A key barrier to translation of biomedical research discoveries is a lack of understanding among scientists regarding the complexity and process of implementation. To address this challenge, the National Science Foundation’s Innovation Corps™ (I-Corps™) program trains researchers in entrepreneurship. We report results from the implementation of an I-Corps™ training program aimed at biomedical scientists from institutions funded by the National Center for Advancing Translational Sciences (NCATS).n = 55 teams), and 3–12 months post-training (n = 34 teams).National/regional instructors delivered 5-week I-Corps@NCATS short courses to 62 teams  across six institutions. Content included customer discovery, value proposition, and validating needs. Teams interviewed real-life customers and presented the value of innovations for specific end-users weekly, culminating in a “Finale” featuring their refined business thesis and business model canvas. Methodology was developed to evaluate the newly adapted program. National mixed-methods evaluation assessed program implementation, reach, effectiveness using observations of training delivery and surveys at Finale , drugs/biologics (20%), software applications (16%), and diagnostics (8%). An average of 24 interviews was conducted. Teams reported increased readiness for commercialization over time . Thirty-nine percent met with institutional technology transfer to pursue licensing/patents and 24% pursued venture capital/investor funding following the short courses.I-Corps@NCATS training provided the NCATS teams a rigorous and repeatable process to aid development of a business model based on customer needs. Outcomes of this pilot program support the expansion of I-Corps™ training to biomedical scientists for accelerating research translation. In April 2017, the National Center for Advancing Translational Sciences (NCATS) funded a 2-year supplement to develop the I-Corps@NCATS program (NIH GRANT UL1TR001417). The goal of the supplement was to develop and disseminate a training modeled on the National Science Foundation’s (NSF’s) Innovation Corps (I-Corps™) program  really comfortable on the front end. I can set up a nice test – RCT [to] test efficacy. I feel really comfortable with that. Often, we stop there in academia, and so [I-Corps™ has] really opened up the back end – the dissemination piece – and how we can actually make this more scalable and be thoughtful about [that] even before the train leaves the station, if you will. That is something that I-Corps™, I think, has really helped.In addition to the instructional and entrepreneurial capacity established during the supplement, evaluation capacity was also achieved. Specifically, national evaluators, in consultation with national and regional instructors, delineated appropriate outcomes; developed, piloted, and refined instruments for tracking teams’ highly contingent commercialization pathways; and, provided preliminary evidence regarding program impact. We learned that program participation can fundamentally change the way clinical and translational investigators think about their research and how they might optimize translational impact. As one participant stated:This finding – that I-Corps@NCATS can enhance translational and entrepreneurial thinking – has profound implications for longer-term outcomes related to grant writing, research productivity and impact, academic and career trajectories, teaching and mentorship. The evaluation also highlighted that commercialization, not unlike other types of translation, takes time. Specifically, the proportion of teams who reported that they were ready for commercialization increased incrementally over the first few months following program participation. Still, other teams realized relatively quickly that they needed to make a “no go” decision – another positive outcome of I-Corps@NCATS, which gives teams the tools and techniques to “fail fast” before investing time and monetary resources in either a) developing a research solution for a problem that does not exist (from the perspective of the user) or, b) if the problem does exist, investing in the development of a solution that is not a good fit.For teams moving forward with the product that was the focus of the I-Corps@NCATS short course , mentorship support, particularly from industry, was critically important and a major need. Longitudinal survey data suggest that teams lack industry mentorship and commercial connections even though many remain connected to I-Corps@NCATS instructors. Because they are based in academic biomedical research institutions, CTSAs may struggle to establish relationships with industry. Yet, not having connections to industry can negatively impact translation. While very few teams were ready to pitch their ideas to industry, such connections might facilitate networking to continue the customer discovery process and provide access to other types of resources, including locations for field testing innovations and connections to future investors . The finThe I-Corps™ at NIH program specifically supports SBIR-STTR awardees, which must have established a company structure. Establishing a company has not been a benchmark of success for biomedical researchers who are challenged, instead, to maintain continuous grant funding and produce peer-reviewed publications in high-impact journals. Furthermore, starting a company may have even less salience for teams working at different phases of the translational research spectrum; for example, “translation to population” teams may be looking for non-profit sustainability models for their health interventions. Also, teams working on drugs, devices, and diagnostics may define success as out-licensing, rather than creating a company, given that out-licensing has been a model more commonly pursued by university-based technology transfer offices . This miWhile I-Corps@NCATS teams were eligible to participate in the NSF I-Corps™ National program, we found that the 7-week duration of the NSF National I-Corps™ program, and the 100+ customer interview requirement, may not be feasible for biomedical researchers. Medical campuses are more likely to have a “soft money” academic funding model and 12-month academic appointments. Consequently, faculty compensation and promotion are dependent upon generating clinical revenue and/or funding from federal grants. Teams may have to plan a semester or more in advance as they juggle clinical, research, and administrative responsibilities with other teams and administrative units.It is noteworthy that during the supplement no teams applied to the national NSF I-Corps™ program, even though teams that had completed I-Corps@NCATS were eligible. Site PIs noted, however, that teams from their sites, who completed the short course previously, had gone on to participate in the national NSF program. Taken together, these findings suggest that teams completing the course during the supplement may not have matured to the point that they were ready for the national NSF program. It may also be that, while the short course has been successfully adapted for clinical and translational scientists and the context of CTSAs, a similar effort to tailor the national program for this audience is needed to enhance acceptability, accessibility, and participation. In processing the finding regarding lack of participation in the national program, site PIs and instructors noted the following aspects of the national I-Corps™ at NIH program that make it difficult for researchers, clinicians, and trainees in life sciences to participate:Exploring ways to tailor the I-Corps™ at NIH program for clinical and translational scientists and teams may be an important future direction to consider. Site PIs and instructors noted strategies to help bridge the short course and the national NIH program. For example, some sites incorporated seed grants into their CTSA programs to provide teams that had successfully completed the short course with additional funding to continue the customer discovery process and to travel to professional meetings and trade shows to network and initiate industry-based mentorship relationships. Site PIs and instructors also noted the importance of having team members at an earlier stage of their careers. Graduate students, trainees and early-career investigators may be more agile in terms of their ability to carve out time and may be more willing to consider alternative career paths, with the latter serving as a major source of motivation to invest in attending the national training program. One site PI hypothesized that “the more we can engage trainees, the more likely we are to see teams go to the national program.” The site PI called this “flow through talent,” referring to the person on the team who may be less invested in pursuing a more traditional academic research trajectory and, therefore, willing to assume a leadership role (and the associated risk inherent) in starting a company.We will increase the reach of I-Corps@NCATS across CTSA institutional boundaries by offering online programs. This past year, all I-Corps™ national programs have had to quickly pivot to a completely online format. For at least the first year of implementation, I-Corps@NCATS will also be offered online. This has the potential to significantly expand access to the program for potential teams, while reducing costs associated with travel. The online format enables us to accept teams from any CTSA hub, as well as include additional CTSA hubs as observer/mentee sites.We will expand access to the resources needed for staffing the I-Corps@NCATS training program by connecting with each CTSA hub’s unique translational and entrepreneurial ecosystems. Personnel are needed to enhance site PI capacity to recruit teams; disseminate information regarding the program ; and, to connect teams to industry mentors. Many of our participating CTSA hubs are linked to existing I-Corps™ resources, including NSF I-Corps™ sites, regional nodes, and state-run programs, such as I-Corps@Ohio, although in many instances these programs are at best only loosely connected. By working across institutional internal and external boundaries, I-Corps@NCATS participation will help build local entrepreneurial ecosystems by connecting I-Corps™ activities among NIH funded life sciences, NSF funded STEM innovations, local innovation centers, and industry partners.To sustain high-level fidelity, we will maintain a structure for connection and collaboration across I-Corps@NCATS sites to build a national community of practice to share insights and lessons learned. This will also allow us to better leverage the CTSA network to facilitate I-Corps@NCATS teams’ engagement in customer discovery. Clinical and translational scientists need to better understand how things work in hospital settings, for patients, nurses, and surgeons, and the CTSA hubs are the place to find people to interview. This is an essential value-add of creating synergies between the CTSA hub network and I-Corps™ programs to accelerate the translation of biomedical discoveries into improved patient care.Finally, we will disseminate evaluation products  with the program model to standardize data collection and reporting. This will support the ability to aggregate process and outcome measures across teams and CTSA sites to assess collective capacity for consistent, effective program delivery and impact.Building upon the successful development and dissemination of the I-Corps@NCATS pilot program, in 2020 the University of Alabama at Birmingham CTSA hub received supplemental funding to expand the I-Corps@NCATS program through a CTSA Competitive Revision award, grant number 3UL1TR003096-02S1. Leveraging the nine CTSA hubs participating in the pilot as mentor sites, we will train an additional 13 CTSA Hubs over the next 3 years to bring the total number of I-Corps@NCATS-trained CTSA hubs to 22 – over a third of the CTSA hub network. The following CTSA hubs are serving as mentee sites: Case Western Reserve, Columbia University, the Medical College of Wisconsin, the Medical University of South Carolina, Northwestern University, Oregon Health & Science University, Rutgers University, University of Buffalo, University of Chicago, University of Rochester, University of Texas – Medical Branch, and the University of Virginia. Building upon the lessons learned featured in this paper, we will integrate the following program enhancements into future I-Corps@NCATS program offerings as we seek to further expand I-Corps@NCATS within the CTSA context:Over the next 3 years, we aim to offer 21 I-Corps@NCATS short courses across 22 CTSAs, reaching over 3000 translational scientists throughout the career arc and accelerating the translation of over 600 biomedical innovations for improved patient care. With the addition of online programs, we are able to expand our reach to translational scientists across the CTSA hub network, including partner institutions that may not have access to local alternatives. Through I-Corps@NCATS, we aim to significantly accelerate the path from lab discovery to improved human health by ensuring our research teams not only conduct scientifically rigorous research, but also research that has demonstrated relevance to our healthcare communities and the potential for impact through the pathway of commercialization.


