Is a targeted population health management intervention developed for children enrolled in Medicaid and cared for in a large pediatric health system associated with changes in hospital admissions or bed-days?In this quality improvement study using difference-in-differences analysis of Medicaid-enrolled children, children exposed to an integrated population health management program experienced a reduction of 0.39 monthly admissions and 2.20 monthly bed-days per 1000 children compared with similar children in the community who were not exposed to the program. Annualized, these differences could translate to a reduction of 3600 bed-days for a population of 93 000 children eligible for Medicaid.Mobilizing interdisciplinary care teams for targeted children with high risk and spreading registry-based information technology tools across a Medicaid population may provide a scalable strategy for other health systems that aim to improve the value of services provided to this population. This quality improvement study estimates the association of a targeted population health management intervention for children eligible for Medicaid with changes in monthly hospital admissions and bed-days. As the proportion of children with Medicaid coverage increases, many pediatric health systems are searching for effective strategies to improve management of this high-risk population and reduce the need for inpatient resources.To estimate the association of a targeted population health management intervention for children eligible for Medicaid with changes in monthly hospital admissions and bed-days.This quality improvement study, using difference-in-differences analysis, deployed integrated team interventions in an academic pediatric health system with 31 in-network primary care practices among children enrolled in Medicaid who received care at the health system’s hospital and primary care practices. Data were collected from January 2014 to June 2017. Data analysis took place from January 2018 to June 2019.Targeted deployment of integrated team interventions, each including electronic medical record registry development and reporting alongside a common longitudinal quality improvement framework to distribute workflow among interdisciplinary clinicians and community health workers.Trends in monthly inpatient admissions and bed-days (per 1000 beneficiaries) during the preimplementation period  compared with the postimplementation period .P = .009) and 2.20  monthly bed-days per 1000 beneficiaries (P = .001). Accounting for disproportionate growth in the number of children with medical complexity who were in-network to the health system, this group experienced a monthly decrease in admissions of 0.54  per 1000 beneficiaries (P = .01) and in bed-days of 3.25  per 1000 beneficiaries (P = .001) compared with out-of-network patients. Annualized, these differences could translate to a reduction of 3600 bed-days for a population of 93 000 children eligible for Medicaid.Of 25 460 children admitted to the hospital’s health system during the study period, 8418 (33.1%)  were from in-network practices, and 17 042 (67.9%)  were from out-of-network practices. Compared with out-of-network patients, in-network patients experienced a decrease of 0.39  monthly admissions per 1000 beneficiaries (In this quality improvement study, a population health management approach providing targeted integrated care team interventions for children with medical and social complexity being cared for in a primary care network was associated with a reduction in service utilization compared with an out-of-network comparison group. Standardizing the work of care teams with quality improvement methods and integrated information technology tools may provide a scalable strategy for health systems to mitigate risk from a growing population of children who are eligible for Medicaid. Despite an improving economy, Medicaid and Children’s Health Insurance Program growth remains strong, as many low-income and moderate-income families are turning to these programs as a less costly and more comprehensive alternative to the high-deductible and relatively unaffordable coverage options offered by parents’ employers.8 Often qualifying for Medicaid coverage on the basis of disability, these children account for an increasing proportion of inpatient days within these hospital systems. Between 2004 and 2009, the number of bed-days at children’s hospitals attributed to children with medical complexity increased by 30%, compared with a 10% increase among other children.9 Finally, as the Medicaid program has grown in size, many systems are facing increasing pressure from payers to engage in risk contracting that requires value-based care for Medicaid recipients.13Pediatric health systems are responding to these new challenges according to local market conditions. For hospitals increasingly serving as the safety net for pediatric tertiary care, capacity challenges for specialty care patients often occur in the context of increasing numbers of children enrolled in Medicaid visiting their emergency departments and requiring inpatient hospitalization. For others, these capacity challenges have been further exacerbated by children with complex medical conditions increasingly relying on the limited numbers of specialty care clinicians who tend to aggregate to children’s hospitals and large pediatric systems.15 In pediatrics, few rigorous evaluations of system-level approaches to population management seeking to decrease use of inpatient services exist.16In this context, many pediatric health systems and hospitals are in need of population-directed initiatives to reduce preventable admissions and shorten lengths of stay among children enrolled in Medicaid without compromising quality of care. To date, the evidence of the success of such initiatives has been mixed, particularly for organizations assuming accountable care contracts.The purpose of this study was to assess the association of a targeted population health management program with changes in admissions and bed-days among children enrolled in Medicaid and attributed to a primary care network in a large pediatric health system. We used a quasi-experimental design to evaluate the population health program, assessing differences in hospital stays between children who were enrolled