact of telehealth on client–practitioner relationshipsPractitioner and client satisfactionAcceptanceAccessibilityEngagementModes of delivery Geographical considerationsTraining and educationImpact of telehealth on clinical observationsOutcomes relating to the following areas were considered: Reviews , primary studies and grey literature holding directrelevance to the intervention of study and/or the emerging context ofCOVID-19 were eligible for inclusion.Abstracts must include one or more terms relating to the intervention andoutcomes/areas of interest. Only reviews published in the English languagefrom 2005 to 2021 were eligible. Additionally, only studies with relevanceto high-income settings were eligible for inclusion. Studies relating onlyto low- and middle-income countries were excluded.Databases searched included Medline, the Cochrane Library, and CINAHL. Allsearches were conducted between 26 August 2020 and 21 September 2021.Supplementary file 1 for full search strategy). The searchwas limited to sources published from 2005 onwards. The same search strategywas used for all databases.Search terms were developed based on the PICOST formulation for population,intervention, outcomes, and study design, as outlined in Covidence software. Two reviewers (KMand TH) blind screened papers independently at all stages of the screeningprocess with disagreements being resolved by further discussion with allauthors.All results were screened based on the eligibility criteria, usingTwo reviewers (KM and TH) conducted title and abstract screening based on theinclusion of key terms in the title or abstract and relevancy to the topic.Once both reviewers had completed the initial screening, conflicts wereresolved through discussion with all reviewers, and sources were moved tofull-text screening.Full-text articles were also screened by two reviewers (KM and TH). Onereviewer (KM) also screened all excluded full-text articles before dataextraction occurred.Data extraction was undertaken and cross-checked by two reviewers (KM andTH). A predefined data extraction form was used to gather informationregarding the purpose of each study, the populations, interventions,outcomes, results, and risk of bias and any limitations were documented. Onereviewer (KM) checked the extracted data for correctness andcompleteness.22 AMSTAR is frequently used in rapid reviews as itallows for the assessment of both qualitative and quantitative study designsas well as data heterogeneity. One reviewer (TH) assessed the quality ofeach review using the AMSTAR tool. A second reviewer (KM) then verified andcross-checked results.Quality assessment was conducted using the AMSTAR appraisal tool forsystematic reviews.Supplementary sources were identified via limited and targeted searching ofkey databases and Google Scholar to include recent (<1 year fromSeptember 2020) primary studies holding direct relevance to the researchquestions and emerging context of COVID-19. Key references and FNP programmedocuments were also provided by the stakeholders to enhance the relevancy ofthe review.Quality assessment for supplementary sources was limited within theconstraints of a rapid review. The risk of bias and quality assessment wasbased on validity, self-reported limitations by study authors, andjudgements made by the reviewers.All evidence was thematically categorised and synthesised narratively. Ourgoal was to find commonalities across studies and group these into themes ofinterest based on the aim of the review.Supplementary file 2. The identification, eligibilityassessment, and exclusion of sources are illustrated in A total of 881 records were identified from database searching and 18 studiesfulfilled all inclusion criteria. The review findings are summarised andpresented in n = 11), scoping reviews (n = 4), qualitativeevidence syntheses (n = 2), and narrative review(n = 1). With regard to the study quality of the reviewsincluded, two were deemed high quality, six were of a moderate quality, and 10were considered low quality.Included review types were classified as systematic reviews.39Seven studies examined therapeutic relationships and connections betweenclients and healthcare practitioners. Therapeutic relationships are anessential aspect of FNP and similar home visiting programmes. It is atrusting relationship built between a client and practitioners that seeks tosupport learning, emotional development, and positive behaviour change inclients.41 and one primarystudy27 reported that telehealth had a slight degree ofpositive impact on client–provider relationships by providing opportunitiesfor regular support and connectedness, as well as additional flexibility andconvenience about how and when clients were able to engage with apractitioner.41 Practitioners feltthat options for mobile phone communication strengthened relationships withclients and provided clients with opportunities to initiate engagement withtheir practitioners which demonstrated clients being able to take moreownership over their health.40 One review found thatstudies comparing the effectiveness of telehealth with in-person programmesshowed greater positive effects for face-to-face interventions, in terms ofeffecting behaviour change.42Findings concerning the overall impact of telehealth on therapeuticrelationships were nuanced. No significant positive or negative associationswere evident, yet some studies highlighted the importance of face-to-facecontact between clients and providers when establishing and maintainingrelationships. Three reviews41 Over time, however,many of these women considered online therapeutic relationships to becomparable with face-to-face delivery, allowing effective working alliances,an important aspect of therapeutic relationships, to form between them andtheir healthcare providers.41 However, someparticipants felt that therapeutic relationships were less close andpersonal in the absence of face-to-face contact. One review also reportedthat telehealth helped to establish continuity of care for