Coxiella burnetii; however, evidence reinforcing their role in human infection is scarce. Most published human Q fever outbreaks relate to exposure to small ruminants, notably goats. Anti-phase II C. burnetii IgG and IgM were measured by indirect fluorescent antibody tests in 27 farm and veterinary diagnostic laboratory workers to ascertain whether occupational exposure to cattle aborting due to C. burnetii was the probable source of exposure. Four serological profiles were identified on the basis of anti-phase II IgG and IgM titres. Profile 1, characterised by high IgM levels and concurrent, lower IgG titres ; Profile 2, with both isotypes with IgG titres higher than IgM ; Profile 3 with only IgG phase II ; and Profile 4, in which neither IgM nor IgG were detected . Profiles 1 and 2 are suggestive of recent C. burnetii exposure, most likely 2.5–4.5 months before testing and, hence, during the window of exposure to the bovine abortions. Profile 3 suggested C. burnetii exposure that most likely predated the window of exposure to aborting cattle, while Profile 4 represented seronegative individuals and, hence, likely uninfected. This study formally linked human Q fever to exposure to C. burnetii infected cattle as a specific occupational hazard for farm and laboratory workers handling bovine aborted material.Cattle are broadly deemed a source of  Coxiella burnetii causes the zoonosis Q fever, a disease which typically occurs after the inhalation of aerosolised contaminated material from the placenta or birth fluids of ruminants following either abortion or normal delivery [Coxiella burnetii by ingestion of contaminated raw dairy products is equivocal; infection was reported after consumption of raw cow’s milk [C. burnetii in cattle [C. burnetii as the cause of bovine abortions that were epidemiologically associated with Q fever outbreaks in Germany and Poland, but other common bovine abortifacient agents such as Neospora caninum and Brucella abortus were not investigated [C. burnetii-positive bovine abortions.delivery ,2. Evidew’s milk  and contw’s milk ,5, but nw’s milk . Althougn cattle  and cattn cattle ,9,10,11.n cattle ,13. Onlystigated ,15. We aQ fever is asymptomatic in approximately 60% of cases . Acute cC. burnetii immunoglobulins . During infection, phase II antigens appear to dominate immunoglobulin responses [Variation in the lipopolysaccharides of the bacterial outer membrane results in antigenic phases that determine diverse types of anti-esponses  and immuesponses ,23,24. Iesponses ,26.C. burnetii, this study presents more substantial laboratory evidence for a specific occupational hazard for workers exposed to aborted cattle or handling material from bovine abortions.While no previous human Q fever outbreak has been firmly related to bovine abortion caused by C. burnetii antigen in trophoblasts by immunohistochemistry and PCR amplification of DNA, and other abortifacients of cattle were ruled out by comprehensive testing [C. burnetii.Following an outbreak of bovine abortion in a dairy herd in Colonia Department, Uruguay, placentas and full-term foetuses from four aborting cattle were collected by farmworkers and submitted to the local veterinary diagnostic laboratory between 10 April and 2 June 2017. Bovine coxiellosis was confirmed on the basis of typical placental lesions on histopathology, with identification of intralesional  testing . The outC. burnetii phase II IgM and IgG antibodies. Data were made available by explicit agreement of the workers who were assured of confidentiality. Details about medical treatments could not be accessed. No animal or human samples were collected or analysed expressly for this study and results of laboratory testing were evaluated for this study as a secondary analysis. The study was granted ethical approval by the ethical committee from the University of Bristol (Ref.95382/Id.342095).Written consent was obtained from all patients and their information was anonymised. Records comprised demographic data such as age, gender, clinical findings obtained during a medical examination, pre-existing medical conditions and the individual laboratory indirect fluorescent antibody test (IFAT) results for anti-C. burnetii.Records of diagnoses made by the local veterinary diagnostic laboratory between 10 April 2016 and 21 August 2017 were examined to rule out other potential exposures of laboratory workers to C. burnetii phase II IgM and IgG antibodies by the Mayo Clinic Laboratory  using the indirect fluorescent antibody test (IFAT) for anti-C. burnetii phase II IgM and IgG antibodies [Serum samples were analysed for anti-tibodies ,29.C. burnetii phase II IgM and IgG antibodies were considered to be seronegative and those greater or equal to 1/16 were considered to be seropositive. The percentage of seropositivity was calculated as the number of seropositive individuals (titre ≥ 1/16) divided by the total number of workers tested. Phase II IgG to IgM ratios were calculated by dividing the IgG titre by the IgM titre. Univariable and multivariable analyses were conducted in which the IFAT status (seropositive or seronegative) was considered as the binary response variable. Gender , age group  and work activity (farm and laboratory) were included as explanatory variables in univariable and multivariable logistic regression models used to gain insight into factors (and their interactions) influencing C. burnetii seropositivity and to calculate odds ratios (OR) and their confidence intervals (CI95%). Statistical analysis was performed using RStudio software [Titres less than 1/16 in the IFAT for anti-The study population comprised 27 individuals who worked either on the farm, in the laboratory or both. Twenty-three individuals conducted at least some of their work on the farm, these comprising thirteen farm workers, two veterinary practitioners and eight laboratory workers. Twelve individuals conducted at least some of their work in the veterinary laboratory, these comprising the eight laboratory workers, who also conducted some farm work, and four further laboratory workers who did not.C. burnetii phase II greater or equal to 1/16, and, of these, five also had detectable titres of IgM. Of the 23 conducting work on the farm, eight (34.8%) were IgG positive and four (17.4%) of these were also IgM positive. Seven of the twelve (58.3%) conducting lab work had detectable IgG titres, and four (33.3%) of these were also IgM positive, noting that eight individuals undertook both types of work  for IgG seropositivity and 7.0  for IgM seropositivity, i.e., statistically significant for IgG and close to significance for IgM. The corresponding univariable odds ratios for conducting farm work were 0.533  for IgG seropositivity and 0.632  for IgM seropositivity, i.e., not significant in either case.Ten of the 27 individuals had detectable titres of IgG antibody to  of work . The uni95% 0.623–18.7; p = 0.162) as in males  for IgG, but only slightly higher in females  than males  for IgM, in neither case statistically significant differences.The rate of seropositivity was twice as high in female workers  was significantly higher than those greater than 40  for IgG whereas for IgM, seropositivity in individuals less than or equal to 40  was not significantly higher than those greater than 40 . Four of the five (80%) individuals seropositive for IgM were in the 31–40 year age group, which was significant .Rates of IgG seropositivity in age groups 21–30  and 31–40  were identical and these were collapsed into a single category. Seropositivity in individuals less than or equal to 40 years old  and IgM .Seropositivity levels for IgG were similar in symptomatic and asymptomatic  individuals for both IgG , suggesting this was already the minimum adequate model (p = 0.039). However, lab work was apparently confounded with age, with 11 of the 12 individuals conducting lab work being under 40 years of age. On collapsing the age group to just two levels, as already noted, nine of the eighteen (50%) workers less or equal to 40 years of age were seropositive for IgG, but just one of the nine (11.1%) workers over 40 years of age was IgG seropositive (odds ratio and CI95% as above), and this was also the only individual in the over 40 age group conducting lab work; contrastingly, there were broadly similar numbers of IgG seropositives  and seronegatives  conducting lab work in the 40 and under age group (Fisher’s exact test p ≈ 1).In the multivariable analysis for IgG seropositivity addition of none of the terms farm work, age group, gender or symptoms improved upon the univariable model with laboratory work as the sole explanatory variable  for a meaningful multivariable analysis; it was, however, noteworthy that four of the five conducted farm work, four conducted lab work, with three conducting both farm and lab work, and that all four of those IgM positive individuals conducting field work were in the 31–40 age category, the remaining IgM seropositive individual, who conducted only lab work, being in the 41–50 age category.C. burnetii phase II IgM and IgG titres were interpreted in conjunction, four distinct serological profiles could be identified among the workers (When anti- workers . Five wop ≈ 1.00).Six of the ten seropositive workers manifested a variety of non-specific symptoms, whereas the remaining four seropositive workers remained asymptomatic. Among those with clinical disease, sweating, fever, fatigue and odynophagia were the most frequently reported. Most of the symptomatic workers  manifested clinically by middle–late May, i.e., three months before their serologic evaluation. Two workers (IDs 2 and 10) reported non-specific symptoms occurring around mid–late July . None of the seropositive workers had any medical condition known to predispose them to subsequent medical complications ,19,20. ALeptospira medium-based EMJH agar. Additionally, Neospora caninum, Campylobacter spp., Tritrichomonas foetus, Bovine parainfluenza virus 3 and Bovine viral diarrhoea virus 1 were investigated by immunohistochemistry, direct immunofluorescence, dark-field microscopy examination or PCR. None of these 