Mesenchymal stromal cells (MSCs) are currently widely used in cell based therapy regarding to their remarkable efficacy in controlling the inflammatory status in patients. Despite recent progress and encouraging results, inconstant therapeutic benefits are reported suggesting that significant breakthroughs in the understanding of MSCs immunomodulatory mechanisms of action remains to be investigated and certainly apprehended from original point of view. This review will focus on the recent findings regarding MSCs close relationship with the innate immune compartment, i.e. granulocytes and myeloid cells. The review will also consider the intercellular mechanism of communication involved, such as factor secretion, cell-cell contact, extracellular vesicles, mitochondria transfer and efferocytosis. Immune-like-properties of MSCs supporting part of their therapeutic effect in the clinical setting will be discussed, as well as their potentials  and effects mediated, such as cell polarization, differentiation, death and survival on various immune and tissue cell targets determinant in triggering tissue regeneration. Their metabolic properties in term of sensing, reacting and producing metabolites influencing tissue inflammation will be highlighted. The review will finally open to discussion how ongoing scientific advances on MSCs could be efficiently translated to clinic in chronic and age-related inflammatory diseases and the current limits and gaps that remain to be overcome to achieving tissue regeneration and rejuvenation. Mesenchymal stromal cells (MSCs) are present in all tissues as a major structural and connective component sensing microenvironment signals and acting to maintain tissue homeostasis. They represent a heterogeneous cell population among which the presence of a canonic mesenchymal stem cell subpopulation is largely questioned. The role of such a multipotent progenitor subpopulation is out of the scope of the present review that will be focused on the stromal and supportive functions of MSCs. Cell-based therapy harnesses these activities to orchestrate tissue reconstruction and rescue functional and structural integrity upon injury and disease. Recent findings outline that metabolism is driving MSCs mobilization and responses and that immune cells, also present in all tissues, remain one of the privileged targets, acting together for driving the therapeutic outcome. Based on clinical results using MSCs as advanced medicinal products (ATMP) a focus will be made on the immunomodulatory effect observed in various regenerative medicine applications. The object of the present review is thus to provide an overview of the recent progress in deciphering cellular, molecular and metabolic communication between MSCs and innate immunity cells. The positioning of MSCs as a component of the immune system will be questioned. We will discuss how MSCs and macrophages organize into a highly interconnected network where cell metabolism and energy management reflect and modulate both mesenchymal and immune functions. Finally, the discussion will open to novel consideration of such metabolic immune-mesenchymal axis to maintain or restore tissue homeostasis.MSCs are good candidates for cell therapy to treat inflammatory diseases such as graft versus host disease (GVHD) , sepsis The first therapeutic use of MSCs was to treat severe GVHD. Severe GVHD is a life-threatening complication after allogeneic transplantation with hematopoietic stem cells (HSCs) that is characterized by the activation of the immune system with systemic inflammation and tissue injury. Steroids are the first-line treatment for established GVHD however, 50% of patients are non-responders and have a poor outcome . TherefoMore robust results were obtained in inflammatory bowel diseases (IBD), Crohn’s disease and ulcerative colitis where MSCs demonstrate a great efficacy. IBD is characterized by a chronic and destructive inflammation of the gastrointestinal tract. Indeed, IBD pathogenesis is associated with IL-23 and IL-12 pro-inflammatory cytokines that promote in the intestine the switch of T lymphocytes toward a Th1 pro-inflammatory profile and the formation of Th17 lymphocytes playing an important role in inflammation and tissue damage in autoimmune diseases such as Crohn diseases . The Th1in vivo preclinical and phase 1 clinical studies seem to demonstrate that MSCs could also be a new treatment for acute inflammatory diseases such as sepsis , acute lung injury (ALI) , 28 or cThe immunomodulatory potential of MSCs is thus supported by experimental and clinical data and rely on an organized and complex network interfacing immune cells with MSCs. While immunosuppressive activity of MSCs on adaptive immune cells is already largely documented , and in MSCs play a critical role in the two phases of inflammation essential for an effective healing process: the early acute phase that initiate inflammation and its subsequent resolution necessary to achieve the repair process Figure 1In vitro studies demonstrated that MSCs trigger the polarization of macrophages from a pro-inflammatory M1 phenotype to an anti-inflammatory-like M2 phenotype  and 4 (EP4) on macrophages, producing higher amounts of IL-10. IL-10 seems prevent neutrophils from migrating into tissues limiting organ damage and reducing inflammation   and PGE2high MSCs increase the survival of mice in a GVHD model by migrating to secondary lymph node where they suppress DCs maturation and Th1-differentiation of CD4+ T cells  , 96. Durolerance .When MSCs undergo apoptosis, they can be eliminated by macrophages. Galleu et al. demonstrated that MSCs after infusion in a mouse model of GVHD undergo apoptosis through a cytotoxic activity and still exert immunosuppressive activity. Injection of apoptotic MSCs and their phagocytosis by macrophages induce an IDO-dependent immunosuppression , 100. SuIn line with this close and reciprocal interaction with immune cells and their immunomodulatory properties, MSCs have been reported to be “immunoprivileged” suggesting there could be protected against immune detection and rejection when injected in allogenic setting. To date it is considered that MSCs are rather “immunoevasive” meaning weakly immunogenic . It meanIt is admitted that immune functions are however not restricted to hematopoietic cells and also include stromal or structural cells, and MSCs as such, that are able to express a large range of immune regulators and cytokines. It is noticeable that MSCs may also trigger some immune functions by themselves, such as mechanisms against pathogen defense that can, to some extent, be compared to professional phagocytes.V. cholerea  and CXCL2, which attracts pro-inflammatory M1 macrophages that have antimicrobial activities , 113. Adrophages . Transferophages .in vivo experiments are required.MSCs can also be efficient as carrier to deliver antibiotics. BM-MSCs are capable to uptake ciprofloxacin and then release active antibiotic up to 24 hours to inhibit bacterial proliferation . SeveralTo move forward, the next provocative question would be can MSCs be considered as macrophage-like cells? This striking question takes its roots in seminal paper describing that preadipocytes/ASCs share numerous features with macrophages such as inflammatory cytokine release and phagocytosis of apoptotic bodies  that wasFinally, the analogy of MSCs with macrophages extends to their phenotypic polarization as inflammatory cytokines such as INF-γ, TNF-α or TLR3 stimulation primes MSCs into an anti-inflammatory and immunosuppressive MSC-2 phenotype  whereas TLR4 activation rather induces a pro-inflammatory MSC-1 phenotype  , 131.Cellular metabolism supports all tissue functions ensuring on demand energy supply required for cell activity. Additionally, nutrient-derived metabolites are important mediators of cellular metabolic fluxes and signaling. Both immune and metabolic functions are regulated by common pathways that act in concert when sensing tissue threats to provide a coherent adaptive response converging organism resources towards an appropriate energy production for vital functions such as tissue defense and regeneration. Inflammatory signaling factors  and hypoxia can orientate metabolic pathways in various cells other than immune cells, adipocytes, hepatocytes, neurons and MSCs for example.Immunometabolism classically refers to immune cells metabolism that governs their fate and function. It is greatly documented how cellular metabolic fluxes and metabolite detection dictate the immune response developed by macrophages, dendritic cells, neutrophils and lymphocytes –134. It Evidences of direct metabolic coupling between MSCs and immune cells are poorly documented. It is just demonstrated that human MSCs induce the acquisition of M2 macrophage phenotype through a lactate-mediated metabolic reprogramming . ReciproIndirect coupling evidences are more obvious in the literature. MSCs are sensitive to micro-environment changes appearing with tissue dysfunction and can operate metabolic switch and functional adaptations in their biology that in turn will impact the immune response and inflammatory status. Modulation of the redox environment and oxidative stress resulting from free radical accumulation , pH, oxygen tension and nutrient gradient perturbations are associated with cell injury, organ failure and the aging process , 143. MSMitochondria thus appears to play a pivotal role in immune cell metabolic reprogramming ensuring, as a signaling hub, the adequate crosstalk between immunity control and cellular energy providing , 159–162It was recently reported that liver tumor cell growth was associated with mitochondrial fusion causing an increase in oxygen consumption and ATP production . The posOther metabolic pathways in MSCs immunomodulatory activity relies on enzymes degrading amino acids and producing metabolites that may boost or dampen immune responses. Tryptophan is an essential amino acid catabolized through the kynurenine pathway by the rate-limited enzyme indoleamine 2,3-dioxygenase (IDO). In MSCs the activation of IDO in response to inflammatory factors is triggering immunosuppression as a result of tryptophan depletion causing apoptosis of T cells, inhibition of T cells and NK cells proliferation, inhibition of DCs maturation, and induction of Treg immune suppressor cells . On the Finally, mesenchymal and immune cells that both act as sensor and actor of tissue integrity, are tightly connected entities where their respective metabolic and functional activities result and influence each other. They both constantly integrate environmental signals and communicate for a concerted and efficient metabolic reset to properly fuel functional adaptations of the immune response Figure 2Ultimately, immunometabolism has to be investigated at the whole organism level considering its generalized high impact effect in homeostasis as well as pathogenesis and aged-related chronic diseases . SystemiMany unsolved questions remain to overcome present limitations to reach sustain and significant efficacy that is not yet achieve in late-phase clinical trials. The translation of MSCs into clinic is more difficult than expected. Indeed, the cell therapy outcome is not solely depending on ATMP properties but also conditioned by the route of delivery. This major issue is currently questioned and must be considered as an adaptable option to fit with the multiple possible applications . IntraveBesides, in order to succeed in prompting MSCs therapy into suitable clinical practices, the current major challenges reside in (i) MSCs manufacturing towards standardized and optimized culture processes, (ii) improving the MSCs characterization including multiscale and multiparametric analyses, (iii) developing dynamic potency tests to qualify MSCs batches that bring guaranties of their therapeutic