service users inthe community beyond traditional care settings.30One review found that women seeking therapy for depression were initiallysceptical about developing therapeutic relationships with healthcareproviders using telehealth.43 Three reviewsreported that it took more time for healthcare providers to build rapportwith service users virtually and that telehealth clients experienced moredistant and less personal therapeutic relationships overall. In someinstances, this led to the provision of additional face-to-face contact toservice users.41Reduced opportunities for face-to-face contact had a negative impact on jobsatisfaction among nurses who felt that delivering care via telehealthchallenged relationships with clients.27 Women were reportedto prefer the use of telehealth in blended, or hybrid, programme models,viewing telehealth as complementary to in-person care rather than as astandalone method, compared with men.42One supplementary study argued that mixed-model delivery, utilisingtelehealth in addition to in-person care, was important and allowedpractitioners and service users to experience both good levels of personalengagement and the convenience of telehealth.40 reported that telehealth allowed healthcare workers totake up new tasks, work flexibly, and effectively reach clients inhard-to-reach areas. Telehealth was appreciated when it improved factorssuch as feedback, speed, workflow, travel time, and the efficiency ofcare.44 However, some studies reported that usingtelehealth contributed to additional workloads overall.45Eight reviews emphasised benefits relating to the flexibility conferred bytelehealth in healthcare settings and for individual service users. Odendaalet al.24 Similarly, femaleusers were attracted to the flexibility offered by telehealth allowing themto control their engagement with healthcare more widely at a time, pace, andsetting of their choosing.41 Unlike in-homevisits, service users felt less pressure to prepare their homes for visitorsprior to arrival, eliminating some of the stress associated withthis.44 Telehealth also provided convenience to mothers whofaced challenges accessing in-person where barriers such as transportation,location, or weather conditions impeded their ability to travel.32Young people tended to prefer SMS (text messaging) and software apps oversynchronous technologies  as they granted moreautonomy and allowed them to engage with services in their own time, whichcould feel less intrusive.41 identified that somewomen viewed the flexibility offered by telehealth as a barrier toengagement as it created a reduced sense of obligation and motivation toattend appointments compared to face-to-face appointments. Nordtug etal.44 discussed the importance of remote contacts beingscheduled in advance and clearly identifying who should initiate contact,when, how often, and where, to encourage engagement and appointmentattendance.In contrast, Verhoeks et al.37 pilot feasibilitystudy explored the delivery of home-based parenting programmes viatelehealth and identified that the most common reasons for enrolling in theonline programme were convenience, privacy, and word of mouth.Nine reviews and one supplementary source presented findings relating toparticipation and engagement. Traube et al.'s42Two studies identified an association between the duration of an interventionand participation. Shorter interventions were associated with greaterpositive outcomes for service users and their children compared to longerinterventions requiring prolonged commitment which created significantobstacles for socially disadvantaged families who are more likely to beexperiencing additional stressors and time constraints.41Telehealth programmes tailored to meet individual's needs were found toenhance factors such as intrinsic motivation and engagement. A systematicreview exploring women's expectations and experience regarding e-healthprogrammes found that practitioners played a key role in ensuring thatprogrammes felt personalised to individuals highlighting that this was a keydeterminant towards minimising barriers to engagement and increasingmotivation.26 While studies suggest that individuals living withmental health conditions reported higher levels of acceptance towardstelehealth interventions,46 higher rates ofattrition were also reported within these population groups.46 Incontrast, Hanach et al.38 found that completionrates were slightly higher for women suffering from postpartum depressionusing telehealth compared with those using in-person interventions. Thesestudies indicate that the type or severity of a mental health condition maydetermine the degree to which an individual is able to participate intelehealth interventions. Both reviews found that these findings werecompounded by factors such as a lack of prompting or guidance which couldcontribute to service users feeling unsupported.Participation and retention rates were also enhanced when telehealthinterventions were based on relevant behaviour change theories and whenintervention outcomes were aligned closely with the programmecontent.40In terms of staff participation and engagement, some healthcare workersappreciated being more connected to colleagues via telehealth, believingthat this improved coordination and quality of care for serviceusers.47 conducted a review of19 randomised controlled trials that assessed the effectiveness of mobiletechnologies in the management of care and found that most trials reported areduction in time between the presentation and management of a health issuewhen practitioners were communicating with specialists via mobiletechnologies. This has the potential to facilitate preventative carepractices such as early identification, timely referral, and earlyintervention for parents and children requiring care or support.Gonçalves-Bradley et al.29Five reviews explored confidentiality and privacy concerns relating to theuse of telehealth. Clients at risk of social stigmatisation ordiscrimination  expressed concerns around