55 foetuses presented any typical lesions leading to suspicion of coxiellosis. The cause of the bovine abortion was diagnosed in 25 of these cases (25/50). Most were diagnosed as infectious abortions (23/25) including agents such as N. caninum (11/23), Campylobacter fetus subsp. venerealis (1/23) and Bovine parainfluenza virus 3 (1/23), as well as opportunistic agents (8/23). In two out of the five cases of ovine abortion, Campylobacter jejuni and Campylobacter fetus were detected by PCR, while the other three cases remained undiagnosed.The local veterinary laboratory examined submissions from fifty bovine and five ovine cases of abortion. Each case comprised either the foetus, the placenta or both. All cases were routinely examined for gross and histologic lesions, and cultured onto MacConkey and blood agar, Skirrow’s medium and C. burnetii to ascertain whether these aborted cattle were likely to have been the source of human exposure. Surprisingly, given the importance assigned to Q fever as a zoonotic disease globally, there is an extreme paucity of evidence in accessible peer-reviewed literature associating Q fever with cattle. Most of the publications that have investigated human Q fever outbreaks conducted serological assessments in people, followed by, at most, a description of the epidemiological link between people and cattle ; a few complemented this with PCR evaluations. Some studies also conducted serological evaluation in animals. However, serological approaches are not particularly informative in cattle as seroconversion can occur without bacterial shedding, and animals can remain seropositive long after overcoming the infection; conversely cattle can shed C. burnetii before the development of detectable antibodies and may even shed the agent without ever seroconverting [The chronology of serological responses and the immunoglobulin classes involved were investigated in a group of workers exposed to bovine abortions caused by nverting . In contC. burnetii was estimated to comprise a timeframe of 54 days  is pathogen dose-dependent, estimated at between 7 and 32 days (one to five weeks) [In our study, based on the dates of the first and last known bovine abortion cases, the window of exposure to  54 days . On thise weeks) ,32,33. HC. burnetii antigens was used to provide insight into the timing of the acquisition of infection based on the known kinetics of antibody development in clinical Q fever [C. burnetii [The profile of immunoglobulins reactive against  Q fever ,35. In tThe IgG phase II antibody has a greater half-life than IgM phase II, with persistence up to 2.5 years, making it an indicator of past infection . In our In addition to the profile of immunoglobulins, the IgG/IgM ratio can be used as a rough estimator of the time after infection and can be used to discern between infection within three months and infection more than six months ago . The IgGC. burnetii. Likewise, symptoms reported by seronegative workers could be due to other seasonal illnesses, and their responses on symptomatology could have been affected by their awareness of the investigation (Hawthorne bias).Two of the workers (IDs 2 and 10) had serological profiles suggestive of long past infection; they reported non-specific symptoms that were likely due to another aetiology as they occurred long after probable exposure to C. burnetii seropositivity in laboratory workers, including those also undertaking occasional field activities, were greater than those for field workers for both anti-phase II IgG (OR 5.6 CI95% 1.09–35.6) and anti-phase II IgM (OR 7.0 CI95% 0.853–150). Most of the farmworkers did not assist at calving and, hence, were exposed to C. burnetii infection indirectly, e.g., through urine and faeces. Considering that shedding of C. burnetii by cows through these routes is scarce and intermittent [β-estradiol [The odds of rmittent , field wstradiol , infectistradiol . For IgGstradiol  would inC. burnetii infection. Although other sources of C. burnetii exposure in laboratory workers beyond the analysed bovine outbreak cannot be altogether excluded, the known exposure to well-documented cases of bovine abortion caused by coxiellosis appears to be a far more likely and plausible source of infection for the human cases described in this study.Other than the previously documented cases of bovine abortion due to coxiellosis , none ofC. burnetii infection in humans exposed to infected bovines or their abortion products. While the aetiology of the bovine abortions themselves was confirmed using molecular methods (PCR) as well as histopathology and immunohistochemistry [C. burnetii [p > 0.95). This might have been possible with a larger number of cases, but this was a study of a naturally occurring disease event and the sample size was not within our control. In this study, we used a titre of 1/16 or greater in the Phase II IFA as the seropositivity threshold for both IgG and IgM, as this was considered above the reference level by the testing laboratory (Mayo Clinic Laboratories), and, indeed, some authorities have used even lower IFA titres in epidemiological studies [95% 1.85–297) and a lower p-value (p < 0.01); for IgM there were four rather than five positives overall and the revised odds ratio  remained suggestive but non-significant (p = 0.179). Lastly, the persistence of phase II IgM must be considered in the interpretation of results when investigating acute Q fever, particularly in endemic, post-epidemic and late epidemic contexts [This study had a number of limitations that could be considered in future work aiming at furnishing further evidence for hemistry , the subhemistry  would haburnetii , we were studies . We, nevcontexts .C. burnetii exposure in people working in direct contact with either aborted cattle or their foetuses, placentas and vaginal discharges. Cattle aborting due to C. burnetii should not be underestimated as a potential hazard and possible source of human infection. Q fever should be considered in the spectrum of diseases in patients with an epidemiological link with animals, or with occupational-related exposure, especially those with fever of unknown origin. Vaccination should be considered for people at risk of Q fever through occupational exposure.In conclusion this epidemiological investigation, the first closely linking Q fever to bovine abortion, provides novel serological evidence of


It is nearly ubiquitous in Escherichia coli strains justifying the use of its phenotype, the ability to consume lactose, for species identification. Lactose is the primary sugar found in milk, which is abundant in mammals during the first weeks of life. However, lactose is virtually non-existent after the weaning period, with humans being an exception as many consume dairy products throughout their lives. The absence of lactose during adulthood in most mammals and the rarity of lactose in the environment, means that the selective pressure for maintaining the lac operon could be weak for long periods of time. Despite the ability to metabolize lactose being a hallmark of E. coli’s success when colonizing its primary habitat, the mammalian intestine, the selective value of this trait remains unknown in this ecosystem during adulthood. Here we determine the competitive advantage conferred by the lac operon to a commensal strain of E. coli when colonizing the mouse gut. We find that its benefit, which can be as high as 11%, is contingent on the presence of lactose in the diet and on the presence of other microbiota members in the gut, but the operon is never deleterious. These results help explaining the pervasiveness of the lac operon in E. coli, but also its polymorphism, as lac-negative E. coli strains albeit rare can naturally occur in the gut.The  To our surprise, the ad libitum. GF mice were bred and raised at the IGC gnotobiology facility in dedicated axenic isolators . Young adults were transferred into sterile ISOcages (Tecniplast) before the competition experiments. This research project was approved by both the Ethics Committee and the IGC Animal Welfare Body (license reference: A009.2018), and by the Portuguese National Entity that regulates the use of laboratory animals . All experiments were performed following the Portuguese (Decreto-Lei n° 113/2013) and European (Directive 2010/63/EU) legislations concerning animal welfare.All experiments were conducted using female 6–8 weeks old C57BL6/6J mice under germ free (GF) or specific pathogen-free (SPF) conditions at the Instituto Gulbenkian de Ciência (IGC) animal facilities. Mice were individually caged and had access to water and food E. coli strains used in this work were derived from E. coli K-12 MG1655 and were resistant to streptomycin due to the point mutation rpsL K43T (StrR). The two strains are isogenic except for the deletion of the lacZ , differing only in the ability to metabolize lactose. L. murinus was isolated from feces of SPF mice and species identity was confirmed by sequencing the whole 16S rRNA gene. Bacteroides thetaiotaomicron strain (VPI-5482) was acquired from the German Collection of Microorganisms and Cell Cultures (DSMZ 2079).The two E. coli, while GF mice were either mono-colonized (E. coli), double-colonized (E. coli + L. murinus), or triple-colonized (E. coli + L. murinus + B. thetaiotaomicron). In all colonization conditions, mice were given autoclaved drinking water supplemented with streptomycin (5 g/L) for 24 h.To colonize the mouse intestine, we used a streptomycin treated colonization model  under tw8 colony forming units (CFUs) of a mixture (1:1) of lac− and lac + (SPF and mono-colonization). Double and triple colonizations started with the gavage of 100 μL of a suspension of 108 CFU containing equal amounts of E. coli and each of the other species.After 4 h of starvation for water and food, animals were gavaged with 100 μL of a suspension of 10E. coli was grown in LB broth overnight with aeration followed by a 1:100 dilution and grown in BHI broth until reaching an optical density of 2. L. murinus was inoculated in De Man, Rogosa and Sharpe (MRS) broth and incubated in anaerobiosis. B. thetaiotaomicron