potential, (iv) identifying from completed trials MSCs parameters correlated with clinical benefit in order to propose predictive markers for a given physio-pathologic background. The study of MSCs biology over the last decade underlines that beyond their intrinsic potential  , 191, flin vitro is not sufficient to predict their efficacy in patient. Retrospectives analyses of clinical outcomes and recovery in cohorts of patients receiving allogenic MSCs should allow to identify specific markers or signature associated with MSCs treatment benefit. Such approaches should help to address the question of responder and non-responder identification. Based on clinical trial data and MSCs testing in vitro, Artificial Intelligence and Deep Learning models could be trained to predict therapeutic MSCs efficacy in a given pathologic background.A next critical issue resides in being able to select the most permissive cell product for personalized therapeutics benefit according to patient characteristics. Indeed, extensive analyses of MSCs properties With aging the complex and dynamic networks involving native MSCs activity may gradually deteriorate due to alteration accumulation in MSCs and/or modification of their surrounding environment. Declines that progressively operate may at some point exceed MSCs resilience capacity and ultimately compromise tissue homeostasis and functional integrity , 199. WiThe risk for developing a wide range of chronic disorders rises with aging and represent a growing public health issue with the increased lifespan of the population. The geroscience approach aims to prevent, delay and possibly reverse the occurrence or the severity of age-associated chronic pathologies by acting on key molecular, cellular and systemic aging processes. Allogenic MSCs from healthy donors thus appear as a promising candidate due to their pleiotropic effects to offer new options to treat age-related disorders associated with chronic inflammation. MSCs therapy trials in the elderly already showed benefits in osteoarthritis , 209, peSupported by recent single cell RNA sequencing in mouse, resident immune and stromal cells organize into a cross-tissue cellular network. Together with endothelial and dendritic cells they represent the recurrent components contributing and defining each tissue micro-environment, highlighting their crucial role in local response that can extend to the systemic level . StromalTo conclude, where the reductionist approach consisting in managing each disease independently have proved to be ineffective in the treatment of age-related pathologies, allogenic MSCs therapy can be proposed as an alternative solution for patients elected through reliable criteria. Inflammation and metabolism can be considered as biological rheostat able to reset the entire system and MSCs as a determinant regulator of both functions towards homeostasis restoration. Based on relevant selection criteria and optimized production process, allogenic MSCs position as multimodal tools able to take in charge biological functions interfacing with all organs. Allogenic MSCs therapy by targeting inflammaging and metabolism-aging thus appears in line with geroscience perspectives  and is aVB and AV conceived the main conceptual ideas and structure of the review. VB, AV and LC wrote the manuscript, analyzed and sorted the literature, revised and provided critical feedback on the manuscript. VB provided funding. All authors contributed to the article and approved the submitted version.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.


Availability hypothesis contends that reduced opportunities to drink due to the closure of outlets and consumption sites should lead to decreases in alcohol use, whereas the Stress and Coping hypothesis argues that those exposed to stressful situations may increase drinking. The primary aim of this study was to examine changes—separately by gender—in the prevalence of drinking patterns among Italian young adults (18–34 years) before and during a COVID-19 lockdown. Study design was a repeated cross-sectional study, whereby data collected in 2015 and 2020 from nationally representative samples were analyzed. Latent class analysis identified five, fully invariant for women and partially invariant for men, drinking pattern classes among both cohorts: current non-drinkers (CND), weekend risky (WRD) and weekend non-risky drinkers (WnRD), daily non-risky (DnRD) and daily risky drinkers (DRD). In support of the Availability hypothesis, increases in abstaining and moderate drinking women and men were observed from 2015 to 2020. Concomitantly, among men only there were also increases in the prevalence of patterns characterized by risky drinking, coping drinking motives and related harm (Stress and Coping hypothesis). The pandemic and the three-tier lockdown imposed by the Italian government likely reduced overall alcohol use in the general population who drink moderately. However, there was a substantial increase in the prevalence of a small but significant group of men who drank daily and heavily to cope. Outreach and prevention efforts should target primarily this group, but also consider the opportunities that the exceptional circumstances of a quarantine offer to any individuals to reshape their lifestyle and health-related behaviors.Two not mutually exclusive theories explain the effects of the COVID-19 pandemic on alcohol use. The The online version contains supplementary material available at 10.1007/s10935-022-00675-2. The COVID-19 outbreak has dramatically affected the life of young people throughout the world, as nations implemented social distancing, isolation measures and restrictions to social life and to the operations of drinking venues in the attempt to reduce the spread of the virus. These measures are likely to have had an impact on several outcomes, including alcohol use. Alcohol use and misuse is one area of special concern for policymakers, practitioners, and academics, and it is therefore important to develop a nuanced understanding of the ways in which drinking patterns were affected by the health emergency. As the global pandemic continues, this knowledge is important as prevention scientists identify high-risk groups that may need targeted support and develop interventions accordingly.Availability hypothesis contends that reduced opportunities to drink due to social distance measures and the closure of outlets and consumption sites should lead to decreases in alcohol use in the general population and especially among lighter drinkers. The Stress and Coping hypothesis argues that those exposed to stressful situations, such as social isolation and socioeconomic insecurity, may experience mental health issues, which may contribute to increases in alcohol use as a dysfunctional coping strategy . The tendency to self-medicate can be further exacerbated because traditional support mechanisms  around alcohol reduction may have become less accessible during the lockdown  in an attempt to avoid a second national lockdown  before and during a COVID-19 lockdown. We also examined the associations between membership to drinker profiles and lockdown tiers.There has been an increase in the prevalence of profiles characterized by abstention along with a decrease in moderate drinking patterns ;Among men but not women, there has been an increase in the prevalence of high-risk drinking patterns characterized by drinking to cope;Living in stricter lockdown tiers would be associated with belonging to profiles that are characterized by abstention and moderate drinking.Based on findings of previous studies using LCA indicating that drinker class solutions tend to be relatively stable across gender and time . Data were collected from nationally representative samples of Italian young adults (18 to 34 years old) in two cohorts: December 2015 and December 2020 during the second COVID-19 lockdown in Italy. Sampling and Computer Assisted Web Interview (CAWI) data collection was conducted by Ipsos s.r.l. Each cohort data is weighted to account for the non-random nature of the sample and guarantee sample representativeness in respect to several socio-demographic characteristics including gender, age-range, educational level, occupation status, and geographic area , using the Daily Drinking Questionnaire    the morning after I had been drinking)   depending on their region of residence allocation during the four weeks prior to data collection. In those cases when regions changed tier during that period, they were assigned to the tier they have been assigned the longest. Five, nine and seven regions were assigned to the yellow, orange, and red tier, respectively (Table S1).Based on the ten indicators of drinking, sub-groups of individuals characterized by common patterns of multiple alcohol use behaviors were identified using LCA. Following established recommendations , weekend risky (WRD) and weekend non-risky drinkers (WnRD). However, we found that those characterized by high probabilities of drinking on all seven days of the week were distinguished into two subgroups: daily non-risky (DnRD) and daily risky drinkers (DRD), depending on whether they were likely to report any of the two risky drinking behaviors . In sum, we found one class characterized by abstention, two by moderate and two by risky drinking patterns. In the 2015 cohort, one-way analyses of variance and post-hoc analyses showed that, in both genders, DRDs reported the greatest coping drinking motives  and the greatest number of alcohol-related negative consequences  as compared to WRDs and the other more moderate drinking patterns, thus adding to the conceptual validity of the classes .As shown in Table p < 0.01) and male (p < 0.001) participants, results indicated non equivalence. We then saved participants’ most likely class membership and calculated 2015 and 2020 weighted class prevalence rates. Ninety-five per cent confidence intervals were used to determine any variation across cohort  paired with decreases in the proportion of those who drink moderately over the weekend  (Hp1). These results offer support to the Availability hypothesis: in Italy’s “wet” drinking culture  decreased, whereas the proportion of risky drinkers  increased from 2015 to during the pandemic in 2020 (Hp2). Given these two latter groups were characterized by the greatest coping drinking motives, this result provides support to a self-medication use of alcohol under the Stress and Coping hypothesis among heavy drinking men. This result is novel and casts light on the gendered stress—alcohol misuse relation during the pandemic , increasingly restrictive lockdown tiers were not associated with increased likelihood to belong to lighter drinking patterns. We speculate this is because on one side alcohol availability was greatly limited in all tiers , and on the other because other sources of alcoholic beverages  remained easily accessible throughout the lockdown. These countervailing effects may explain why our results are not consistent with other that introducing policy to reduce alcohol availability  or restrictive marketing practices bear public health benefits by reducing alcohol use in the population and alleviating pressure on the healthcare system  nor allows determining the direction of the transitions from and to drinking patterns. In addition, because the two cohorts were five years apart, secular trends of reduced alcohol intake among young people may at least in part explain the differences we found. We also note there were inconsistencies in how data were collected in the two surveys, the main being the time frame (past three months Vs. one month) of a typical week for responding to some alcohol use indicators. The degree of bias introduced by such inconsistency is likely to be limited given the three-month time frame does not include