the maintenance of privacy andconfidentiality during telehealth consultations including the consequencesof any breaches or disclosures that could occur as a result of receivingdigital healthcare.45 Busier open settingsfor telehealth consultations, such as nurses’ stations created concernsamong clients regarding privacy and confidentiality.45 Incontrast, service users with the ability to control their own environmentfor video calls found that this positively influenced their sense of privacyand confidentiality.44The use of telehealth was influenced by the environmental setting of both theclient and the provider.24 Theuse of mobile phones offered users personal space, allowing for an increasedsense of autonomy, control, and self-esteem. While recognising theadvantages of mobile phone usage, the authors reported that 29% of studiesreported confidentiality and privacy to be the most common concern amongtelehealth users. In particular, the loss of a mobile phone was thought tobe a serious privacy concern.One study found that mobile phone calls provided service users with adequateprivacy to support sensitive therapeutic activities.29 Odendaal etal.40 noted that healthcare providers had a strongawareness of the importance to protect client confidentiality when usingmobile devices.Privacy and confidentiality concerns were also identified as a barrier toacceptability.43 Limited internet and mobile network connectivityamongst users was a common barrier, particularly in the use ofvideoconferencing.24 Whilst video qualityhas significantly improved over time, issues such as spoiled video feeds arestill deemed to be an issue.44 Human interaction andpotential for errors are also of relevance here, for example, ensuring anetwork signal is appropriately on or off.44 Addressing resourcedisparities relating to factors such as inadequate internet speeds anddevice ownership were viewed as key elements to overcome for equitabletelehealth participation.31Four reviews and one supplementary source presented findings related toequipment and technical considerations. Experiencing technological problemshad a negative impact on the acceptance of telehealth by front-linestaff.48Owen27 also found that peer-led upskilling of cliniciansin the use of video calls resulted in increased knowledge, skills, andcomfort with using these technologies. Low levels of technologicalconfidence and training in practitioners were identified as a significantbarrier to the implementation of telehealth interventions.31Findings around training and support were identified within five reviews andone supplementary source. Access to training and support positivelyinfluences each of the outcome areas presented in this review. Access totelehealth training and support led to more acceptance and positiveattitudes towards the use of telehealth amongst healthcare staff.44In terms of service users, one review highlighted that while someinterventions are user-friendly, providing service users with informationand guidance on the use of a telehealth platform and signpostingtechnological support and assistance positively influences uptake andengagement.This review presents key factors that can influence the impact of telehealth and laythe landscape for understanding where important barriers and facilitators maylie.6 This is linked to the large-scale use of devices such asmobile phones and tablets amongst the client age group (24 years and under),user-friendly telehealth technologies, opportunities to overcome geographicalbarriers, and opportunities for client groups to engage more conveniently andflexibly with services while managing responsibilities relating to caregiving,education, training, and employment.Overall, the findings suggest that telehealth can provide unique opportunities toimprove access for young mothers and parents to engage with early years services.The findings also suggest that telehealth interventions can provide improvedhealthcare access for vulnerable population groups such as young people, pregnantwomen, first-time mothers, women living with mental health conditions, women withfewer resources, and migrant groups, that share many characteristics with FNP clientpopulations.49 and NHS Digitalguide,50 digital inclusion is subject to overcoming initial barriersrelating to access, connectivity, skills, confidence, and motivation beforeaddressing secondary barriers relating to design, awareness, and the capabilityand/or capacity of healthcare staff. Our findings correlate closely with many ofthese factors and should be given deliberation in this regard.In accordance with the UK Government digital strategyIndividual and socioeconomic circumstances are influential to the uptake andacceptance of telehealth and should be taken into consideration when introducingtelehealth in place of in-person care for young parents and families. Greateracceptance of telehealth is seen when the intervention is tailored towardsindividuals and feels personal. For healthcare practitioners, acceptance appears tobe highest when the intervention is user-friendly and good levels of training,resources, and support are provided from the outset. Considerable accessibilitybarriers for both clients and practitioners remain in the form of connectivityissues, access to adequate technology, the costs of receiving and sending SMSmessages or calls, and low levels of training.51Across the UK it is estimated that 22% of the population do not have the necessaryessential digital skills required for everyday life.52 Aside from age, thepopulation sub-groups most likely to be digitally excluded include lower income andunemployed groups; people living in social housing; people living with disabilities;people with fewer educational qualifications; early school leavers; people living inrural areas; and people whose first language is not English.50 In terms ofsociodemographic markers, early parenthood is likely to be inter-linked with thesub-groups most at risk of digital exclusion and as such, decision-makers andpractitioners should