was inoculated in Chopped Meat Medium with Carbohydrates and grown in anaerobiosis. All bacteria were incubated overnight at 37°C and 1 mL of each culture was centrifuged and resuspended in PBS 1x + 0.1% cysteine.Bacteria for gavage were prepared as follows: E. coli) and MRS agar (for L. murinus) or in LB agar with X-Gal and 100 μg/mL of streptomycin. E. coli and L. murinus were grown at 37°C for 18 and 24 h, respectively in aerobiosis. When grown in MacConkey, E. coli lac + and lac− strains were discriminated by colony color .Water with streptomycin was maintained throughout the 6 days of experiment and replaced after 3 days, except for the colonization where streptomycin was only administered for 24 h before gavage. In half of the animals, the water was also supplemented with 2% lactose. This percentage was chosen to mimic to the concentration found in mice milk . Fecal slac operon confers an advantage to E. coli in the tested conditions, total numbers and relative frequencies of the bacteria were determined by counting the number of colonies of each strain. The selection coefficient (fitness gain) per generation of the lac + strain in vivo was calculated as the slope of the linear regression of ln (freqlac+/freqlac–) divided by the number of generations for E. coli per day. The number of days considered to calculate the selection coefficient in the colonization of SPF mice (1 day of streptomycin) was 2 (n = 3), 3 (n = 1), 4 (n = 3), or 5 (n = 1), to use a time interval with a linear tendency of selection. For the remaining colonizations, the first 3 days were considered. As for the number of generations per day, we considered this value to be 18 based on the previous estimation of 80-min generation time for E. coli in streptomycin-treated mice . 16S sequence data from animals treated with streptomycin for only 1 day is available from phyloseq  and statistical analysis in Prism or in R version 3.6.3 , by allowing for its competition with a lac− strain in the intestine of mice after a short treatment (1 day) with streptomycin. This procedure maintains a complex microbiota while allowing for E. coli colonization (lac + and lac−) isogenic strains, except for the deletion of the lacZ in the lac- strain, by oral gavage. We further supplemented the diet of 4 animals with 2% lactose whereas the remaining 4 animals were fed regular chow. The frequencies of lac +/lac− strains were assessed by daily collecting fecal samples and plating appropriate dilutions for 6 days.Here we evaluated the selective advantage conferred by the nization . We starlac + remained close to the initial 50% in two animals and increased slightly in the other two  = 5.63, p = 0.0003] and a more variable effect was observed for the selective advantage of the lac + strain, ranging from 1.4 to 11%, with a mean of 5 ± 4% (SEM) (The presence of lactose had a significant effect in the 4% (SEM) .lac operon in the gut of different mice.Besides the presence of lactose, differences between measurements likely reflect the common variation in microbiota composition between individuals which is known to further increase with the antibiotic treatment . The efflac operon can afford a significant advantage to an E. coli strain while colonizing the intestine, but its benefit is influenced by lactose and possibly microbiota composition.These results led us to conclude that the lac operon, we engaged in a series of colonizations within a range of microbiota diversities. These comprised a mono, double and a triple colonization. A group of animals continuously treated with antibiotic (7 days) was further included, representing a complex yet simpler microbiota than the group treated only for a short period (1 day).To isolate the effect of lactose and test for the influence of a microbiota diversity to the selective coefficient of the Although not statistically significant, after antibiotic treatment the two regimes differed in microbiota richness, with an average of 20 (continuous regime) and 26 (1 day regime) ASVs .E. coli, which could influence the abundance of lactose and other nutritional sources.These microbiota compositions likely represent different levels of competition to lac +/lac−) E. coli and followed its frequency for a period of 6 days. As before, a group of animals received a lactose supplemented diet (n = 4) whereas the remaining animals were fed regular chow. Interestingly we observed that when E. coli is the only inhabitant of the gut, the ability to metabolize lactose, irrespectively of the presence of its cognate substrate, is a neutral trait  = 4.41, p = 0.0082], providing a selective advantage around 1.3 ± 1% (SEM) per generation ].Coherently, in the context of continuously antibiotic treated mice and in the presence of lactose, the effect of the neration  which alneration . Interesc regime , in agrelac operon is potentiated by the presence of lactose and increases with the number of co-colonizers  increases with the number of co-colonizers in ex-GF mice, but then it drops when the gut environment reaches the complexity of a regular microbiota (E. coli in the double colonization in 4 out of the 5 days of the experiment (E. coli was on average 3 times more abundant in the double (∼4.4 × 109 CFU/g) than in the mono colonization (∼1.3 × 109 CFU/g).Here we observe that crobiota . Specifiperiment . Upon 5 E. coli was measured .The sharpest increase was observed when comparing the mono with the triple colonization where a significant difference (∼10 times) in the average loads of E. coli’s niche is expanded by the presence of L. murinus and B. thetaiotaomicron, hinting at a synergistic relationship between these bacteria and E. coli.These data suggest that E. coli in an environment with multiple species of bacteria, such as the microbiota of streptomycin-treated mice, regardless of the antibiotic regime, was limited to ∼108 CFU/g upon 6 days of colonization, likely due to the predominance of interspecies competition.In contrast, the expansion of lac + and lac− strains separately , showed us that, from the perspective of E. coli, synergism dominated in this scenario. This is consistent with the notion that E. coli consumes the byproducts of complex nutrients’ degraded by B. thetaiotaomicron, such as maltose and fucose which result from the breakdown of dietary glycans (The observation that the population size of  glycans . This seE. coli was antagonized by B. thetaiotaomicron and another species of Lactobacillus (L. johnsonii). Here the oral administration of these species was enough to reduce the overgrowth of E. coli , its absolute success decreased and the most likely scenario was one dominated by competition . A scenaoccasion .E. coli’s absolute success was higher, suggesting that the fitness effect of the lac operon may be density dependent. Future work should address this issue, possibly through investigating the geographic distribution of bacteria abundances and possible differences in the lac operon selective advantage along the intestinal tract. Since lactose is mainly absorbed in the small intestine, this could be the place where lac + is positively selected with the cecum being the intestinal compartment where E. coli expands irrespectively of its ability to consume lactose. Such a hypothetical situation would simultaneously explain the larger advantage of a lac + strain and the higher absolute success of the species.Surprisingly, when comparing the mono with the triple colonization, lactose showed to be more advantageous in the situation where lac operon selective effect and microbiota heterogeneity. This was unraveled by the two antibiotic regimes but probably best resemble the natural diversity of the microbiota of animals which are not genetically homogenous or eat the same controlled diet as in our experimental setup.Another interesting observation was the correlation between the variance of the E. coli, and, therefore, the balance between beneficial and antagonistic interactions, determines its niche size and location. The adaptive value of the lac operon for E. coli is dependent on the competitors and the availability of nutritional resources and might be especially useful in highly competitive environments and for exploring new niches.Overall, the results indicate that the specificity of interactions established by The original contributions presented in the study are included in the article/The animal study was reviewed and approved by Direção Geral de Alimentacão e Veterinária (license reference: 009676) and Instituto Gulbenkian de Ciência Animal Welfare Body (license reference: A009.2018).CP, IG, and AS conceived and designed the experiments. CP performed the experiments. CP, RM-M, and AS analyzed the data. IG and AS contributed reagents, materials, and analysis tools. RM-M and AS wrote the manuscript. CP and IG contributed to the writing of the manuscript. 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.


Practitioners frequently tailor programming to meet participant characteristics and logistic constraints, or to incorporate diverse participants, such as intergenerational programming. Adapted programming may be responsive but reduce impact on outcomes. With growing interest in and limited availability of intergenerational protocol, implementation science guides program tailoring to ensure that youth and older adults mutually benefit from adapted programming. We integrated guidelines for tailoring interventions (Framework for Reporting Adaptations and Modifications-Expanded: FRAME) and evidence-based intergenerational practice. We illustrate how program fidelity can be supported in intergenerational settings using examples from an adapted USDA-approved preschool nutrition curriculum delivered intergenerationally. Program acceptability, appropriateness, and feasibility were rated favorably by program stakeholders, and observational implementation data suggest fidelity can be maintained using evidence-based intergenerational strategies. Our findings support the potential for protocol developed for one age group to benefit youth and older adults when it is adapted using implementation and intergenerational guidelines.