periods that are known for seasonal fluctuations in alcohol use (namely summer and winter breaks). Further longitudinal and mixed-method research is needed to better examine causal relationships, assess changes in further waves and restrictions, and get a deeper understanding of these issues. An additional limitation is that the present study employed only self-report measures, which might be susceptible to response bias.Availability hypothesis, increases in abstaining and moderate drinker classes were observed among both young women and young men. From a public health perspective, however, declines in alcohol consumption exhibited by most youth should not obscure the finding that, among men, there were also increases in the prevalence of patterns characterized by heavy risky drinking to cope with stress (Stress and Coping hypothesis). Accordingly, it is important for policy makers, prevention scientists and practitioners, and outreach health services to focus on those who drink daily and heavily. Future research should investigate whether the prevalence (> 10%) of this group of young men stabilized or have returned to usual levels as lockdown restrictions were lifted and people resumed their normal lives.This study contributes to the literature on alcohol use during the COVID-19 health emergency. Results indicate gender-specific changes in the prevalence of the five drinker profiles. In support of the An unexpected result was that drinking classes were unaffected by differences in the limitation to the operation of drinking outlets across Italian regions. This is likely because, even under the stricter rules, alcoholic beverages were easily accessible across a variety of sites and through delivery as it is in usual times. Finally, we suggest that our study makes an important methodological contribution to the field. Our use of LCA allowed developing a multifaceted and thorough portrait of alcohol use patterns during a public health emergency. We recommend LCA as an important tool for future studies in this field.Supplementary file1 (DOCX 144 kb)Below is the link to the electronic supplementary material.


It is now clear from studies such as the ACOSOG Z0011 randomized controlled trial that a subset group of patients presenting with primary breast cancer with positive (involved) axillary lymph nodes at sentinel lymph node biopsy (SLNB) may be able to avoid an axillary lymph node dissection (ALND) with its associated morbidities  in terms of local, regional, or overall loco-regional recurrences, or in disease-free survival. Further studies including the POSNOC study , a multiAs there is an inexorable trend toward less radical surgery in the axilla in the management of patients presenting with breast cancer, the preoperative staging of the axilla is becoming of greater significance. While ultrasound scanning with needle biopsy of some sort (either fine-needle aspiration cytology or wide-bore needle core biopsy) remains the standard of practice internationally, it should be remembered that neither sampling technique has been evaluated context of a rigorous randomized controlled trial for this indication. It could be argued there is a limited evidence base for our current normal practice of preoperative axillary staging.It is likely that clinical questions about surgery involving the axilla will not be restricted by a binary solution of a positive/negative result, but rather will involve an assessment of the overall burden of disease, as it may well be that low volume axillary nodal disease, found at SLNB, may be managed conservatively.Multidetector CT has many advantages over ultrasound as an imaging tool. CT provides images in multiplanar images and gives an excellent overview of the anatomy of the axilla, the number of total nodes present, the internal morphology of the nodes, and the proximity of the nodal disease to vascular structures.Currently, there is no international consensus as to which breast cancer patients should have staging investigation and which specific investigations are indicated. Certainly, there is no agreement that all patients diagnosed with breast cancer should have a staging CT examination.European (ESMO) guidelines recommend performing chest, and abdominal imaging  and with consideration of a bone scan for patients with clinically positive axillary nodes, large tumors T3/4), or tumors with aggressive biology  tumors or with heavy lymph node burden (N2 disease) with or without bone scan and a PET-CT for suspected inflammatory breast cancer .The North American National Comprehensive Cancer Network (NCCN) guidelines recommend a bone scan, abdominal CT/MRI (including the pelvis if symptomatic), chest CT/18F-NaF PET-CT, in symptomatic patients or in stage I-IIB breast cancer with abnormal liver function tests, elevated serum alkaline phosphatase, and localized bone pain .Chen et al.  have demAs has been demonstrated by other authors, high quality and reproducible images can be achieved by using a simple, standardized CT protocol can be supplied to experienced radiographers, even with CT scanners made by a variety of manufacturers. The intra-operator variability which hinders ultrasound assessment and also the variability of ultrasound equipment performance is therefore avoided. CT images can be reconstructed in any plan of choice for the purposes for example of MDT review or preoperative planning .Multidetector CT has potential in evaluating disease burden before axillary conservation and in follow-up of the “conserved” axilla. Further research using the latest generation of CT scanners is needed to evaluate the effectiveness of CT in this, a different paradigm of radical surgery to the axilla.JC and JS have jointly coauthored this commentary. All authors contributed to the article and approved the submitted version.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.


Several theories linking post-prison employment to recidivism suggest that the quality of employment has a causal effect on future criminal justice contact. However, previous work testing these theories has not accounted for differential selection into high-quality employment. Using six years of post-release employment records, I document how post-prison job quality varies by industry. Then, I use inverse propensity score weighting to estimate the effect of job quality on future arrests and prison spells. Some evidence indicates that parolees who find high-quality employment experience fewer arrests or returns to prison than otherwise similar parolees who find low-quality employment, with the effects most evident when comparing employment in the highest- and lowest-quality industries. Low-quality employment does not appear to reduce future criminal justice contact relative to unemployment. More than 625,000 prisoners were released from state and federal prisons in the United States in 2016 . A largeSociologists and criminologists emphasize the role of employment in reducing future criminal justice contact after release from prison. Employment has been theorized to reduce economic motivations for crime , facilitHowever, previous research investigating the connection between post-prison employment quality and recidivism or other forms of criminal justice contact in the United States  has failIn this article, I estimate whether individuals who are first employed after prison in industries that offer relatively high-quality employment are significantly less likely than those who are first employed after prison in industries that offer relatively low-quality employment to be arrested or return to prison in the two years following the beginning of employment. I do so using comprehensive labor market information collected on all prisoners paroled in the state of Michigan in 2003 for six years after the quarter of release from prison, alongside an array of rich demographic, human capital, and criminal justice-related measures. I first measure employment quality within industries along four objective dimensions: average quarterly wages among the sample of parolees, average job tenure among the sample of parolees, average quarterly wages among all employees at employers who hire parolees in the sample, and union coverage among all Michigan workers. I then use inverse propensity score weighting to compare the future criminal justice contact of parolees who are equally likely  to find work in a high-quality industry but who find work in industries that offer a different quality of employment. This results in an estimate of the effect of employment quality on future criminal justice contact net of a wide variety of controls that may jointly affect both employment quality and future criminal behavior.I find that those whose first job after prison is in an industry that offers relatively high-quality employment are, in general, less likely to be arrested or recidivate during the two years after hire. The results of the models that account for differential selection into employment based on observable characteristics provide mixed evidence about whether high-quality employment is associated with reduced future criminal justice contact. When comparing those who find employment in the industries that offer the highest job quality—namely, manufacturing and transportation or warehousing—to those who find it in those that offer the lowest—namely, the employment services industry—the relationship between employment quality and the likelihood of being arrested in the two years after hire is more clear.Notably, when comparing employment of varying quality to the counterfactual of not finding employment, I find evidence that high-quality, but not low-quality, employment is associated with a lower likelihood of returning to prison.Researchers studying the connection between post-prison employment and future criminal justice contact have offered a variety of mechanisms through which employment after incarceration should reduce the risk of recidivism. Most obviously, employment may reduce the risk of reoffending by reducing the motivation to commit crime for economic gain . Similar1In particular, these mechanisms suggest that it is not just employment after release from prison but also the quality of the employment—as measured by objective markers such as earnings, job stability, and earnings growth—that should have a significant effect on future criminal justice contact. For one, highly paid employment may reduce immediate economic motivations for crime. Further, the social control perspective holds that jobs that provide longer tenure or offer regular, full-time work may be especially likely to inhibit future criminal justice contact, by leading to interdependence with professional social networks  and to t2However, Poor Discipline, Jonathan Employment quality could also not affect recidivism if the pathway through which employment affects recidivism is decreased state surveillance. In One way that researchers have examined the connection between the quality of available employment and the propensity to commit crime is by using aggregate measures of local labor markets as a proxy for the quality of available employment. For example, These results are strongly consistent with the thesis that it is the quality of employment, not merely being employed, that matters for future criminal justice contact. However, the cited studies generally have individual-level data on criminal justice system involvement but not on employment. They therefore do not allow us to disentangle the degree to which changes in local labor market conditions affect the likelihood of future criminal justice contact directly by affecting the quality of employment of recently released prisoners , rather than indirectly through other mechanisms .3 Christopher Other research examining the connection between the quality of employment and future criminal justice contact has relied