make informed judgements regarding the use of telehealth withtheir client groups.While factors such as high device ownership are typically reported in younger agegroups, findings from the COVID-19 pandemic highlighted the pervasive extent ofdigital exclusion and inequalities experienced by young people and families livingin the UK.51 suggested that a key factorin addressing this is to identify citizens who are ‘limited’ users of digitalsystems and avoid ‘one size fits all’ or ‘technology-led’ approaches if the skillsand needs of the target population are not aligned with this.Digital exclusion therefore encompasses a breadth of issues that can limit engagementfor multiple population groups. This presents profound consequences for someindividuals’ abilities to engage with employment, education, and healthcareservices. Interventions with central digital engagement components should thereforeseek to measure and monitor digital inequalities among various population groups toensure equitable service provision. Yates53 In terms of healthcare alone, 58% of participants reportedan improvement in their ability to access healthcare services after receivingsupport from Connecting Scotland.54 Investments such as these areintegral to addressing digital exclusion by providing families with the ability tointeract with a range of essential services, including those with telehealthcomponents.Where resource disparities or limited digital skills are a factor, programmes such asConnecting Scotland that received large-scale government investment to directlytarget digital exclusion have demonstrated positive impact by providing devices,support and connectivity options to vulnerable and low-income households during theCOVID-19 pandemic.High acceptability rates also appeared to be closely linked with intervention designand were positively influenced by the inclusion of behaviour change theories, whichhelped to maintain engagement. The engagement was largely determined by factorsrelating to programme delivery and accessibility where more supportive and hands-onprogrammes produced higher levels of engagement overall, particularly among femaletelehealth users. Healthcare practitioners also play a key role in encouraging andsustaining engagement levels.Technical considerations play a significant role in the delivery of telehealth andcan act as a barrier to uptake. Common problems include poor network access, a lackof technical knowledge or confidence, and limited support availability. Reviewshighlighted that access to appropriate, user-friendly equipment and technologies wasa key factor in the utilisation of telehealth interventions.While there is limited evidence to suggest whether a lack of face-to-face interactionsignificantly impacts on users’ acceptability of telehealth, some evidence pointedto preferences for hybrid delivery models that offer opportunities for face-to-faceinteraction in addition to telehealth contacts. Blended intervention types,utilising telehealth alongside face-to-face encounters could be a widely acceptableand successful form of intervention delivery. There is recognition that hybridisedmodels provide services with the benefits of extended reach, widened access, andconvenience while retaining more personal forms of face-to-face engagement,relationship building, and observation that cannot be achieved digitally.11 Adopting a hybrid approach,offering telehealth as a supplementary element of care, could help to build a strongpositive relationship between clients and providers whilst mitigating some of thebarriers posed by virtual interactions.Telehealth interactions were rated similarly or comparably to in-person care in anumber of reviews. However, some findings indicate that rapport and relationshipbuilding takes longer to develop virtually compared with face-to-face settings.Given that the FNP service is a home visiting programme based on mentorship anddeveloping a strong therapeutic relationship between nurses and clients, this is animportant aspect to consider in terms of clients’ abilities to achieve programmegoals and effect positive changes in their lives.Some reviews identified that telehealth tools enabled more connection amongsthealthcare colleagues and improved the coordination and quality of care for clients.Other studies highlighted that some practitioners expressed preferences forface-to-face interactions, citing frustrations with a lack of, or even hostilecommunication, occurring via virtual platforms. It is important for serviceproviders to consider offering flexible arrangements for practitioners based onoverall levels of satisfaction and their ability to use telehealth technologiesremotely or in a professional setting. Staff should be comfortable in their workingenvironment and be able to communicate well with colleagues to provide the bestquality of care for service users. Service providers should aim to regularly reviewvirtual and hybrid team-working structures in tandem with in-person workingpractices to minimise exclusion.There was consensus among studies that telehealth interventions could affordhealthcare providers and service users opportunities for flexibility, autonomy,convenience, and efficiency. However, the findings also suggest that maintaining alevel of structure and punctuality when scheduling telehealth appointments couldwork to ensure higher attendance levels and help to manage staff time moreeffectively.56 Some studies identified that a practitioner's work environmentcan negatively influence a service user's level of comfort and desire to disclosepersonal information during a consultation. Busy office or clinical settings where aclient is aware of other people in the background or where there is a perceived lackof privacy can have a significant negative impact on their experience with ahealthcare provider. Home-working and virtual communication requirements implementeddue to the COVID-19 pandemic may have also elicited similar concerns regarding therisk of occupants in a practitioner's home overhearing