Several predictors for work restoration and maintenance of restoration have been examined among employees with mood and/or anxiety disorders, but whether frequency of participation in a return-to-work (RTW) program can predict successful work restoration and maintenance remains unclear. In the present study, we attempted to investigate the hypothesis that the frequency of RTW program participation can predict successful work restoration and maintenance. Among seventy-seven patients attending an RTW program, the frequency of participation was positively associated with work restoration but not with maintenance. The result was in partial agreement (restoration) and partial disagreement (maintenance of restoration) with our hypothesis. Thus, the present study suggests that the frequency of participation in an RTW program can predict successful work restoration but not maintenance. Several predictors of work restoration among employees with mood and/or anxiety disorders have been examined by past studies. With respect to work participation, Lagerveld et al.  performen = 152 with adjustment disorder or exhaustion disorder) and DepAnxIn subgroup . The stress subgroup showed a superior reduction of stress-related symptoms after CBT compared to RTW intervention, but there was no significant difference between the COMBO and RTW intervention or CBT. Moreover, there was no difference between treatments with respect to days on sick leave the year after randomization. In the DepAnxIn group, there was no significant difference between treatments with respect to symptom reduction. With respect to days on sick leave, patients had 92 fewer days on sick leave after RTW intervention compared to CBT and 76 fewer days on sick leave after COMBO compared to CBT. Thus, RTW intervention may be more effective than CBT for the DepAnxIn subgroup rather than the stress subgroup, but RTW intervention often includes CBT, and it seems difficult to identify the specific effects of RTW intervention. In addition, sick leave days are important because it reflects directly mental and physical health and indirectly work stress, which is linked to the effects of RTW intervention.Regarding interventions that may enhance RTW, systematic reviews suggest that medication, enhanced primary care, and psychotherapeutic interventions aimed at symptom reduction  do not improve RTW among employees on sick leave due to mental health problems , 4. In cTo date, it has not been investigated whether the frequency of participation in an RTW program is associated with successful work restoration and maintenance of restoration. It seems plausible that more frequent RTW program participation would entail more success in work restoration and maintenance. On the other hand, the duration of participation in an RTW program might be affected arbitrarily by the circumstances of individual companies to which each patient would be restored. For example, some workers may take relatively longer sick leave days whereas other workers can take relatively shorter sick leave days due to the rules of individual companies. Rather, the frequency is, to some extent, free from the circumstances of individual companies because for example one can try to participate in an RTW program 5 days per week for 4 weeks which is equal to a participation of 2 days per week for 10 weeks in the frequency of 20 if the upper limitation of sick leave days is 4 weeks. Thus, in the present study, we attempted to investigate the hypothesis that the frequency of RTW program participation is positively associated with successful work restoration and maintenance.N = 9), F32 (N = 38), F34 (N = 1), F40 (N = 3), F41 (N = 1), F42 (N = 2), F43 (N = 21), F44 (N = 1), and F45 (N = 1). That is, there were 48 patients with mood disorders and 29 patients with anxiety disorders. The mean total work experience was 21.7 ± 9.7 years. The frequency of RTW program participation was 67.8 ± 41.2 times. Informed consent was obtained from 33 patients attending the new program, which was approved by the ethics committee of Oita University Faculty of Medicine, and the alternative opt-out method was applied to 44 patients attending the old program, which was approved by the ethics committee of Oita Okanoue Hospital.Oita Okanoue Hospital in Japan had a rehabilitation unit that conducted the RTW program. Strictly speaking, there were two programs—old and new. The old program was in effect from November 2013 to May 2017, and the new program has been implemented since June 2017. The last patient of this study started the new program on February 10, 2020, and this patient and other patients were followed up to September 1, 2020. The patients with new program were followed up for 577.4 ± 302.2 days . The old program had entry criteria of Beck Depression Inventory scores equal to or <12 and capability of pre-participation in pre-RTW program 3 times a week for 2 weeks, while the new one had entry criteria of Hamilton Depression Rating Scale scores equal to or <9 and capability of pre-participation in pre-RTW program 3 times a week for 2 weeks. The schedule of the old program included office work, meeting, yoga, CBT, social skill training, and light sports, while that of the new program included an additional element of cognitive training such as operating a personal computer for composition, reading, calculation, and so on. Of the 77 participants (56 men and 21 women) in this study, 44 patients had attended the old program and 33 patients attended the new program. Their mean age was 43.2 ± 8.5 (standard deviation) years. The psychiatric diagnoses according to the International Classification of Diseases Tenth Revision were F31  from restoration to the next leave of absence from work or to the last observation while keeping restoration.t-test (crude model). Next, a binary logistic regression analysis was performed using restoration or non-restoration as a dependent factor, and age, gender, frequency of RTW program participation, program (old or new), and total work experience (years) as independent factors (adjusted model).The association between the frequency of RTW program participation and work restoration was compared between patients who could be restored to their jobs (restoration group) and those who could not be restored (non-restoration group) using a The association of RTW program participation with maintenance of work restoration was analyzed using the Kaplan-Meier survival analysis (crude model) and Cox regression analysis, wherein whether restoration was maintained or not was the dependent factor and age, gender, frequency of RTW program participation, program (old or new), and total work experience (years) were independent factors (adjusted model). SPSS Statistics 26 was used for these analyses.t = 3.1, p = 0.005)  and that the frequency of RTW program participation was significantly associated with restoration , but not with the other factors  with only two independent factors  and that the frequency of RTW program participation was significantly associated with restoration , but not with total work experience . This result was in agreement with that of forced entry with five independent factors.The restoration group had a significantly higher frequency of RTW program participation than the non-restoration group  . The ran factors . Particu2 = 7.225, p = 0.027) and that maintenance of restoration was significantly associated with gender  and partial disagreement (maintenance of restoration) with our hypothesis. It is possible that the effects of the RTW program disappeared over time. Interestingly, maintenance of restoration was significantly associated with gender (significantly better among men than women). It seems possible that when confronting difficulties in maintaining work restoration, female workers may be prone to discontinuing their jobs than male workers, but this should be clarified in future research.Several reports have shown predictive factors for maintenance of restoration. Hori et al.  reportedSproken et al.  identifiThe limitations of this study are the relatively small sample size and that the RTW location was a private hospital, which might preclude generalization. Moreover, there were some other confounding factors that might be associated with work restoration and maintenance, such as differences in psychiatric diagnosis and severity of the disorders. Owing to the nature of a retrospective observational study, it was difficult to clarify the causal relationship between RTW program and work restoration and maintenance. Although the RTW program in this hospital seems to be average in Japan, it cannot be denied that the RTW program and/or the participants and/or the staffs were deviated and the present findings were also deviated. Moreover, various workers from several companies participated in the RTW program which provided various tasks for several duration. That is, the present findings derived from heterogenous situation. Moreover, honestly speaking, it is unknown whether the present findings are reconfirmed or not and it cannot be completely denied that there is a bell-shaped dose relationship where optimal frequency exists and less or more than the optimal frequency is not good for restoration. Further studies are required to resolve these problems.In conclusion, the present study suggests that the frequency of RTW program participation can predict successful work restoration but not maintenance of restoration.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.Informed consent was obtained from 33 patients attending the new program, which was approved by the ethics committee of Oita University Faculty of Medicine, and the alternative opt-out method was applied to 44 patients attending the old program, which was approved by the ethics committee of Oita Okanoue Hospital.YH and TT planned this study, analyzed the data, discussed the results, wrote the manuscript, and approved the final manuscript. YH collected the data.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.


This quality improvement project suggested that TC is a feasible exercise that might have the potential to reduce risk of falls in older adults, and the program was well accepted with no serious or other adverse events reported. Further research studies are needed to examine the potential effects of TC programs with an appropriately powered RCT and longer intervention period.One in four American older adults fall every year, resulting in injuries, death, and significant financial burden. Although fall etiology is multifactorial, the medical problems and aging factors that lead to unsteady gait and imbalance represent one of the major fall risks among older adults. A growing number of research studies support the health benefits of regular Tai Chi (TC) practice including improved physical, cognitive, and psychological function. The purpose of this quality improvement project was to assess the feasibility of establishing a 12-week (45 min per session) Tai Chi (TC) program (Sun Style Tai Chi) in a 75 bed assisted living facility as well as to evaluate the potential of the TC program to improve the fear of falling and functional mobility  and quality of life (QoL). A nurse who was a certified TC instructor taught the program. Twenty-three participants, 96% female and 96% white, mean (SD) age 83 (±7) years, attended one or more TC classes. Class attendance, self-reported questionnaires , and objective measure Timed Up and Go (TUG) were used to collect data. Nine participants (39%) completed 9 out of 12 sessions. Eleven participants (48%) completed both pre- and post-intervention measurements and twelve (52%) provided feedback on a post-intervention satisfaction survey. Participants showed 20% improvement in fear of falling (mean relative change) and 21% decrease (mean relative change) in TUG test ( More than one in four adults aged 65 and over falls every year in the United States, resulting in 3 million emergency visits and over 800,000 hospitalizations. These falls contribute to an increasing death rate each year for older adults . Falls lAlthough fall etiology is multifactorial, the medical problems and aging factors that lead to unsteady gait and imbalance represent some of the major fall risks among older adults . ExpertsTai Chi, originating in China and derived from Chinese martial arts, has been practiced for hundreds of years in China to enhance people’s wellbeing. In the past few decades, Tai Chi (TC) has gained popularity in Western countries. TC is characterized by slow, gentle, continuous, and mindful movements accompanied by synchronized breathing aiming to improve physical and mental health . ExpertsTC has been linked to a variety of health benefits including physical and mental health as well as improved quality of life ,12. In pThe Social Cognitive Theory (SCT) ,21 was uAlthough mounting empirical evidence suggests TC is an effective approach in reducing