on individual-level data that include information on both employment and criminal justice contact after release.Recent research by I rely on longitudinal data on the employment outcomes of all prisoners paroled in the state of Michigan in 2003, collected from the Michigan Unemployment Insurance Agency and Workforce Development Agency. The benefit of unemployment insurance (UI) data is its comprehensive coverage: UI data capture virtually all formal employment undertaken in the state of Michigan for twenty-four quarters after the sampled individual’s release from prison. In each person-quarter, the data contain individual-level information on total wages earned from each Michigan-based employer, alongside employer-level information on the average quarterly wages paid to employees in the given quarter and the employer’s detailed six-digit North American Industry Classification (NAICS) Code.I focus on the 10,794 individuals who are no older than fifty-five at the time of release. I estimate job quality using UI data from all these individuals; however, when I estimate the effect of employment quality on future criminal justice contact, I focus in particular on those who find employment, have not been arrested or returned to prison at any point between their sampled release from prison in 2003 and the end of the quarter in which they find such employment, and who do not have missing values for any covariates used in the estimation of the effect of job quality on future criminal justice contact.Because UI data do not include information about workers’ occupations, only the industries of their employers, I measure job quality at the level of the industry, using four distinct measures of job quality.First, I compare average industry-level quarterly earnings of workers to average quarterly earnings in all other industries. Earnings are clearly a central component of job quality: higher earnings make it easier for workers to meet consumption needs and to grow savings. For parolees in particular, higher earnings may reduce recidivism by reducing economic motivations for crime. Calculating industry-level earnings within UI data is complicated by the fact that UI data do not have information on hourly wage rates or the number of hours that employees work within a quarter. Further, differences in job tenure between industries could affect calculations of average industry-level wages, both because higher-tenured workers earn more and because workers are more likely to work only for part of quarter in low-tenure industries. Thus, I compare industry-level wages between workers who work only at one job, are in their second quarter of employment at that job, and work at that job in the next quarter.Second, I compare average industry-level employment tenure to average employment tenure in all other industries. Tenure is also an important dimension of job quality, reflecting stability of employment as well as the ability of workers to have careers within firms. Further, employers that provide greater employment stability may curb recidivism by providing a set of routine activities to replace those that led to imprisonment and creating deeper ties to individuals who are not in contact with the criminal justice system. I measure employment tenure as the number of consecutive quarters in a given employment spell with a given employer.4 Although this measure does not directly capture dimensions of job quality such as fringe benefits, growth opportunities, or safety, evidence suggests that these other dimensions are positively correlated with firm-level earnings effects , the stark differences between industries in these measures of job quality strongly suggest that the measures meaningfully reflect how job quality varies between industries for individuals finding work after release from prison.For each industry, I use two-tailed t-tests to determine whether average wages, average employment tenure, average quarterly wages per employee, and statewide union coverage are significantly greater than or less than average wages, average employment tenure, average quarterly wages per employee, and statewide union coverage in all other industries combined. I define an industry as offering high-quality employment if at least three out of four of these measures are significantly greater within the industry than in the rest of the sample, the fourth measure not being significantly lower. Conversely, I define an industry as offering low-quality employment if at least three out of four measures are significantly lower than in the rest of the sample, the fourth measure not being significantly higher. Within high-quality and low-quality industries, I also identify the highest-quality and lowest-quality industries that are above or below average in all four dimensions of job quality.The highest-quality industries in which sampled individuals find employment are manufacturing  and transportation and warehousing ; both industries offer above-average quarterly earnings, job tenure, firm-level quarterly earnings per employee, and state-level union coverage. Among common industries, construction  is also a high-quality industry, offering both above-average earnings, firm-level quarterly earnings per employee and state-level union coverage.In contrast, employment services  is the lowest-quality industry in which individuals paroled in Michigan in 2003 found employment, coming in below average in every measured dimension of employment quality. Industries classified as offering low-quality employment include limited service eating places , full service restaurants , and services to buildings and dwellings .I code the treatment variable as an indicator variable, equal to 1 if a sampled individual obtains their first employment after the sampled prison spell in a high-quality or highest-quality industry, and 0 if in a low-quality or lowest-quality industry. To more closely study the relationship between employment quality and future criminal justice contact, I focus on respondents who find post-prison employment before experiencing arrest or a return to prison. I assign individuals who have their first record of employment in a high-quality industry in the same quarter as they have their first record of employment in a low-quality industry a value of 1 for the treatment variable.I also report results from a similarly constructed treatment variable where 1 indicates that a parolee finds employment in a highest-quality industry before getting arrested or returning to prison, and 0 indicates a lowest-quality industry. I use this treatment variable to test for the existence of any discernible effects of post-prison job quality on future criminal justice contact: if models that account for differential selection into job quality find no significant difference in future criminal justice contact between those who find the highest-quality employment and those who find the lowest-quality employment, no such effect likely exists.Finally, I create four treatment variables to test for the effect of finding post-prison employment in an industry offering a given level of job quality relative to not finding employment. For each of four industry quality classifications , I set an indicator variable equal to 1 if a parolee finds employment in that industry category within one quarter of the quarter of release from prison, and 0 if not. As with other treatment variables, I drop observations when a parolee is arrested or has returned to prison within the time frame.I measure two types of criminal justice contact: arrests and returns to prison. Prison terms are certainly more consequential than arrests, and much of the literature on the effect of employment on future criminal justice contact focuses on recidivism as a dependent variable. Yet arrests are also an indicator of criminal behavior, and the various theories connecting employment quality to recidivism all suggest that high-quality employment should reduce criminal behavior more generally. I measure each of these types of criminal justice contact in each of the eight quarters after the quarter in which an individual finds employment in a high- or low-quality job. Data on arrests come from the Michigan State Police, and data on returns to prison come from the Michigan Department of Corrections.Selection into a high-quality industry, relative to a low-quality industry, is a nonrandom process. Further, some of the same traits that predict this selection process are also likely to predict whether an individual is likely to recidivate. Therefore, to more closely estimate the causal effect of finding employment after release from prison in a high-quality industry , it is necessary to control for factors that could affect both the quality of industry in which parolees find employment and the likelihood that parolees experience future criminal justice contact.5 an indicator for being married at time of release, whether an individual has a high school degree or GED, and the logged maximum quarterly earnings recorded in the Michigan UI data between 1997 and the time of release. I also include as covariates the quarterly unemployment rate at the time that the parolee first found employment in the county in which the parolee first lived after release from prison (collected from the Michigan Department of Labor and Economic Growth), and the quarter after release from prison in which the respondent found employment.I include as covariates several variables that measure parolees’ demographic and human capital characteristics—age at time of release, sex, race ,Finally, I include a host of covariates collected by the Michigan Department of Corrections that reflect both parolees’ exposure to the criminal justice system through the sampled release from prison and factors used in previous research to predict post-prison employment and criminal justice outcomes . Notably6Yit is an indicator variable equal to 1 if individual i has experienced a given form of criminal justice contact in the t quarters since finding high- or low-quality employment and 0 if not, HQi is the treatment variable described, and εi is a standard error term. These models estimate what the effect of post-prison employment quality would be on future criminal justice contact if selection into post-prison employment quality were random, and essentially capture the difference in probability of experiencing future criminal justice contact between those who find high-quality and low-quality employment. Negative values of β1 indicate that those with high-quality employment are less likely to experience a given form of future criminal justice contact, whereas positive values indicate that those with high-quality employment are more likely.I first estimate the naïve treatment effect of employment quality on each of the measures of future criminal justice contact using a series of linear probability regression models:XI is the vector of covariates listed for individual i and other variables are as previously defined. Then, I use the predicted propensity scores from the above regression to assign each individual i weights as follows:7Next, I compare these naïve estimates of effects of employment quality on future criminal justice contact to estimates that use inverse propensity score weighting (IPW)  to their counterparts in the lowest-quality industry. Finally, I use the same method to estimate the respective effects of finding employment in a highest-quality, high-quality, low-quality, and lowest-quality industry within the first quarter after the quarter of release from prison, relative to not finding employment in that time frame.I first discuss estimates of the effect of employment quality on future criminal justice contact. I then turn to discussing how estimates of the relationship between employment and future criminal justice contact vary by employment quality.The