in Medicaid and in-network  and those who were out-of-network .The site of the population management program was a large mid-Atlantic children’s hospital and primary care network with 31 practices. The health system serves approximately 500 000 children annually, more than half of whom are served in primary care. This study was exempt from institutional review board oversight as analyses were conducted under operational program improvement initiatives.The target population for the intervention consisted of children enrolled in Medicaid aged 0 to 18 years who were in-network patients. This population was defined between January 1, 2014, and June 30, 2017. In each month, patients were considered in-network if they had visited a physician or nurse practitioner in the health system’s primary care network during the prior 24 months.The comparison population  consisted of children in the region who were enrolled in Medicaid but had not seen an in-network primary care clinician in the past 24 months. This population was estimated for each month in the study period using publicly available, monthly Medicaid enrollment files for the 5-county region in the state in which the hospital was located, excluding all in-network patients.17 . Because the distribution of patient bed-days was highly right-skewed owing to a small number of patients with very long lengths of stay, we computed bed-days based on length of stay winsorized at the 99th percentile  to minimize the effect of extreme outliers.We calculated total monthly admissions and bed-days for in-network and out-of-network patients. We excluded admissions and bed-days from the neonatal intensive care unit because those children could not have been enrolled in the population management solutions without prior primary care exposure. To estimate in-network and out-of-network rates of service utilization for each month, monthly admission and bed-day counts were converted to rates per 1000 Medicaid beneficiaries in each population.In base models of trends over time, we included monthly indicator variables to account for seasonal variation in admissions and bed-days during the year. Adjusted models accounted for differences across the admitted populations in age, sex, and race/ethnicity.18 The classification system was updated and validated for this analysis using the health system’s EHR of all International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes given to patients over the 3-year period. In each month, the comparison population of medically complex children included out-of-network patients with at least 2 CCCs who were enrolled in Medicaid, were aged 0 to 18 years, resided in the catchment area, and had visited an in-network subspecialty practice but had not visited the system’s primary care clinics in the past 24 months. Because health information was not available from Medicaid enrollment files, this comparison group served as a proxy for Medicaid beneficiaries with multiple CCCs who are out-of-network and therefore unexposed to the health system’s population health intervention.To control for potential differential changes in the case mix of the intervention and comparison groups during the study period, adjusted models also accounted for the proportion of in-network and out-of-network Medicaid enrollees diagnosed with at least 2 CCCs, where CCCs are defined as “any medical condition that can be reasonably expected to last at least 12 months (unless death intervenes) and to involve either several different organ systems or 1 organ system severely enough to require specialty pediatric care and probably some period of hospitalization in a tertiary care center.”We computed the distributions of demographic characteristics  and the number of CCCs of in-network and out-of-network study participants. Children with medical complexity were considered a time-dependent variable because the population of children with medical complexity attributed to the in-network practices increased at a greater rate than that attributed to the out-of-network practices during the study period ; 1[intervention] indicates whether the group is the in-network intervention group ; 1[post] indicates whether the observation date is on or after the start of the intervention ; [covariates] is a vector of covariates; ε is the disturbance term; g indexes the group ; and t indexes the time in months.To obtain difference-in-differences estimates, we compared changes in utilization among the in-network intervention group with changes in utilization among the out-of-network comparison group. Formally, the statistical model estimated was YWe tested for parallel preintervention trends by estimating the unadjusted model with the addition of the group indicator interacted with a linear time trend. Rejection of the null hypothesis that the population coefficient on the group-time trend interaction term is 0 indicated rejection of the parallel trends assumption.We obtained difference-in-differences estimates in both unadjusted and adjusted models, reported with 95% CIs for monthly admissions and bed-days per 1000 Medicaid beneficiaries. The unadjusted model included only monthly dummy variables, while the fully adjusted models adjusted for monthly measures of the proportion of patients who were of female sex, black race or Latino ethnicity, or had at least 2 CCCs to account for differential growth in the number of children who were in-network and presented with increasingly complex medical conditions over time.P < .05, and all tests were 2-tailed.All analyses were conducted using Stata version 14 (StataCorp). Statistical significance was set at Between January 1, 2014, and June 30, 2017, a mean of 93 365 children enrolled in Medicaid were designated as in-network to the health system’s primary care practices each month. This cohort increased by 32.1% during the study period, from 76 258 children in January 2014 to 100 767 children in June 2017. The number of children with medical complexity who received in-network care increased by 44.1%, from 1131 children in January 2014 to 1632 children in June 2017, surpassing the increase among out-of-network children  and patient bed-days .P = .009). In-network patients similarly experienced a decrease of 2.20  bed-days per 1000 beneficiaries compared with out-of-network patients (P = .001).The