sensitive information.Increased use of telehealth may also prevent more vulnerable service users fromaccessing safe spaces where confidential disclosures can be made to a practitioner.Service users may also hold concerns about communicating sensitive informationvirtually to their healthcare providers.Addressing client and practitioner concerns around privacy and confidentiality ishighly important when using telehealth. Concerns may be particularly acute for womenseeking support for stigmatised issues , which could create a sense of unease between aservice user and provider.Healthcare practitioners should pay close attention to a client's privacy environmentand ensure that alternative provisions can be made. Good levels of organisationalsupport should be in place to ensure that rigorous standards of data protection,information governance, and confidentiality can be maintained by staff usingtelehealth.At an organisational level, secure, regularly updated software and devices should beavailable for practitioners and appropriate support channels should be in place forpractitioners and service users. It is also recommended that organisations provideappropriate and private on-site spaces for staff to conduct telehealthconsultations. Regular training should also be available to ensure that appropriateprivacy and confidentiality standards and safe working practices can be maintainedin clinical and home-working settings.Access to training and support for healthcare providers using telehealth are vitalfactors for successful implementation and delivery and were found to be a keydeterminant of acceptability. Access to sufficient training in relevant technologiespositively impacted staff and client experiences during telehealth consultations.Upskilling staff can also increase capacity and career development opportunities forhealth professionals, who are likely to experience expedited transformation oftraditional healthcare to online settings in the near future.The review also highlights the delicate interplays between the opportunities that maybe afforded by telehealth and the need to consider the complex needs andvulnerabilities present in client populations such as those enrolling into FNP.While there may be unique opportunities to expand service access, telehealth isunlikely to provide a ‘one-size fits all’ solution for all service users, especiallythose with complex vulnerabilities. Professional judgement therefore should be atthe heart of decision-making to ensure that clients are being engaged with in themost appropriate and supportive manner. For some, this may involve increasedtelehealth interactions that allow flexibility, convenience and control for clientsto engage with programmes more autonomously. For others, face-to-face contact may beessential if clients are uncomfortable with virtual engagement, or if there arechallenges associated with digital access .The review has several limitations. However, the rigorous process of multiplereviewers searching, blind screening, and cross-checking is likely to reducethese limitations.20 to ensure a manageable volume of results for screeningin a timely manner. Due to these constraints, it is possible that a proportionof relevant literature may have been overlooked that would otherwise have beencaptured by a more thorough systematic review process. For example, theexclusion of studies from low-income countries means that the review has notcaptured findings from lower-resource and culturally diverse settings that couldhold additional key lessons for telehealth delivery across a variety of contextsand population sub-groups. We would encourage researchers undertaking a fulltraditional systematic review to explore evidence from a range of settings withmixed resource and skill availability to draw transferable lessons andgeneralisable findings appropriate for diverse global contexts.The search strategy sought to capture a breadth of related intervention types andcontexts of interest, however, the list of terminology used is not exhaustive.Search limits were put into place, in line with rapid review methodologyguidance,The review is also limited by the temporality of the phenomenon. Most reviewsincluded were published prior to the COVID-19 pandemic, and thus may not fullyrepresent the current reality of telehealth implementation in programmes such asthe FNP. Findings from older studies may also be limited due to the pace andscale of digital transformation and enhancements that have occurred generally inrecent years. Supplementary primary studies relevant to COVID-19 were includedto contextualise the findings in recognition of a unique situation, however,inclusion of these studies is far from comprehensive. While rapid implementationof telehealth has taken place in response to COVID-19, we hope many of theretrospective findings presented here will continue to retain contextualrelevance for future implementation.Relevant findings from different intervention types, settings, and populationssharing similarities with home visiting programmes such as FNP have beenpresented here. Findings therefore may not be fully representative of thecurrent experiences of practitioners and clients specifically involved in FNP asthe extent of telehealth utilisation and delivery modes will vary according tovarious programmes, locations, and client vulnerability. Most included studiespresented findings from international contexts out with Scotland and the UK sosome cultural and organisational differences may also exist in terms ofpopulation needs, challenges, and service provision.This rapid review highlights opportunities and disadvantages of incorporatingtelehealth into early parenthood programmes such as FNP. Notably, the evidencehighlights examples of telehealth improving access for key population sub-groupsinclusive of young people, pregnant women, first-time mothers, women living withmental health conditions, and women with fewer resources and migrant groups.Acceptance of telehealth in client groups is enhanced when