naïve estimates of the effect of employment quality on future criminal justice contact restate the findings in Here we do see a more consistent effect of employment quality on future criminal justice contact, especially for arrests. After accounting for observable characteristics, those who find employment in the highest-quality industries are just over 4 percentage points less likely to be arrested between starting employment and eight quarters afterward; this corresponds to a roughly 10 percent decrease in the likelihood of being arrested over the period. Similarly, those who find employment in the highest-quality industries are almost 4 percentage points less likely to return to prison in the eight quarters after starting employment than those who find employment in employment services; this translates to about a 13 percent decrease in the likelihood of returning to prison.We see in Social scientists have put forth several causal explanations for criminal behavior, including economic motivation, anomic isolation, lack of social control, and lack of routine activities. Each of these theories suggests that, for those who have had previous criminal justice contact, not just employment but employment quality should matter for future criminal justice contact. Although previous work has found an effect of employment quality on recidivism in the context of the United States, the question of whether this effect can be accounted for by selection into various types of employment is unanswered. Further, this work focused on extraeconomic components of job quality, although economic aspects of job quality are also thought to be important for reducing motivations for crime.I use matching techniques to compare otherwise similar parolees who find employment in industries characterized by varying levels of employment quality, as defined by average earnings, job tenure, firm-wide earnings per employee, and state-level union coverage. Some evidence indicates that high-quality employment reduces the risk of future criminal justice contact relative to lowest-quality employment, though this effect is most apparent when comparing the industries that offer the best employment quality to the industry that offers the worst.I also analyze how employment in industries of varying quality affects the future likelihood of arrest or reimprisonment relative to those who do not find employment. I find that securing employment in high-quality industries reduces the risk of future criminal justice contact, but that in low-quality industries it does not. This may imply that, due to the increasing precarity of work in the United States , much ofThese findings should be qualified in several ways. Perhaps the most salient limitation is that the UI data do not include information about workers’ occupations, which would likely give more precise information about workers’ job quality than is available at the industry level. If there is heterogeneity in job quality within industries classified here as high-quality or low-quality, then this would attenuate the estimates of the effect of job quality on future criminal justice contact toward zero. Given the limitations of this data, it is impossible to determine the extent to which this is the case. However, despite variation in job quality within industries in general, those who have been to prison are likely to mostly be able to find employment in jobs that are among the lowest quality within industries, given their poor job prospects overall . This woA second qualification is that UI data do not capture informal employment, which some surveys have found is as common as formal employment within the first year of release from prison . InformaThird, and relatedly, this study focuses on only a small sample of the population of those who have been released from prison. Most notably, formal employment is generally rare in this sample: fewer than one in three parolees are employed in the formal labor market in any given quarter after release . These low rates are similar to those found in previous research , and areFourth, it is possible that the relationship found here between employment quality and future criminal justice contact could result from those who are ready to desist from crime pursuing higher-quality employment as a “signal”  to otherFinally, this study follows only one cohort of parolees who exit prison into a particular social and economic context, and so the external validity of these findings is limited. It would be useful to conduct similar analyses of the effect of job quality on recidivism in different times and places to build a more robust body of evidence about this relationship.Although I find that employment quality reduces future criminal justice contact, it should still be emphasized that sampled individuals experience relatively short job tenures across all industries, and the difference in job tenure between high- and low-quality industries is often less than one quarter. Thus, any protective effects of relatively high-quality employment may be unlikely to last. Although those who have been to prison may be generally less likely than others to find and maintain stable, well-paying employment, it also seems probable that parolees are especially likely to experience precarious work, given that work has become more precarious generally in the United States , especiaSuch a shift in the focus of research and policy interventions—from recidivism to the broader environment to which parolees return to after release from prison—echoes recent commentaries  that emp


Little is known about the impact of peer support programmes on physical health populations or on the methods used to evaluate such programmes. The present study undertakes a scoping review of research related to peer support programmes or interventions in physical health populations, guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews (PRISMA-ScR).The search was carried out across the Medline, PsycINFO, and Cochrane databases and focused on papers that evaluated peer support intervention(s) in adults with physical health conditions. The search identified an initial 7,903 records, which were narrowed down to 21 records that met the inclusion criteria; their findings were narratively synthesized.The scoping review found considerable heterogeneity among eligible records in terms of their study design, outcome measurements and findings reported. Qualitative methods of evaluation generated more consistent findings compared to objective outcome measures and suggested that peer support was beneficial for patients’ health and wellbeing by reducing feelings of isolation and creating a sense of community as well as providing an opportunity for information consolidation. The scoping review highlights the inconsistencies in methods used to evaluate peer support interventions and programmes in healthcare settings among different physical health populations. It also draws attention to the lack of peer support research in particular areas, including in acute physical health populations such as in major trauma. The scoping review emphasizes the need for future studies to address this gap in peer support research. Peer suThere is an abundance of peer support research in healthcare that focuses on mental health and HIV, and now more attention is being directed towards alternative population groups, including those with long-term physical health conditions. Research has also shown that peer support is especially valued by young people and British Black, Asian and Minority Ethnic (BAME) adults . Those fThere is an increasing evidence base suggesting a range of benefits of peer support for people across various populations. A review commissioned in 2015 that included more than 1,000 research studies concluded that peer support has the potential to improve experience, psycho-social outcomes, behaviour, health outcomes and service use among people with long-term physical and mental health conditions .The objectives of this scoping review were twofold. First, to gain a better understanding of how various peer support programmes impact patient outcomes in patients with physical health conditions. Second, to gain an insight into how peer support programmes are evaluated. This method of review was selected to enable outcomes to be synthesized in order to provide more context to the evidence base and inform clinical practice. The following research question was generated: What is known about peer support programmes in physical health populations, and how are these programmes evaluated in terms of their effectiveness?Protocol and registrationhttps://figshare.com/articles/preprint/Scoping_review_protocol_The_impact_of_peer_support_on_patient_outcomes_in_adults_with_physical_health_conditions/15178059) and the review was conducted with reference to this protocol.The final protocol was registered prospectively with Figshare (Eligibility criteriaPapers were eligible if they: (1) evaluated a peer support programme in a physical health setting(s) including in primary, secondary or community care settings; (2) included individuals with any physical health condition; (3) included any type of peer support programme/intervention; (5) were published in peer-reviewed journals.Information sourcesThe search was carried out across multiple healthcare databases: Medline (Interface: EBSCOhost), PsycINFO  and the Central (Interface: Cochrane Library). Search results were imported into a citation manager software (Endnote), and duplicates were removed via a combination of the removal of duplicates function on the programme and a manual check by one of the authors.SearchThe following search terms were used to search for eligible studies in all databases up to July 01 2021. Search terms were intentionally few to reduce the likelihood of omitting papers that may not have specifically indicated including participants from within the broad umbrella of those with physical health conditions but rather mentioned the condition itself. Search terms were limited to within titles and abstracts of studies.1. Peer support*AND2. Evaluation* OR Review*Selection of sources of evidenceScreening of papers was guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) framework. One reviewer screened all of the publications, including the title, abstract and full-text screening and was supported by the other reviewers. All reviewers were involved in determining the quality of the screening process and any queries or disagreements were resolved through in-depth discussion.Data charting processData from selected studies were extracted using a standardized data collection form amended for this review. This tool captured information related to the characteristics of studies, including study aim(s), design, population demographics, nature of intervention(s), description of outcome(s) and method(s) of evaluation of data. One reviewer extracted data from the studies with guidance from the other two reviewers. Data were then added to the characteristics of sources of evidence table (Appendix).Data itemsData abstracted included country of origin, population group, type of peer support programme or intervention, including method of delivery, evaluation methods used, main outcomes, including objective measures for quantitative studies, and derived themes for qualitative studies and conclusions.Synthesis of resultsStudies were grouped by their method of evaluating the peer support programme . Synthesis of quantitative findings within studies involved summarizing the population group, peer support intervention(s)  and primary outcome measures described. Similar qualitative findings between studies were grouped and over-arching themes are discussed.ResultsSelection of Sources of EvidenceFollowing the removal of duplicates, a total of 4,151 studies remained. Figure Characteristics of