fall risk and public health authorities recommend and endorse it, older adults in assisted living facilities have limited access to TC programs. There are many barriers to translating and disseminating TC research findings into community practice ,23. One This project was reviewed for Human Subject Protection using the University of Minnesota online Institutional Review Board (IRB) determination tool and met the criteria for Quality Assurance (QA)/Quality Improvement (QI). Therefore, no additional IRB approval was required for this project.This quality improvement project took place at a 75-bed assisted living facility, which was part of a senior care center located in east suburban Minnesota. A comprehensive needs assessment was conducted by interviewing facility leaders, staff, and residents, revealing significant interest in developing and implementing a Tai Chi program. This senior care center had no prior Tai Chi program, but there was an existing exercise program for assisted living residents that consisted of weightlifting exercise, chair yoga, ball exercise, and drumming. These residents had access to a daily 30 min exercise program, with daily attendance fluctuating between 5 and 12 participants. This exercise program had been offered for the past 5 years, and the organization had expressed a growing interest in expanding the program to include a weekly evidence-based Tai Chi program to enhance the health and wellbeing of their residents. The inclusion criteria for participation in this study were: (1) ≥55 years old  (2) did not have cognitive impairment or mental disabilities that might limit the practice of TC; and (3) possessed basic English communication capability. The participants were not excluded if they needed an assistive device  for locomotion. Participants excluded themselves if their medical providers discouraged them from participating in TC. The exercise programs were open to all residents interested in attending. All participants were residents living independently or with some assistance in the 75-bed assisted living building. Program recruitment was initiated with a 45-min educational presentation that was available to residents and staff. Informational flyers about the educational presentation were posted in areas visible to residents and staff, and table flyers were placed on the dining tables for residents to view during mealtime. The presentation was offered one week prior to the first TC class and included: (1) an introduction to the quality improvement project; (2) TC philosophy and benefits; and (3) TC experiential practice. Twenty residents, the Community Life Director, and the Director of Integrative Health and Wellness attended the presentation. The project utilized a quasi-experimental, one group pre-test/post-test design. The TC program was available to all residents who were interested in attending the class and were able to be physically present in the activity room where the class was held. Weekly Tai Chi classes were held for 12 consecutive weeks from September to November 2017 in the assisted living facility’s activity room and taught by a certified TC instructor who was also a registered nurse and the project leader. The TC program was adapted from Tai Chi for Arthritis and Fall Prevention program, which was designed by Dr. Paul Lam to reduce pain, prevent falls, improve balance, and promote general wellbeing . The proEach 45-min class was structured with the following activities: 15–20 min of TC warm up exercises, 5 min for water break, 15–20 min of TC practice, and a 5-min cool-down. To accommodate the residents’ mobility, the class started with seated movements, progressed to options of standing with or without chair assist, and then ended with seated relaxation movements. Synchronized breathing (breathing with the movements) and guided imagery  were integrated into TC movements. The Community Life Director and the Director of Integrative Health and Wellness participated in all the classes in order to learn TC movements with the residents, support the program, and monitor the safety of the participants. During the very last 4 weeks, the two directors participated in co-teaching with the TC instructor, and received direct feedback after each class. At the end of the program implementation, a one-hour private training session was provided for the directors to support teaching confidence and TC program continuation. Written handouts with TC photos and descriptions of movements were provided to participants. Other supporting materials were also given to the facility to support staff education and program sustainability including written scripts of the teaching, the book of “Teaching Tai Chi Effectively”, an official DVD of the Tai Chi for Arthritis program created by Dr. Paul Lam, which demonstrated the movements that were taught in classes, and two Tai Chi music CDs. At the end of the program, photo books, depicting each TC movement in pictures, were created by the instructor in collaboration with the residents and staff. Class participants received a commemorative copy of the photo book. Feasibility of this TC program, the primary aim of this project, was evaluated by recording class attendance and completion of a post-intervention satisfaction survey. At the end of the program, a 10-question satisfaction survey including 9 multiple choice questions and one open-ended question was distributed to the participants to evaluate their satisfaction and enjoyment of the program see . Safety Outcomes for the secondary aim, fear of falling, functional mobility, and QoL, were evaluated using three measures. Fear of falling and functional mobility were assessed by the short version of Falls Efficacy Scale-International (FES-I) , and theQoL was assessed by the brief Older People’s Quality of Life (OPQOL-brief) questionnaire, consisting of 13 questions and one single item that assessed the global QoL that was included in the total score calculation. This is a short version of the widely used QoL questionnaire named OPQOL-35. The OPQOL-brief questionnaire has demonstrated acceptable validity and high reliability with Cronbach’s alpha 0.88 . Each ofAttendance was recorded by the instructor and confirmed by the Community Life Director during the weekly class. Satisfaction surveys were distributed at the end of the program to evaluate participants’ program satisfaction. Safety was monitored by staff and instructor to record any falls or injuries related to Tai Chi class. Short FES-I, TUG test, and OPQOL-brief were collected prior to the intervention in early September, and again at the end of the 12-week intervention on 24 November 2017. To protect the privacy of the participants, each participant was given a code to label their surveys. Collected data was entered into a spreadsheet on a password-protected computer and assessed for accuracy and completeness by the instructor.Descriptive statistics and graphical representations were used to summarize and analyze all collected data. Tools were scored according to published scoring procedures. Class attendance and post-intervention satisfaction survey results were summarized qualitatively and quantitatively. Absolute and relative changes in fear of falling, functional mobility, and QoL from pre- to post-intervention were estimated. Differences in TUG times from pre- to post-intervention were examined using paired t-test. Two-sided type I error rate of 5% was used to assess statistical significance. SPSS software  was used for all analyses.Twenty-three out of 75 (31%) residents in the assisted living facility attended the TC program. Participants’ ages ranged from 70 to 93, with an average age 83 (±7) years, 96% participants were female and 96% were white. Participants included those who could walk independently without assistive devices and those who required a wheelchair, walker, or cane for locomotion. During the first class, participants were asked why they came for the TC class and if they had any experience with TC. Many participants stated that they came because they were curious about what TC was and hoped it would help them regain their balance and relieve pain. Most of the participants had heard about TC but never practiced it, with the exception of one who practiced TC for a short time several years ago.Nine (39%) residents, average age 83 (±7), attended at least 9 out of 12 classes with an average of 11 participants per class. Eleven (48%) participants provided both pre- and post-intervention data. The satisfaction survey also indicated that participants were satisfied with the program and would like to continue with the program. Some residents commented that this new type of exercise stimulated their learning and believed it was beneficial to their memory. Staff observed no falls or injuries occurred during the implementation period. There were no serious or other adverse events associated with practicing Tai Chi reported by residents.At the end of the program, 12 (52%) residents completed the satisfaction survey, including two items assessing residents’ enjoyment in and benefits of the TC class on a 4-point Likert Scale . They reported that they enjoyed the TC practice, with 50% selecting Strongly Agree and 50% Agree. Similarly, all believed the TC practice was helpful in improving their health and wellbeing, with half selecting Strongly Agree and the other half Agree. In addition, all of them reported (100%) that they would recommend the TC program to their friends and neighbors. They all agreed to continue the TC program. A total of 83% of the participants listed learning TC movements as their favorite part of the class, whereas scheduling conflicts and illnesses were mentioned as the major barriers for participating in the TC practice. A few participants consulted their primary care providers about TC practice and their confidence of making the right choice by practicing TC was boosted when affirmation of the positive benefits of TC were reinforced by their physicians. Another participant decided to stop practicing TC after her physician advised her to discontinue due to unknown medical reasons.The two directors believed attending the classes, co-teaching, and private training sessions were very helpful in promoting greater confidence in teaching. A great interest was expressed in continuing the program after implementation period both from the residents and the leadership team.Participants’ mean short FES-I score decreased from 15 at pre-test to 12 post-test, corresponding to a mean relative decrease of 20% in the fear of falling score. Notably, 7 out of 11 (64%) participants had lower FES-I scores at post-intervention as compared to pre-test see .p = 0.001) from pre- to post-intervention was observed. Participants’ mean TUG time decreased from 22.4 at pre-test to 17.6 post-test. Ten out of 11 (90%) participants had lower mean TUG times at post-intervention as compared to pre-test (see A mean decrease of 5 s (relative change of 21%) in mean TUG time , test see .p > 0.05) as measured by OPQOL-brief score were observed , but they should also learn alternative activities to reduce risk of falling in older adults, such as an evidence-based TC practice. Prelicensure and graduate gerontological curriculum could include selected elements of TC programs to increase the knowledge and skills related to TC practice. From our experience, participants feel encouraged and more confident if their healthcare providers support and reinforce the benefits of practicing TC. In addition, healthcare providers can learn to be effective in teaching TC and assume leadership in the development and implementation of TC programs for older adults.As the generation of baby boomers age and lifespan continues to increase, the aging population is projected to increase. It is plausible, therefore, that more senior residents will occupy assisted living facilities. Healthcare providers in these senior living facilities play a crucial role in providing leadership in geriatric care and introducing appropriate evidence-based interventions, such as an exercise intervention like TC. This project demonstrated that establishing a TC program by a novice TC instructor in an assisted living facility was feasible; the TC program was safe and was well-received by older adults in the community setting as well as by health providers. The program might have a potential to improve functional mobility and reduce fear of falling, which in turn might reduce risk of falls. In addition, staff in senior living communities could be trained and certified as TC instructors to assist with implementing the evidence-based TC program and to sustain the program in the long run. Future research is needed to assess the effectiveness of TC programs to reduce risk of falls among older adults in community settings utilizing an appropriately powered randomized-controlled trial design and a longer intervention period.