interventions aretailored or personalised towards individuals. For practitioners, acceptance isimproved when interventions are user-friendly and accompanied by high levels oftraining and support.The overall success of telehealth interventions in home visiting programmes willlikely be determined by their design and implementation strategy. Interventions thathave a strong grounding in behaviour change theories, such as FNP, are also morelikely to yield higher levels of engagement and impact. Hybrid models were alsopositively regarded, providing a means for the benefits of in-person interactions,such as relationship and rapport building to be realised with those of telehealth.Technical issues, including limited connectivity and access to devices, comprise someof the biggest barriers to successful uptake. Decision-makers should be mindful ofmitigating and minimising digital exclusion amongst service users by providingadequate support, information, and exercising professional judgement around theappropriateness of virtual engagement for various clients.Maintaining high standards of privacy and confidentiality is of vital considerationwhen planning to use telehealth. Clients may have complex concerns and practitionersshould seek to identify and address these from an early stage. Practitioners shouldbe well supported by strong levels of organisational support and training to ensurethat rigorous standards of data protection, privacy, and confidentiality can beadhered to.These findings are timely in response to the rapid implementation and expansion oftelehealth during COVID-19 and it is hoped that these can be taken intoconsideration to support the implementation and sustainability of telehealth tosupport families in this context. Further research is required to understandbarriers and facilitators specific to telehealth implementation in home visitingprogrammes and to explore the sustainability and impact of incorporating telehealthmore widely into these services.Click here for additional data file.Supplemental material, sj-docx-1-dhj-10.1177_20552076221123711 for Understandingthe use of telehealth in the context of the Family Nurse Partnership and otherearly years home visiting programmes: A rapid review by Kathleen Morrison,Thomas Hughes and Lawrence Doi in Digital HealthClick here for additional data file.Supplemental material, sj-docx-2-dhj-10.1177_20552076221123711 for Understandingthe use of telehealth in the context of the Family Nurse Partnership and otherearly years home visiting programmes: A rapid review by Kathleen Morrison,Thomas Hughes and Lawrence Doi in Digital HealthClick here for additional data file.Supplemental material, sj-docx-3-dhj-10.1177_20552076221123711 for Understandingthe use of telehealth in the context of the Family Nurse Partnership and otherearly years home visiting programmes: A rapid review by Kathleen Morrison,Thomas Hughes and Lawrence Doi in Digital Health


The antimicrobial resistance (AMR) crisis from bacterial pathogens is frequently emerging and rapidly disseminated during the sustained antimicrobial exposure in human-dominated communities, posing a compelling threat as one of the biggest challenges in humans. The frequent incidences of some common but untreatable infections unfold the public health catastrophe that antimicrobial-resistant pathogens have outpaced the available countermeasures, now explicitly amplified during the COVID-19 pandemic. Nowadays, biotechnology and machine learning advancements help create more fundamental knowledge of distinct spatiotemporal dynamics in AMR bacterial adaptation and evolutionary processes. Integrated with reliable diagnostic tools and powerful analytic approaches, a collaborative and systematic surveillance platform with high accuracy and predictability should be established and implemented, which is not just for an effective controlling strategy on AMR but also for protecting the longevity of valuable antimicrobials currently and in the future. The increasing prevalence of antimicrobial resistance (AMR) among bacterial pathogens poses one of the greatest threats to public health all over the world , mainly To identify common AMR and guide diagnostics and effective treatment for bacterial infections, a gold-standard laboratory test used to determine the antimicrobial sensitivity of AMR organisms, termed antimicrobial susceptibility tests (AST), has been adopted in clinics for over 50 years. Traditional AST involves broth microdilution and disc diffusion on agar to determine the minimum inhibitory concentration (MIC). The MIC value indicates the lowest concentration of antibiotics where bacterial growth stops, and the growth level is usually measured by absorbance or light scattering. Before and during testing, multiple turnarounds of culturing the bacteria in the sample and isolating colonies and growth needed to be accomplished before AST. The whole pipeline takes at least 48 h, which usually provides the results after using an empirical prescription of antibiotics that might be misused. It has been estimated that around one-fifth of prescribed antibiotics from 2013 to 2015 were inappropriate in the United Kingdom . Also, cPseudomonas aeruginosa exhibit high plasticity of resistance phenotype driven by environmental changes  for AMR diagnosing has been considered an efficient avenue for combating AMR . The gen changes . Overall changes . AMR bacThe COVID-19 pandemic has seriously affected global efforts against AMR , magnifyYersinia pestis  by determining the cellular fluorescence intensity owing to antibiotic-caused membrane damage and the resulting uptake of propidium iodide or rose Bengal , aacA-aphD (aminoglycoside resistance), tetK, tetM (tetracycline resistance), erm(A), erm(C) (macrolide-lincosamide-streptogramin B resistance), vat(A), vat(B), and vat(C) (streptogramin A resistance) , AMR genes , and even could detect cancer mutations with attomolar sensitivity and single-base mismatch specificity  or RT-PCR , microflistance) . With thn 25 min ; 10 copiated