difference-in-differences estimates reported in P = .01). Similarly, the reduction in monthly bed-days among in-network patients increased to 3.25  bed-days per 1000 beneficiaries compared with out-of-network patients (P = .001)  per 1000 beneficiaries compared with out-of-network patients ( = .001) . AnnualiThis quality improvement study demonstrated that a targeted population health management strategy providing broad registry-based tools across a health system’s Medicaid-enrolled primary care population, alongside more precise integrated care team interventions for children with higher risk within the cohort, was associated with a large aggregate decrease in admissions and bed-days to the parent hospital. Our findings add to existing literature on population health programs because of our strong quasi-experimental design and the novel application of a unified population health improvement framework that stratified the intensity of resources across several risk groups simultaneously.24 Prior studies27 revealed a potential benefit of targeted care management programs for medically complex children and multicomponent improvement collaborative for children with asthma, while others had more equivocal or modest results. A global capitation model24 for children enrolled in Medicaid demonstrated similarly mixed results, with restrained growth in Medicaid costs compared with private insurance and single-arm improvement for some quality metrics but no reduction in hospitalization rates for asthma.As pediatric health systems seek to integrate population health programs, few robust evaluations of such initiatives exist, particularly among children enrolled in Medicaid.28 Although other health systems may focus interventions on patients with different clinical profiles, the success of this population-level intervention was driven by financial investments in the development of integrated care teams, alignment between clinical and quality improvement methods, and the wide availability of EHR tools. Our approach used interdisciplinary teams and quality improvement methods to align clinical workflow across team members using tools within the EHR. Technology developed in recent years to support interdisciplinary clinical teams offers a lens through which the Medicaid program and pediatric health systems can assess costs and benefits of programmatic interventions targeted at patients with high risk. The magnitude of the bed-day reduction, when scaled to the monthly attribution of all in-network patients who were enrolled in Medicaid, was estimated to exceed 10 beds daily or 3600 bed-days annually, representing a substantial potential savings of inpatient costs to the Medicaid program.The targeted approach described in our study provides a scalable and cost-effective strategy for other health systems as they determine the size of their investments and prioritization of programs for population health initiatives.Although our results are promising, important conditions promoting success may not be present in all health systems. The health system in this study had advantages in managing its patients with the highest risk through a primary care model, given its employed physician staffing model and unified EHR platform across its network practices, emergency department, and hospital. Nevertheless, despite barriers in practice integration or EHRs that other health systems may face, the quality improvement methods used to develop these targeted interventions can help standardize population health management approaches.29We examined the value of this intervention from the perspective of the health system. The magnitude of savings achieved for reducing inpatient bed-days was nearly 6-fold the investment that the health system made in hiring integrated care teams and expanding access to registry and reporting tools. Ambulatory utilization also increased. However, from the perspective of the payer, the degree to which increased ambulatory utilization and potential home nursing or pharmacy services might have attenuated economic savings remains uncertain.This study has limitations. First, while we included time-dependent adjustment for medical complexity, there may have been residual unobservable case-mix differences between the in-network and out-of-network populations. To some degree, the difference-in-differences analysis is robust to selection bias in comparison groups, so long as selection differences do not vary over time. For example, our team considered that the control group might have increasingly ventured outside the health system over time, but separate demographic characteristic analyses revealed consistent trends in neighborhoods nearest and furthest from the hospital (data not shown). Second, we did not have information on children’s admissions to hospitals outside our network. However, preferential use of a health system’s inpatient facilities by children within its primary care practices might be expected. If selection difference increased over time, we might have underestimated the consequences of the population management programs. Third, while we have a precise estimate of enrollment in the primary care network, this may not have fully captured the magnitude of children who were out-of-network to the health system. To account for this, we used state Medicaid enrollment files to estimate changes during the study period in the region’s census of the Medicaid-enrolled pediatric population who were not attributed to the health system’s practices. Our team believed these trends reflected increasing number of out-of-network children in the greater metropolitan area, even if the monthly estimates themselves may not have been precise.Market consolidation, increasing regional responsibility for hospital and subspecialty care, and growing Medicaid enrollment among patients have created new challenges for large pediatric health systems that provide care to children with medical complexity. This study provided quasi-experimental data for how population management, imbued with interdisciplinary teams, quality improvement, and information technology, can help large pediatric health systems respond to the needs of an increasing, medically complex, Medicaid-enrolled population and mitigate capacity challenges by reducing inpatient hospitalization among the managed population.