Here, we describe the development of the in-house anti-Zika virus (ZIKV) IgM antibody capture ELISA (in-house ZIKV IgM ELISA) for the detection and diagnosis of acute ZIKV infections. We compared the in-house ZIKV IgM ELISA assay performance against two commercial kits, Euroimmun ZIKV IgM and InBios 2.0 ZIKV IgM ELISA. We tested the assays’ ability to detect anti-ZIKV IgM using a well-defined serum sample panel. This panel included 80 ZIKV negative samples  and 67 ZIKV reverse transcriptase–polymerase chain reaction–positive acute serum samples. The OD values were calculated to enzyme immunoassay (EIA) unts by comparing them to weak positive controls. The results demonstrated the high sensitivity (88.06%) and specificity (90.00%) of our in-house ZIKV IgM ELISA and its 89.12% overall percentage agreement. The kappa values were deemed to be within excellent range and comparable to the InBios ZIKV IgM ELISA. Some cross-reactivity was observed among secondary DENV and JEV samples, and to a much lower extent, among primary DENV samples. These data indicate that our in-house ZIKV IgM ELISA is a reliable assay for the detection of anti-ZIKV IgM antibodies in serum. Flaviviridae family, in the Spondweni sero-complex group.Macaca mulatta) during a yellow fever study in the Zika forest near Entebbe, Uganda, in 1947.Aedes africans circulating in the same forest.Aedes mosquitoes,,Aedes aegypti mosquitoes,Zika virus (ZIKV) is a mosquito- borne pathogen, belonging to the ––The first ZIKV infection in humans was reported in Nigeria in 1954.,,The laboratory diagnosis of ZIKV mostly relies on the detection of viral RNA in whole blood , cerebrospinal fluid, saliva, urine, and semen.N = 20), primary DENV infections (N = 20), or secondary DENV infections (N = 20) and were Japanese encephalitis virus (JEV) IgM positive (N = 20).The human serum samples used in this study  were obtViral RNA was extracted using QIAamp viral RNA mini kit  according to the manufacturer’s instruction. Samples were tested by nested RT-PCR for detection of DENV and JEV,Test − ODNC)/(ODWPC − ODNC)]; EIA units of IgM ≥ 40 were used as a positive cut-off value. Evidence of dengue infection was classified by a ratio of DENV IgM/JEV IgM ≥ 1.0, and JEV infection when the ratio was < 1.0. Primary DENV infection was interpreted when the ratio of DENV IgM/DENV IgG was ≥ 1.8, and secondary DENV infection was considered when the ratio was < 1.8.Anti-DENV/JEV IgM and IgG ELISAs were performed in three independent experiments following procedure described elsewhere.,Macaca mulatta) 15 days after inoculation with 5 × 106 PFU of ZIKV .A capture ELISA method was used to develop an in-house ZIKV IgM ELISA. Briefly, flat-bottom microplates were coated with 100 μL/well of 1:1,600 dilution of goat anti-human IgM  in 0.018 M carbonate buffer (pH 9.0). After overnight incubation at 4°C, the plates were washed with PBS (pH 7.4) containing 0.5% Tween 20 (PBS-T). Next, 50 μL/well of 1:100 dilution of test serum, NC, WPC and SPC in PBS were added and incubated overnight at 4°C. After washing with PBS-T, 50 μL/well of sucrose acetone extracted suckling mouse brain ZIKV  antigen (50–100 HA units) was added to the microplate. After incubation for 2 h at 37°C, 30 μL/well of human anti-flavivirus IgG–HRP conjugated was added and incubated for 1 h at 37°C. After washing with PBS-T, 100 μL/well of TMB substrate (KPL) was added and incubated for 10–30 min. The reaction was stopped by adding 50 μL/well of 0.2 M sulfuric acid. The absorbance at OD450 was measured and calculated for EIA units as previously described.The Euroimmun ZIKA IgM ELISA test kit was designed to detect specific IgM against recombinant ZIKV NS1 coated on the plate. The Euroimmun Zika Virus ELISA kits (Cat. No. EI2668-9601M) were produced by Euroimmun AG . The assays were carried out according to the manufacturer’s instructions.The InBios ZIKV IgM ELISA detects IgM antibodies targeting the recombinant ZIKV envelope glycoproteins (Cat. No. ZKM2-1). The InBios ZIKV-IgM ELISA kit was produced by the InBios international, Inc.  and performed according to the manufacturer’s instructions.Prism-GraphPad  was used to create the receiver operating characteristic (ROC) curve to identify an appropriate cut-off value for anti-ZIKV IgM ELISA. The assay performance comparison to commercial kits (assay agreement) was evaluated by Kappa values, indicating excellent agreement if > 0.75, fair agreement if 0.40–0.75, and poor agreement if < 0.40.,N = 16) or JEV (N = 8) when tested with the DEN/JEV IgM/IgG ELISA. The area under the ROC curve (AUC) value of the in-house ZIKV IgM ELISA was 0.941, reflecting excellent diagnostic accuracy. A ROC curve pointing to a cut-off line at 40 EIA units is considered optimal, providing assay sensitivity and specificity of up to 88.06% and 90.00%, respectively. The EIA unit distribution of validated samples is shown in a scatter plot with cut-off line  and false positive rate (1 = specificity) showed that 40 EIA units represents the optimal cut-off point.,We used the in-house DENV/JEV IgM/IgG ELISAThe finding of negative in-house ZIKV IgM ELISA results among ZIKV RT-PCR–positive samples (8/67) could be due to improper sample collection times for IgM detection, including early collection of acute and/or late collection of the convalescent samples. Even though ZIKV cross-reactivity has been observed in the JEV samples, anti-JEV IgM read-outs were higher than anti-ZIKV IgM antibodies, facilitating assay interpretation. The JEV immunization program has been implemented in Thailand since 1990,,Evaluations of various Zika ELISA assays have been published elsewhere.In conclusion, our study demonstrates that the in-house ZIKV IgM ELISA can be an important tool for detecting ZIKV infections in humans. The assay is an affordable and reliable option for diagnosis of ZIKV patients, especially in flavivirus-endemic countries. A limitation in the use of the in-house ZIKV-IgM ELISA is that its interpretation requires the use of DENV and JEV antibodies ELISAs, which may limit its usability in some laboratories.


The diagnostic yield of r-EBUS for OP was 67% and increased to 79% (22/28) when an ultrasound image was obtained. The median time between CT scan and r-EBUS procedure was 14 days (3–94): 11.5 days in the r-EBUS+ group and 22 days in the r-EBUS- group (p < 0.0001). No severe complications were reported. Conclusion: r-EBUS, when performed shortly after a CT scan showing a bronchus sign, is an efficient and safe technique for OP diagnosis.Background: The diagnosis of organizing pneumonia (OP) often requires histological confirmation. The aim of this retrospective study was to evaluate the diagnostic yield and complication rate of radial endobronchial ultrasound (r-EBUS) for OP. Methods: All patients who had r-EBUS as a first diagnostic procedure for a peripheral pulmonary lesion at Rouen University Hospital, France, between April 2008 and December 2020 were included. Cases without a final diagnosis of OP or follow-up were excluded. Patients, lesions, and r-EBUS characteristics were retrospectively analyzed. Results: 2735 r-EBUS procedures were performed, and 33 cases with final OP could be analyzed. Procedures were performed under local anesthesia in 28/33 cases (85%). Among the 33 final OP cases, 17 were considered cryptogenic, and 16 secondary. The lesions were patchy alveolar opacities in 23 cases (70%), masses or pulmonary nodules in 8 cases (24%), and diffuse infiltrative opacities in 2 cases (6%). A bronchus sign on CT scan was found in all cases. In 22 cases (67%), a histopathological diagnosis was obtained from the r-EBUS samples. In 4 cases (12%), histopathological diagnosis was made by surgery, and in 7 cases (21%) the diagnosis was made based on clinical, radiological, and evolution features. An ultrasound image was found in 100% (22/22) of cases in the r-EBUS positive (r-EBUS+) group vs. 60% (6/10) in the r-EBUS negative (r-EBUS-) group, respectively ( Organizing pneumonia (OP) is a form of idiopathic diffuse interstitial lung disease (ILD). OP is characterized radiographically by variable features such as alveolar opacities (with a density varying from ground glass to consolidation), diffuse infiltrative opacities, and solitary mass (or nodule). The histopathological diagnosis is characterized by buds of granulation tissue within the distal air spaces , which are the hallmark of OP. OP may be associated with identifiable etiology including neoplasms, pulmonary infection, drug reaction, and connective tissue diseases, or may be considered cryptogenic, after exclusion of any other etiology . HistoloRadial endobronchial ultrasound (r-EBUS) is a procedure using a 20 Mhz US probe that provides a high-resolution 360-degree view of the surrounding lung. Characteristic ultrasound features of normal and abnormal lung tissue help identify the lesion. After reaching the lesion, the probe is withdrawn while the guide sheath is left in place as an extended working channel. Biopsy forceps are then advanced through the guide sheath to the lesion to obtain tissue samples. In our center, r-EBUS is performed under topical anesthesia without sedation using a virtual bronchoscopy software to guide and shorten the length of the procedure . The reaThis paper describes results obtained in our department using r-EBUS and the virtual bronchoscopy procedure in OP. The aim of this study was to assess r-EBUS for the diagnosis of OP in a larger series of patients and to identify the factors affecting the diagnostic yield. We reviewed data from all patients who had r-EBUS-guided bronchoscopy for the diagnosis of a PPL, at Rouen University Hospital, France, between April 2008 and September 2020. From these, patients with a final diagnosis of OP were included in the analysis.  DiagnosiBefore each r-EBUS procedure, the location of the lesion was analyzed using the virtual bronchoscopy software planner, in order to identify the optimal bronchial path to the lesion  from 2008 to 2011, and LungPoint®, Broncus Medical Inc., San Jose, CA, USA since 2011, from a millimeter (mm) slice chest CT a. A posiA bronchoscopy was then carried out using local or general anesthesia with either the MP160F video bronchoscope or the BF-MP60F bronchofiberscope  with a 4-mm outer diameter and a 2-mm working channel. The ultrasonographic (US) probe used was the 1.4 mm UM-S20-17S probe , introduced into the dedicated 1.9-mm-diameter guide catheter . The procedure was performed without electromagnetic navigation or fluoroscopy. After having memorized the endobronchial route from the planning, the operator reached the most distal subsegmental bronchus. According to Izumo et al., the US image was a hypoechoic signal for patients with predominant alveolar/solid opacities and a mixed blizzard sign/hypoechoic signal for diffuse infiltrative opacities with GGos associated with solid components ,12,13. WOnce the US signal of the nodule was obtained, the probe was removed, and the guide sheath was left in place in the lesion. Sampling, including cytological brush and forceps biopsy , was then performed. Bronchoalveolar lavage was also performed. Rapid On Site Examination (ROSE) was not used. Systematic chest radiographs were obtained after each procedure to ensure the absence of pneumothorax. Diagnosis was confirmed using the r-EBUS samples, when the histological hallmark of OP ) was found .