Sources of EvidenceSample sizes of the included studies varied considerably, ranging from eight participants  to 1,229Peer support interventionsMode of DeliveryTable Evaluation MethodsNine studies (43%) utilized quantitative means of outcome evaluation in order to determine the efficacy of peer support programmes or interventions -19,27-29Primary OutcomesSelf-report measures used to assess primary outcomes are presented in Table Psychological OutcomesThe psychological outcome measures cited across included studies varied greatly, with self-efficacy the most commonly reported psychological outcome. A community-based peer-led diabetic self-management programme that involved face-to-face peer support, concluded that self-efficacy significantly improved during the 12-week study period . NotablyOne study reported a beneficial impact of peer support on diabetes-related distress . In thisOne study reported no impact of peer support on psychological outcomes. This study considered the impact of a peer-delivered telephone intervention for women experiencing a breast cancer recurrence . The stuOne study detected a possible detrimental impact of peer support on psychological outcomes for individuals with type 2 diabetes. This randomised controlled trial (RCT) involved a peer-led face-to-face peer support programme that took place over a two-year period. At the two-year follow-up, it was concluded that for the intervention group, there was a reduction in wellbeing (non-significant) compared to the control group . ImportaTwo studies ,18 reporFunctional, Behavioural and Social OutcomesThe impact of peer support on reported functional, behavioural and social outcomes is mixed. A study that evaluated long-term social reintegration outcomes for burn survivors concluded that those who reported peer support attendance had better social interaction scores than those who did not. This included fewer restrictions in participating in social activities, relating and maintaining friendships and dealing with strangers . A studyIn comparison, a longitudinal study that involved a facilitator-led programme of face-to-face peer support alongside group-based education for people with heart disease who had completed centre-based cardiac rehabilitation reported that social support did not change between baseline and 12-month follow-up . AdditioPhysical Health OutcomesOne study in this review reported a positive impact of peer support on physical health outcomes in individuals with uncontrolled diabetes . A mixedIn contrast, an RCT that evaluated the effect of a telephone-based peer support programme in patients with type 2 diabetes found that peer support did not improve cardiometabolic wellbeing . AnotherEconomic OutcomesAn economic evaluation of a mixed delivery peer support intervention concluded that peer support was associated with lower overall total healthcare costs, which were largely due to a decrease in hospitalization expenses . The evaQualitative FindingsSome participants described peer support as “a significant turning point in their lives”  and someMuch of the qualitative findings suggest that peer support can be beneficial for individuals across various population groups. However, some limitations of peer support were discussed among these positive findings. For example, one study reported that participants experienced raised anxiety related to the future, occasional hopelessness and despair as a result of seeing others with more severe functional disabilities . FurtherDiscussionThe heterogeneity in findings within the included studies is clear across the various outcomes, namely, psychological, functional/social/behavioural, health and economic. Studies that included qualitative analysis as their method of evaluating peer support programmes appear to offer more consistency in terms of findings, with most suggesting a beneficial impact for participants. This could mean that the impact of peer support is experienced by participants in various settings, however, the actual impact may not be observable or measurable.There was considerable variation in the methods used for the delivery of peer support in the included studies. It is therefore difficult to review study findings as a collective. Some interventions focused predominantly on the delivery of peer support as its main component, whilst other interventions focused heavily on education methods with additional peer support. Consequently, it would not be appropriate to attribute peer support as the main influencer of outcomes.Noteworthy, the majority of included studies did not report any long-term outcomes of associated peer support interventions. One study that did, discussed negative feelings reported by participants as a result of seeing others with more severe functional disabilities . This suStudies that included a measurable peer support component ranged considerably in terms of the length of time of the delivery of peer support, from four weeks  to two pThere was considerable variation in the measures used to quantify the impact of peer support. For example, the most commonly cited psychological outcome measure was self-efficacy with two of the included studies reporting this outcome -14. HoweWe also examined the impact of timing provision of peer support. O'Dell et al. reported that spinal cord injury patients were not always prepared to process information in the acute stages after injury, therefore consideration needs to be made around when the patient is the most receptive to receiving peer support . No findLimitationsThis scoping review is limited in terms of the population group considered, namely, those with physical health conditions. Alternative populations that have been shown in the literature to utilize peer support include families and carers of individuals with physical health conditions -31; mentIn conclusion, this scoping review draws attention to the difficulty in assessing the impact of peer support on general physical health populations due to the heterogeneity in participants, study design, intervention implementation, outcome measures and findings within the included studies. In terms of answering the research question, there appears to be greater consistency in the qualitative methods of the evaluation of peer support as compared to objective methods of evaluation. Synthesis of qualitative findings was grouped into general themes across included studies: (1) peer support leading to a sense of belonging or a sense of community, leading to reduced isolation and feeling understood; (2) peer support as a means of providing and/or consolidating information; (3) peer support as helpful for decision-making; (4) peer support leading to empowerment; and (5) peer support helpful for aiding self-management behaviours. The impact of peer support on objective outcome measures is mixed, with some research suggesting that peer support has a greater impact on those with higher levels of negative psychological affect than those with lower levels. Further research could look to explore this suggestion. Finally, this scoping review has highlighted the need for the piloting of peer support in acute physical health settings in order to bridge the gap that this review has identified in peer support research.


Pathogen transmission is a key point not only for infection control and public health interventions but also for understanding the selective pressures in pathogen evolution. The “success” of a pathogen lies not in its ability to cause signs and symptoms of illness but in its ability to be shed from the initial hosts, survive between hosts, and then establish infection in a new host. Recent insights have shown the importance of the interaction between the pathogen and both the commensal microbiome and coinfecting pathogens on shedding, environmental survival, and acquisition of infection. Pathogens have evolved in the context of cooperation and competition with other microbes, and the roles of these cooperations and competitions in transmission can inform novel preventative and therapeutic strategies. Transmission of pathogens is a multifactorial process by which a pathogen must be shed from an infected host, survive its transit between hosts, and then establish an infection in a new host. Understanding transmission dynamics of pathogens is key to control of endemic and epidemic infections. In addition, transmission is a point at which pathogens are under selective pressures, since the ultimate “success” of a pathogen is related not only to its ability to cause disease in its hosts but also to its ability to establish productive infections in new hosts. Pathogen transmission can be direct or indirect, it can involve many host species for a pathogen to undergo a complex life cycle, or it can be confined to a single host species. Transmission can occur over short distances of space or time, or a pathogen can spend a long time or distance in the air or associated with a biotic or abiotic surface between hosts.5 cholera  lambda by gut commensal bacteria can lead to persistent murine norovirus infection . IFN lamnfection ; howevernfection . Local p the gut . Immunom the gut . Alterat the gut .Staphylococcus aureus infection (Lactobacillus crispatus colonization can promote epithelial cell growth and barrier integrity (Gardnerella vaginalis, Atopobium vaginae, and Prevotella bivia, which are considered “bad” vaginal microbiota, act to disrupt tight junctions and can promote the acquisition of the protozoan pathogen Trichomonas vaginalis (Another beneficial function of the microbiota in preventing infection is the promotion of epithelial barrier integrity , with minfection . In the ntegrity , but Garaginalis .Bordetella bronchiseptica led to reduced ciliary action and enhanced susceptibility to colonization and infection with Streptococcus suis (Barrier function in the respiratory tract is enhanced by mucociliary clearance. The human disease cystic fibrosis results in altered viscosity of mucus and reduced mucociliary clearance, enhancing susceptibility to bacterial colonization and infection of the lower respiratory tract. Alterations of mucociliary clearance can also be bacterially mediated. Colonization of porcine lung tissues with cus suis .Lactobacillus reuteri, known as reuterin, leads to production of reactive oxygen species by Clostridioides difficile to reduce C. difficile outgrowth (Cryptosporidium parvum is inhibited by medium- or long-chain saturated fatty acids derived from microbiota, and yet long-chain unsaturated fatty acids enhanced the invasive potential (C. difficile growth, Bloutia and Clostridium sporogenes metabolites can reduce toxin expression by C. difficile (Production of toxic metabolites is another mechanism by which the commensal microbiota prevent colonization and infection by pathogens. A secreted product of the human commensal utgrowth . Microbiotential  of the pifficile , 137. Inifficile .Streptococcus pneumoniae can inhibit IAV infection when bacterial sialidase removes terminal sialic acid residues used for viral attachment and infection (Neisseria gonorrhoeae infection stimulates cytokine production, increasing both immune cell trafficking to the cervix and expression of viral receptors enhancing HIV infection (The microbiota or coinfecting pathogens can alter host cell receptor expression to both enhance and inhibit pathogen infection. Colonizing nfection . Neissernfection .Haemophilus influenzae upregulates pili in virally coinfected cells, increasing colonization and invasive potential (Staphylococcus and Candida (Enterococcus and Candida (Streptococcus agalactiae obtaining antimicrobial resistance from coinfecting sexually transmitted pathogens (Quorum-sensing signals from coinfecting pathogens or cytokine signals from infected hosts—even those infected with a different pathogen—can alter bacterial behavior and lead to enhanced pathogenesis. Nontypeable otential . Pathogeotential  or gut (otential , which c Candida  and Ente Candida  forming athogens .Polymicrobial interactions can enhance or reduce pathogen transmission. Greater understanding of the roles of normal and pathogenic members of the microbiome, mycobiome, and virome on transmission of pathogens can lead to insights into control of both endemic and epidemic transmission. Linking certain natural or altered microbial communities to “supershedding” events could explain spillover events in zoonotic transmission and the asymmetric shedding seen in epidemics when 20% of cases cause 80% of new cases . In addi