SNP ; the majar assay . The twocificity . This CRo copies  and idenrm genes . Curti ehttps://joinarmada.org/), a nonprofit global organization combatting superbugs with a database of bacterial genomes, has been established to create a specific “criminal database” of AMR pathogens, collecting an unprecedented amount of bacterial strains and details of their antibiotic resistance profiles, genetic identity and epidemiology from a global network of hospitals, veterinarians, scientists, and other advocates. WGS emerges as a powerful tool for understanding the genetic makeup of bacteria AMR. As the high-throughput sequencing technology developed in the mid-2000 s, it can illustrate a landscape of the whole resistome in a couple of days with a sophisticated downstream bioinformatic pipeline . The newLearning essential characteristics directly from the data of genomic sequences, machine learning obviates the need for prior knowledge of resistant strains caused by unknown mechanisms. It has been proven valuable for predicting AMR with an unbiased method . Unlike S. aureus  were selected to determine the susceptibility by performing quantitative RT-PCR, and the results are consistent with MIC values. in situ hybridization and immunofluorescence tests to locate and quantify the mRNA and protein existence of the TEM β-lactamase, conferring ampicillin resistance in the E. coli. Campylobacter jejuni and analyzed the data in the Comprehensive Antibiotic Resistance Database for AMR detection. It was found that both genomic and proteomic approaches can identify molecular determinants responsible for resistance to tetracycline and ciprofloxacin, in line with their phenotypes. These methods require several steps and analyses, which are more suitable for basic research, but not feasible for the field application. For rapid RNA detection, the RNA-targeting CRISPR-associated enzyme Cas13a directly binds to the target RNA and releases the positive signal (The DNA-based method only detects the existence of these potential resistance DNA traits without providing information regarding efficient transcription, expression, and antimicrobial susceptibility. The feedback in bacterial transcriptome and proteome to antibiotics exposure offers real-time dynamic information of relevant genes. Their expression change in mRNA and protein levels is endowed with key diagnostic values for AMR detection. Some efforts have also been made in transcriptome and proteome, but remain limited. e signal . Combinee signal . In clinA comprehensive analysis has suggested more factors to make more precision diagnostics and informed preclinical decisions . To dealFrom the clinical perspective, the priority is confirming whether antimicrobial therapies are needed in a particular case; the second is which drug is suitable for an optimized treatment if a bacterial infection is already present. Apparently, the most clinical urgency for patients and physicians is not knowing which bacteria is resistant to what antimicrobial but determining which narrow-spectrum drug can eliminate the pathogen. Most diagnostic methods aim to identify drug-resistant determinants of superbugs, but few studies explored if there are any drug-susceptible determinants or other multi-omics traits in AMR strains. These drug-susceptible feature data can be used for model training in machine learning, and molecular-based assays can detect drug-susceptible markers directly. More innovative efforts are needed in this area in the future.In the coming decade, advancements in technical and computational tools for multi-omics approaches are continually improving knowledge regarding the diverse AMR mechanisms and integrating a deep mechanistic understanding of AMR determinants with a broader systematic analysis of microorganisms. The ultimate goal will lead to a revolutionary change in AMR diagnostics, significantly guiding the surveillance of AMR threats and finally slowing down the rising crisis.


Extrachromosomal circular DNA (eccDNA) is a double-stranded DNA molecule found in various organisms, including humans. In the past few decades, the research on eccDNA has mainly focused on cancers and their associated diseases. Advancements in modern omics technologies have reinvigorated research on eccDNA and shed light on the role of these molecules in a range of diseases and normal cell phenotypes. In this review, we first summarize the formation of eccDNA and its modes of action in eukaryotic cells. We then outline eccDNA as a disease biomarker and reveal its regulatory mechanism. We finally discuss the future prospects of eccDNA, including basic research and clinical application. Thus, with the deepening of understanding and exploration of eccDNAs, they hold great promise in future biomedical research and clinical translational application. In 1965, Alix Bassel and Yasuo Hotta first reported their discovery of extrachromosomal circular DNA (eccDNA) in boar sperm and wheat embryos . Due to eccDNA has been identified in microorganisms, plants, model organisms, and human cells. eccDNAs are often categorized into small polydispersed circular DNA (spcDNA) , episomes (submicroscopic size range), microDNA (200–3000 bp), telomeric circles (t-circles) , double minutes (DMs) (100 kb3 Mb), and cancer-specific circular extrachromosomal DNA (ecDNA) (mega-base-pair amplified) . Modern A topic of interest is the biogenesis of eccDNA. Despite many studies being dedicated to answering this question , the comTo date, studies have been primarily focused on the mechanism and function of eccDNA in cancer. Considering the large amount of research devoted to determining the function of eccDNA under different conditions, we classified the functions of eccDNA into the following categories: (1) oncogene amplification and transcription, (2) hijacking or mobile enhancers, (3) gene fusion and reintegration, (4) molecular sponge and transcriptional regulation , (5) telOverall, the biogenesis, forms, and functions of eccDNA are diverse and complex and