® . Comparisons were performed with a Fischer exact test or chi-squared test for qualitative parameters and a Student test for quantitative parameters. The tests were bilateral and the alpha risk was set to 5%. Descriptive statistics were performed using PrismBetween April 2008 and December 2020, 2735 r-EBUS procedures were performed for PPL, 33 of which had a final diagnosis of OP. Among these 33 final OP diagnoses, 17 were considered cryptogenic, and 16 secondary . All patients had clinical and radiological improvement: 20 (61%) with corticosteroids, 7 spontaneously, and 6 after surgical ablation.On chest CT, the lesions appeared as patchy alveolar opacities in 23 cases (70%), masses or pulmonary nodules in 8 cases (24%), and diffuse infiltrative opacities in 2 cases (6%). They were bilateral in 24 cases (74%). A bronchus sign on CT scan was found in all cases. The median time between the CT scan and r-EBUS procedure was 14 days (3–94).The r-EBUS procedure was performed under local anesthesia in 28/33 cases (85%). Bronchoalveolar lavage was performed in 18 cases (55%), showing an increased rate of lymphocytes in 14 cases (78%). Distal biopsies were performed through the guide sheath in 28/33 cases. A median number of four biopsies per patient was performed. No complications were reported during or after the procedure (pneumothorax or bleeding).A US image was obtained using r-EBUS in 28 cases (85%). In 27 cases, the image was within the lesion and in one case adjacent to the lesion . An examp = 0.002). In four cases (12%), the histological diagnosis was obtained by surgery, and in seven cases (21%) the diagnosis was made by clinical, radiological, and follow-up data. The diagnosis of OP was obtained by r-EBUS biopsy sampling in 22/33 cases (67%), and in 22 of the 28 cases (79%) that were associated with an ultrasound image (p = 0.0001).The median time between the CT scan and r-EBUS procedure was 11.5 days in the r-EBUS+ group and 22 days in the r-EBUS- group   comparedr-EBUS has been previously described as a method for OP diagnosis in a very limited number of cases. In a study by Kim et al. , among 1On the other hand, series of OP explored by standard bronchoscopy with unguided TBLB ,15 were Overall, our study found a comparable diagnostic yield of r-EBUS for OP  as reported using unguided TBLB ,14,15, sRecently, in order to increase the diagnostic yield for ILD, biopsy using a flexible cryoprobe was introduced in clinical practice. Metanalysis reported a 79% diagnostic yield of cryobiopsies. In a recent study, the authors reported a technique using r-EBUS for guided cryobiopsy without fluoroscopy , but witIn terms of complications, the rate of pneumothorax using r-EBUS-guided TBLB for the diagnosis of ILD  appearedIn our study, a factor that may have influenced the diagnostic yield was the time delay between the CT scan and r-EBUS procedure. Indeed, we found that it was significantly shorter in the r-EBUS+ group than in the r-EBUS- group, which is possibly related to the high incidence of migratory alveolar opacities in OP ,19. ThesAs r-EBUS appears efficient, safe, and easy for the histological diagnosis of OP, this should be considered for every suspicion of OP, and moreover, for every consolidation pattern. The histological confirmation will help the physician to guide the steroid treatment, the therapeutic strategy in case of relapse, and search for an etiology. Future research should prospectively compare the non-invasive diagnostic techniques for OP, including r-EBUS, transbronchial biopsy , and trans-thoracic needle aspiration.The results of our study have shown that r-EBUS, performed shortly after a CT scan showing the presence of a bronchus sign, is an efficient and safe technique for the diagnosis of organizing pneumonia, which compares favorably with standard TBLB.


Most emergency medicine (EM) applicants use the internet as a source of information when evaluating residency programs. Previous studies have analyzed the components of residency program websites; however, there is a paucity of information regarding EM program websites. The purpose of our study was to analyze information on EM residency program websites.In April–May 2020, we evaluated 249 United States EM residency program websites for presence or absence of 38 items relevant to EM applicants. Descriptive statistics were performed, including means and standard deviations.Of the 249 EM websites evaluated, the websites contained a mean of 20 of 38 items (53%). Only 16 programs (6%) contained at least three-quarters of the items of interest, and no programs contained all 38 items. The general categories with the least amount of items were social media use (9%), research (46%), and lifestyle (49%), compared to the other general categories such as application process (58%), resident information (63%), general program information (67%), and facility information (69%). The items provided by programs most often included program description (98%), blocks and rotations (91%), and faculty listing (88%). The items provided least often included housing/neighborhood information (17%) and social media links (19%).Our comprehensive review of EM residency websites in the US revealed the absence of many variables on most programs’ websites. Use of this information to enhance accessibility of desired information stands to benefit both applicants and programs in the increasingly competitive specialty of EM. Emergency medicine (EM) is a popular specialty among medical students, evidenced by the growing number of EM residency applicants over the last 10 years, with 2903 applicants in 2011 and 3640 in 2020.To assist medical students in navigating the staggering number of residencies across the United States, databases such as the Fellowship and Residency Electronic Interactive Database (FREIDA) have been designed to allow convenient access to program websites and information on residencies and fellowships.This study was exempt from institutional review bgoard approval because it involves publicly available information. Our methods were adapted from a previous study analyzing otolaryngology residency websites.We searched the available websites of these programs for 38 items listed in Understandably, some factors are more important to applicants than others, such as patient volume, curriculum, faculty, research, and simulation training centers.As the data contained in residency websites can be subjective, we created a standardized process to evaluate the websites, similar to the previous studies in other specialties.We performed a descriptive analysis of the data, including means and standard deviations. To calculate the percentage of items present in each subcategory, we added up the total number of items present among all 249 websites in that subcategory. We then divided this number by the denominator, which was calculated by multiplying the number of variables present in a subcategory by the number of websites examined (249).Microsft Excel 2020 version 16  was used for statistical analysis.Of 256 EM residency programs included in our study, seven programs did not have websites on FREIDA and were not accessible by Google search. Of the 249 websites evaluated, 110 websites (44%) provided a direct link from FREIDA to the residency homepage, while 107 (43%) programs required multiple clicks to get to the residency homepage. Thirty-two programs (13%) did not have a link on FREIDA.On average, websites contained 20 of 38 items (53%) with a standard deviation of 6.35. Only 16 programs (6%) contained at least three-quarters of the items of interest. One program contained 37 of 38 items, and no program contained all items. The items that were least commonly available on websites included information on housing and neighborhoods (17%) and social media links (19%) . Within As prospective applicants evaluate EM programs, careful planning and research is essential. The internet is easily accessible, and multiple studies have shown the importance of websites in recruitment.The “People” section on websites provided widely varying amounts of information. Despite previous analyses demonstrating that this is the most popular content on EM residency websites,The presence of social media on residency websites was also limited. Despite the rise of social media for recreational and professional purposes, only 19% of programs contained links to a form of social media for their EM program. In a study done involving nearly 1000 medical students, 68% of students reported using social media to learn about residency programs and 10% reported that the information found in the social media pages influenced their decisions on where to apply.Additionally, lifestyle factors including salary, vacation, meal allowance, and housing costs were often not found on websites. For example, salary information was listed on 63% of websites, vacation time was listed on 57% of websites, and housing and neighborhood information was listed on 17% of websites. Not only are these items important factors to consider when choosing a residency program, but they can be difficult to ask about during an interview, as applicants may worry that asking questions about compensation and benefits give the wrong impression to the program leadership and residents. These topics are discussed during interviews, but these details can be forgotten. Accessible information on lifestyle, which is currently lacking among many EM residency websites, could eliminate this source of potential inquiry or recall concern for applicants.As the number of residency programs in EM continues to grow,The 2020–21 residency application cycle posed a new challenge for applicants and programs. The lack of availability of visiting rotations and in-person interviews contributed to increased uncertainty among applicants, and most were unable to evaluate programs in person. In-person interviews served not only for programs to interview candidates, but for candidates to evaluate programs. Therefore, more than ever, a robust source of information available to applicants on a residency website serves to benefit both applicant and program alike.Limitations of our study include the subjective nature of analyzing residency program websites. However, we feel our method of data collection was standardized sufficiently to control for ambiguity. Another limitation was the lack of established standardized criteria for evaluating websites. We based our list of 38 items on our literature search of previous residency website analyses in other specialties, and also relied on papers relating to what EM applicants deem important and the expertise of the authors of our study.Future study is needed to provide an updated list of the most important criteria EM applicants could be interested in. The number of programs with “People” sections could be underestimated as many of these programs might have these sections on their social media websites rather than their official residency program websites. Lastly, only including items listed directly on the EM residency website rather than on external links could underestimate the presence of items on websites in our study. However, this was an important factor to determine the accessibility of information and user-friendly status of the websites. Our study does not address accuracy or quality of information contained on websites.Residency program website quality is important to EM applicants, and our study identifies several areas where programs could focus efforts for website renovation, including improving the integration of social media and providing information on residents and residency lifestyle. The results from our study can be used to improve EM residency websites to the mutual benefit of both applicants and residency programs.What do we already know about this issue?Residency program websites have been analyzed in other specialties. However, a comprehensive analysis of emergency medicine (EM) residency websites is lacking.What was the research question?Which components of EM residency websites are most common, and which are least common?What was the major finding of the study?We identified several areas for website renovation, such as social media integration and residency lifestyle.How does this improve population health?The results from our study can be used to improve EM residency websites to the mutual benefit of both applicants and residency programs.