Musculoskeletal conditions are known to involve biological, psychological, social and, often, lifestyle elements. However, these domains are generally considered in isolation from each other. This siloed approach is unlikely to be adequate to understand the complexity of these conditions and likely explains a major component of the disappointing effects of treatment. This paper presents a hypothesis that aims to provide a foundation to understand the interaction and integration between these domains. We propose a hypothesis that provides a plausible link between psychology and lifestyle factors with tissue level effects (such as connective tissue dysregulation/accumulation) in musculoskeletal conditions that is founded on understanding the molecular basis for interaction between systemic and local inflammation. The hypothesis provides plausible and testable links between mind and body, for which empirical evidence can be found for many aspects. We present this hypothesis from the perspective of connective tissue biology and pathology (fibrosis), the role of inflammation locally (tissue level), and how this inflammation is shaped by systemic inflammation through bidirectional pathways, and various psychological and lifestyle factors via their influence on systemic inflammation. This hypothesis provides a foundation for new consideration of the development and refinement of personalized multidimensional treatments for individuals with musculoskeletal conditions. Changes in connective tissue influence the physiological and mechanical functioning of musculoskeletal tissues and are increasingly recognized in musculoskeletal conditions . UnderstTissues, including connective tissues, generate an inflammatory response in multiple contexts. This includes the response that is essential for the clearance of necrotic cells and repair after tissue injury ,3,4, exeSkeletal muscles, tendons and nerves are each hierarchically organized tissues that employ structural bundling. The individual elements—myofibers in muscles, collagen fibrils in tendons and axons and Schwann cell sheaths in nerves—are surrounded by a small amount of delicate connective tissue , which are bundled into fascicles by a slightly denser collagenous connective tissue . The entire muscle, tendon or nerve is surrounded by a dense external sheath of connective tissue . These fascial components act as cushions, allow movement and transfer of force between the tissues and carry blood vessels and nerves into and out of subcomponents ,8. NumerAcute inflammation is characterized by a rapid accumulation of fluid, neutrophils and plasma cells in the affected tissue. The first signals released from damaged and necrotic cells are damage-associated molecular pattern molecules (DAMPS) that include interleukin-1 alpha . DAMPs are chemotactic for neutrophils, as are several chemokines (chemotactic cytokines) produced by neighboring uninjured cells after DAMP exposure . The neuMacrophages are activated and polarized into M1 (proinflammatory) or M2  phenotypes ,15. ManyThe next essential step for tissue repair and regeneration is a transition from a proinflammatory milieu to an anti-inflammatory one . IncreasThis predominantly cytokine-driven acute phase response occurs not only at the localized site of injury for immune cell recruitment but, also, in distant tissues, including the liver and brain, in order to amplify or depress humoral defense components ,23. The Local muscle inflammatory responses and connective tissue adaptation is initiated not only by direct injury to muscle but, also, in response to injuries to related (nearby) joint structures. This has emerged as an explanation for structural changes in the paraspinal muscles (particularly the multifidus muscle) that are commonly observed in low back pain ,25, and Inflammatory cytokines are released from contracting skeletal muscle cells during exercise . IL-6 isAlthough skeletal muscle damage is not required for the release of IL-6 from muscle during and after exercise, prolonged elevated concentrations of muscle-derived IL-6 are thought to indicate greater damage resulting from microtrauma to the contractile elements and connective tissue within muscle ,36. UndeUnder some conditions, the ability to clear injured tissues of pathogens and debris is impaired, mechanisms regulating inflammatory responses are altered and/or injury–repair cycles are too persistent for the complete resolution of inflammation. In either case, inflammation can become enhanced, persist and spread to include previously uninjured tissues. Inflammatory cytokines in tissues can also elevate to detectable levels in circulation, a change that is often paralleled by inflammatory responses at sites distant from the initial injury site . UnresolChronic inflammation is characterized by the prolonged presence of inflammatory M1 macrophages and neutrophils that have amplified the primary acute inflammatory response by their enhanced production of proinflammatory cytokines. Their continued phagocytosis and release of cytotoxic effectors  promotes secondary tissue damage in cells and tissues surrounding the original injury site . The expRepeated injury and damage cycles in muscles are associated with marked increases in noncontractile tissues (primarily collagen) ,43. ThisThe notion that inflammatory events can impact remote tissue health has been identified in some chronic conditions  but has been relatively unexplored in musculoskeletal conditions. The overall concept is underpinned by the dynamic feedback loops between local tissue and systemic inflammation. Elevated systemic inflammation induces a proinflammatory response in tissues, such as muscles distant from an injury site . ConversChanges in systemic inflammation alter the inflammatory environment in musculoskeletal tissues. The induction of acute systemic inflammation via intraperitoneal injection of LPS in animals increases the expression of TNF, IL-6 and IL-1β in skeletal muscle within 2–12 h ,71. MoreThe impact of “chronically” elevated systemic inflammation on local tissue inflammation is complex and difficult to directly assess. Insights can be drawn from studies that have examined muscles from patients with conditions characterized by chronic low-grade systemic inflammation, such as obesity, diabetes and some chronic musculoskeletal conditions . Muscle The impact of systemic inflammation on the local inflammatory environment, and their bidirectional relationship, provides a potential explanation for enhanced fibrosis in musculoskeletal tissues. Elevated levels of circulating proinflammatory cytokines are simultaneously present with fibrosis in a wide range of conditions . ChronicThe Autotaxin/Lysophosphatidic acid (ATX/LPA) pathway mediates inflammation and fibrosis and is upregulated in numerous fibrotic conditions  . LPA is The systemic inflammatory environment is modulated by factors other than those directly associated with “immune” function. These include psychological or lifestyle features, and the health consequences are broad. Growing evidence of the capacity for systemic inflammation to influence local inflammation provides a plausible link between these factors and the health of musculoskeletal tissues.Many psychosocial factors are associated with increased systemic levels of proinflammatory mediators  and decreased anti-inflammatory mediators  ,138,139.Consistent with the capacity for stress to modulate immune function, and the role of psychosocial stress as a risk factor for the development of various psychological conditions ,149, infAlthough very few, if any, studies have focused on the potential implications of inflammation induced by stress/psychology on the health of tissues, the notion is supported by empirical evidence. For example, stress is associated with inflammatory-related symptoms  in rheumatoid arthritis ,159,160.Research is continuing to reveal prominent candidate factors that induce systemic inflammation. Sleep is a well-known modulator of systemic inflammation ,172. SleOther lifestyle factors also impact systemic inflammation. For instance, physical activity/exercise strongly promotes anti-inflammatory processes and suppresses proinflammatory processes ,192, wheThe hypothesis that the systemic inflammatory environment can substantially influence musculoskeletal inflammation and fibrogenesis, and that various psychosocial and lifestyle factors can impact systemic inflammation, provides a new understanding of the bio-psycho-social nature of musculoskeletal conditions and the need to consider musculoskeletal health from a “whole system” perspective that integrates both body and mind. Many of the psychological, lifestyle and biological mediators/moderators of systemic inflammation are reciprocally related, meaning a disturbance to any could have pathological consequences on the other, setting up a vicious cycle that results in excessive inflammation with potential implications for local tissues. On the flipside, this opens the enticing possibility that interventions aimed at one aspect  could positively affect the others.An issue when viewing musculoskeletal health from a “whole system” perspective is that the list of potential contributors is vast. Although research has highlighted factors that potently impact inflammation , further work is necessary to understand the potential clinical relevance of these interactions for the development of connective tissue changes in musculoskeletal conditions. For instance, does the combination of specific factors have a cumulative—or greater—effect on inflammation and musculoskeletal health? Do “good” lifestyle choices  offset the impact of “bad” choices ? Do some factors have a greater short- and/or long-term impact on inflammation and tissue health when present earlier versus later in the injury cycle, and vice versa? The latter may have relevance for considering which factors to treat at different stages  of the injury or condition. This information would be foundational for guiding treatments aimed at preventing and reversing these changes.The hypothesis presented in this paper provides a foundation to consider potential roles for a diverse array of treatments for the prevention and resolution of connective tissue changes in musculoskeletal conditions. The new hypothesis suggests even the potential for tissue-level effects from interventions targeting psychosocial and lifestyle factors. Overall, the interaction between local and systemic inflammation highlighted in this hypothesis provides a foundation to consider the potential diverse effects of many interventions. For example, psychosocial interventions such as cognitive behavioral therapy (CBT) applied to address depression or insomnia can reduce systemic inflammatory activity . MoreoveThis paper presents a hypothesis that provides a new foundation to understand the connection between body and mind in musculoskeletal conditions. With the interaction between local and systemic inflammation at its core, the hypothesis provides a plausible and testable link from psychology and lifestyle to connective tissue health that might guide the development of more effective targeted treatments in musculoskeletal conditions.