many studies on eccDNA are not only limited to cancer, but also other diseases. Below, we summarize new findings relating to eccDNA formation and function and propose several directions for future investigations.In recent years, numerous studies have demonstrated that eccDNAs may be involved in the development of various human diseases . In thisepidermal growth factor receptor (EGFR) gene, which regulate EGFR gene amplification and subsequent cellular fitness  and cyclin-dependent kinase 4 (CDK4) (Numerous studies have suggested that eccDNAs are strongly associated with the oncogenesis or development and progression of tumors  and can  fitness . EGFR en fitness . Recentl fitness . It has  fitness . The col fitness . In addi4 (CDK4) .transcriptional repressor gata binding 1 (TRPS1) gene could result in the deletion of genomic segments , ERBB2, CDK12, EGFR, and MYC, among others. They then found that chromothripsis can lead to the progression of GCA through the focal amplification of oncogenes. They then compared the prognostic value of oncogene focal amplification in GCA and hypothesized that ERBB2 focal amplification might function as a good prognostic marker in GCA patients with the disease for longer than 2 years. Lin et al. showed that eccDNAs are also involved in treatment resistance   . The samt-test) . Anothert-test) . To invenuclease .Such findings are not restricted to the plasma. According to a study by Yang et al., human placenta-derived eccDNAs also contained two peaks at 146 and 340 bp, and double-repeated trinucleotide sequences were equally present on both sides of these circular molecules . In addiPacI was used to linearize mitochondrial DNA (mtDNA) before the digestion of linear DNA by Plasmid-Safe ATP-dependent DNase. Finally, the silica column and silica beads were calibrated to further extract residual linear DNA in the solution. Mouse embryonic stem cells were selected as the main object of their research due to their genetic integrity. Although eccDNAs are widespread across the entire genome, unique characteristics such as their stochastic origins and fixed nucleosome sizes strongly suggest that the ligation of oligonucleosomal DNA fragments may be involved in the generation of these obscure molecules. There is substantial evidence demonstrating that these fragments are the feature of apoptosis  prognosis (unpublished). We extracted plasma eccDNAs from the blood samples of patients with acute MI and performed circularization for in vitro reporting of cleavage effects by sequencing (CIRCLE-seq) to identify MI-related eccDNAs (MIRECDs). The CIRCLE-seq results were validated by qPCR analysis, and Sanger sequencing was used to validate the accurate sequence and the loop structure of the identified molecules. We identified a MIRECD and determined through gene annotation that it may function as an isoform-specific transcriptional enhancer by regulating different isoform usage of the Chromodomain Y Like gene. The Kaplan–Meier survival curves showed that high plasma MIRECD levels were associated with poor prognosis of acute MI. The incorporation of the expression of MIRECD into the prognostic model resulted in a better predictive value of the model. Our research confirmed that MIRECD could serve as a promising predictor for MI prognosis and risk stratification.Oxytricha trifallax and their research has captured rearrangement-specific circular DNA molecules across the genome, making Oxytricha a model system for studying nucleic acid topology  as a study organism and compared the variation of eccDNA from blood and breast muscle  gene to acquire glyphosate resistance  through rolling circle amplification (RCA)  , which ion (RCA) . On the on (RCA) .Arabidopsis thaliana and Homo sapiens, nonmodel organisms such as the crop sugar beet (B. vulgaris) can also be analyzed by ECCsplorer. The horizontal comparison of eccDNA candidates in humans showed ECCsplorer had a longer length distribution than Circle-Map , which enables accurate SV detection by taking advantage of long high-fidelity reads . An attrMssI and PacI according to the existing methods. However, it could also affect the large-sized eccDNAs, especially those containing the restriction enzyme target sites. Feng et al. developed a method that can selectively remove mtDNA from total circular DNA under the guidance of the CRISPR/Cas9 system with one single-guide RNA (sgRNA) or two sgRNAs. The method could also be applied to any eukaryotic species, indicating that this technology is expected to play a role in protecting large DNA circles from endonucleases  and AmpliconReconstructor (AR) are extensively used to define ecDNA in tumors . Reconstucleases . As the ucleases .Machine learning is also a powerful tool for downstream bioinformatics analyses. To thoroughly investigate the interactions between different eccDNAs, it is necessary to build a platform that can integrate the large datasets generated by eccDNA studies. CircleBase , a recenCollectively, eccDNAs are broadly present in eukaryotes. Despite the important advances recently made in this field, eccDNA research is still in its infancy with many aspects that must be improved upon . First, Although many emerging research questions related to the function and mechanism of eccDNA are emerging following the use of eccDNA sequencing and analysis, these issues will certainly provide an impetus for conducting future studies in this direction. For example, study topics should not be restricted to tumor cells, and eccDNAs from other pathological tissues and peripheral blood samples can be considered as biomarkers of tissue-specific diseases. Investigations in animals and plants suggest eccDNA participates in the evolution of different species . Easy acIn addition to research on eccDNA mechanisms and characteristics, eccDNA may also have excellent prospects for clinical application. Firstly, available data from studies suggest eccDNA may act as an alternative biomarker to increase the diagnostic accuracy of rare diseases . Combini