A series of mortalities among musculoskeletal tumour patients secondary to medical illnesses during the first few months of the pandemic highlighted the need to review our methods of communication with patients. Prominent among patients’ concerns had been a fear of consulting at hospitals and a lack of ready access to health care. Recommendations are made for proactive consultation and patient education, identifying at-risk patients for follow-up and probing for possible co-morbidities. Telemedicine use is encouraged bearing in mind its inherent limitations. A network of physicians and pharmaceutical representatives is an added help we can offer our patients who may be isolated by community quarantine. Countries responded initially by enforcing lockdown or enhanced community quarantine (ECQ) in an attempt to contain further spread. In the Philippines, complete lockdown was enforced March 16, 20202. Several tertiary government hospitals, including our center, the University of the Philippines-Philippine General Hospital, were declared COVID-hospitals by the Department of Health, severely curtailing non-COVID related admissions and surgeries in these centers. Private hospitals, overwhelmed by the unexpected initial wave of COVID patients, were also forced to redirect personnel and logistics to address the viral onslaught3.The first cluster of novel coronavirus infection reported in Wuhan, China has mushroomed into a global pandemic, affecting over 65 million people with over 1.5 million deaths worldwide4. This was likely due to travel restrictions, fear of hospital visits with some patients opting to defer surgeries, and the cessation of face to face out-patient consultations.In response to these government and hospital directives, surgical lists were quickly completed, prioritising emergent and urgent cases while cancelling elective surgeries and post-operative in-hospital stays were cut short in order to free up hospital beds for the anticipated deluge. Surgeries on patients not previously admitted were put on hold and cases re-evaluated for urgency of care. Even as musculoskeletal malignancies were given priority, the number of cases also saw a gradual decline after completion of the initial surgical listBut even as the number of orthopaedic tumour surgeries decreased, we received reports of some of our musculoskeletal cancer patients being brought to the emergency room, both at our center and in other medical facilities, only to succumb to seemingly unrelated medical conditions.J.G. 38/M was scheduled for an above-knee-amputation for a large synovial sarcoma of the left leg. Lung metastases and primary tumour remained unchanged despite neoadjuvant chemotherapy. Just before surgery, ECQ was enforced and J.G. started on oral targeted therapy while awaiting surgery schedule. During this time, despite developing a persistent cough, he deferred consultation for several weeks due to fear of COVID infection until he became dyspneic and febrile. At the emergency room, he was intubated; a diagnosis of community-acquired pneumonia was made but he expired shortly after intubation.P.L. 68/F had a recurrent malignant melanoma of the left upper arm for which she deferred surgery since start of the pandemic. She finally decided on surgery four months into the pandemic but while initiating clearances for surgery, she developed fever and disorientation. At the emergency room, it was discovered she had urosepsis and though she had earlier urinary tract symptoms, she had been wary to seek consultation. She succumbed to fatal arrhythmia triggered by the systemic infection.A.M.F. 52/F had papillary thyroid CA with a large metastatic left proximal humerus lesion. In preparation for possible surgery, the tumour was subjected to arterial embolisation, shortly after which a lockdown was declared. The patient returned home to a nearby province and could not travel back to Manila for follow-up or treatment. Neither was she able to secure appropriate medication or schedule a clinic visit in her hometown. Two weeks later, she developed chills and vomiting and was brought to the emergency room of a local hospital where she expired. Cause of death was unknown to us.What had happened? While awaiting surgeries, patients had developed other medical problems but they had either refused to consult at hospitals or were unable to access appropriate medical care. Both scenarios might be a reflection of insufficient communication between health care providers and patients; even if the former had prescribed medications, clarified surgical schedules and provided general instructions for continuing care.5. Chen et al, in a prospective study on lung cancer patients in a Taiwanese hospital during the SARS epidemic, showed that nearly two-thirds of patients were afraid of entering a hospital for fear of acquiring SARS, and some patients ceased chemotherapy altogether6. This was also evident in a group of noncancer paediatric patients where fear of infection with SARS-CoV-2 prevented parents from accessing hospital care, resulting in admissions to ICU and non-COVID related mortalities7. Patients need to be reminded to seek continuing medical care, and equally importantly, be reassured that visits to health providers are safe and possible as long as proper precautions are undertaken. Clinicians, in general, should go beyond their normal scope of work to educate the public and allay their fear and concerns, and assure them that they still have access to high-quality, multidisciplinary care for any medical (illness)8.Providing instructions to patients similar to pre-COVID times may be inadequate as there are other important factors in play which impact on patient health-seeking behaviour during a pandemic. For example, it is important to recognise the increased level of distress that cancer patients and their families might face not only about their diagnosis and treatment but also about the pandemic itselfIt may also be necessary, especially during the pandemic, to provide proactive follow-up on select high-risk patients rather than rely on them to follow-up on their own. This group of patients would include those on adjuvant treatment, whether chemotherapy or radiotherapy, patients with malignant neoplasms and older aged patients.5. Telemedicine has been demonstrated to improve access to care and decrease health care costs9. But while virtual care is one of the best alternatives to reduce hospital footprint, it is also still a method of communicating with patients relatively unfamiliar to clinicians. The details and subtleties of interactions with patients, such as body language and verbal responses may be difficult to capture in teleconsultations10. As such, doctors may be unable to capture and patients unable to fully express their fears about both their condition and their concerns about visits to health care facilities.Telemedicine is now routinely used to communicate with patients remotely via hospital hotline and expanded telehealth capabilities11. Similarly, Omarini et al12 noted a much higher rate of mortality (22%) among cancer patients on active anticancer drugs compared to the population without cancer of the same age. Restriction of movement and confinement to homes with limited walking areas in patients whose musculoskeletal cancers already limit mobility can only further adversely affect both physical and mental health as was evident in the presented patients.It will be helpful therefore for the clinician during teleconsultation with a cancer patient to remember the latter’s vulnerability to infection and the frequent presence of accompanying comorbidities in cancer patients. Probing questions can be asked by the clinician in an attempt to ferret out these problems. Exactly how susceptible cancer patients are to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has yet to be established. But patients with compromised immune systems are thought to be particularly vulnerable. Individuals who are undergoing active treatment with chemotherapy or radiotherapy are deemed to be at heightened risk of severe illness from COVID-1913. Our second patient had recently developed a urinary tract infection which had not been identified and managed during the ECQ. Left untreated, she developed urosepsis and eventually succumbed to the infection. The negative impact of comorbidities on cancer is amplified by their suboptimal treatment during the COVID pandemic, whether from difficulty accessing health care or from the patient’s own fears about visiting health care facilities.At the same time, comorbidities have been consistently found to adversely affect cancer survival15.Finally, as it is not always possible to predict which health facilities will remain open during a pandemic, clinicians can proactively identify a physician network and provide patients with a list of clinicians they can consult with in their hometown. The same can be done for representatives of pharmaceutical companies in order for patients to have easy access to cancer medications. Upon declaration of ECQ, patient 3 could neither travel back to our hospital nor access specialists and medications in her hometown. While these problems are true around the world, some of them are further highlighted in the setting of low and middle-income countries (LMIC)Maintain open lines of communication with patients at all timesActively educate patients about the ongoing pandemicAllay patients’ fears about hospital visits, reassuring them about hospital safety as long as everyone is properly protectedProactively identify at-risk patients and regularly follow-up on them rather than wait for them to follow-upActively use telemedicine but be aware of its inherent limitations especially the difficulty of identifying the details and subtleties of interactions more readily detectable in physical consultationsRemember that cancer patients can be more prone to infections and have associated comorbidities which may remain undetected; thus, the need to try and ferret out these problems with probing questionsProactively identify a physician and pharmaceutical network to provide healthcare and medicine access to patients who may be stranded in their hometowns due to community quarantineIn summary, a series of mortalities during the start of the pandemic among musculoskeletal tumours patients awaiting surgery highlights the need for us clinicians to:While these modifications to our communication with patients are modeled and implemented during this pandemic, they may very well be adopted for future pandemics and calamities in order to further improve health care delivery to our patients.