Background: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common form of cancer worldwide, with approximately 630,000 new cases diagnosed each year. The development of low-cost and non-invasive tools for the detection of HNSCC using volatile organic compounds (VOCs) in the breath could potentially improve patient care. The aim of this study was to investigate the feasibility of selected ion flow tube mass spectrometry (SIFT-MS) technology to identify breath VOCs for the detection of HNSCC. Materials and Methods: Breath samples were obtained from HNSCC patients (N = 23) and healthy volunteers (N = 21). Exhaled alveolar breath samples were collected into FlexFoil® PLUS  sampling bags from newly diagnosed, histologically confirmed, untreated patients with HNSCC and from non-cancer participants. Breath samples were analyzed by Selected Ion Flow Tube-Mass Spectrometry (SIFT-MS)  using Selective Ion Mode (SIM) scans that probed for 91 specific VOCs that had been previously reported as breath biomarkers of HNSCC and other malignancies. Results: Of the 91 compounds analyzed, the median concentration of hydrogen cyanide (HCN) was significantly higher in the HNSCC group  compared to the non-cancer group . A receiver operating curve (ROC) analysis showed an area under the curve (AUC) of 0.801 , suggesting moderate accuracy of HCN in distinguishing HNSCC from non-cancer individuals. There were no statistically significant differences in the concentrations of the other compounds of interest that were analyzed. Conclusions: This pilot study demonstrated the feasibility of SIFT-MS technology to identify VOCs for the detection of HNSCC. Head and neck squamous cell carcinoma (HNSCC) accounts for more than 630,000 cases and 330,000 deaths worldwide each year . There iHelicobacter pylori and to check that the bacteria has been eradicated in patients after treatment.Breath analysis represents a non-invasive, rapid, and painless technique that has been investigated for the early detection of cancers ,4 and inHuman breath contains a complex mixture of gases that includes oxygen, nitrogen, hydrogen, and trace amounts of volatile organic compounds (VOCs) . IdentifRecent studies, using technologies such as Electronic Nose (E-Nose) ,12, Gas This was a prospective cohort study comparing exhaled breath compounds in patients with HNSCC to exhaled breath compounds from non-cancer individuals. Ethics approval was obtained from the Southern Adelaide Local Health Network Human Ethics Committee (HREC/16/SAC/70 66.16) on the 29th of April 2016. (Site Specific Application (SSA) reference number is SSA/16/SAC/76.). Participants were recruited through the Department of Otolaryngology and Head and Neck Surgery at Flinders Medical Centre (FMC) and the Royal Adelaide Hospital (RAH), from May 2016 to November 2016.The HNSCC group was defined as patients with histologically confirmed SCC of the larynx, hypopharynx, oropharynx, and oral cavity prior to beginning treatment for their cancer. Participants in the non-cancer group were over 18 years of age and consisted of healthy volunteers with no previous history of cancer.Participants with recurrent HNSCC, post-treatment of prior HNSCC, or concurrent other cancers were excluded from this study. Those with diabetes mellitus were also excluded, as breath biomarkers of oxidative stress have been found to be significantly elevated in the breath of individuals with type 1 and 2 diabetes mellitus . All parBreath samples were collected into 4 ply 3 L FlexFoil  breath analysis bags via a single polypropylene fitting. Before use, bags were flushed with nitrogen gas a minimum of seven times to remove phenol and other background VOCs associated with the bags. A new FlexFoil bag was used for each participant. The FlexFoil sample bags were chosen due to the sample storage stability for up to 24 h and low background VOC content. A room air sample was collected concurrently with each breath sample to account for non-endogenous VOCs that may be present in the environment. Room air samples were collected using a gas tight glass syringe, and then transferred to a flushed Flex Foil bag using polytetrafluoroethylene (PTFE) tubing.All participants were required to fast and abstain from smoking for a minimum of 6 h prior to breath collection. Breath collection was performed in seated position via a single deep nasal inhalation, followed by complete exhalation through their mouth into the collection bag. FlexFoil bags were transported in a thermal insulator bag for immediate transport and analysis in the breath laboratory. In situations where more than one breath sample was collected from multiple participants on the day, the sealed bags were stored in a 37 °C dry incubator for a maximum of 3 h before analysis by SIFT-MS.Breath samples were analyzed by SIFT-MS  using a full spectral MASS scan. This mass scan was set to measure all 723 product ions with masses ranging from 10 to 250 atomic mass units (amu) over 50 cycles. Selective Ion Mode (SIM) scans were then used to probe for 91 specific VOCs that had been previously reported as breath biomarkers of HNSCC and other malignancies . The proStatistical analysis was performed with the IBM SPSS statistics version 20  and Stata version 15.1 . Data was expressed as medians and interquartile ranges, or frequencies, as appropriate. Demographics, smoking, and alcohol-related data between the groups were analyzed using the Mann–Whitney U and Chi square tests. The SIM scan data was analyzed with the Mann–Whitney U test. Type I error from multiple hypothesis testing was addressed with False Discovery Rate correction using the Benjamini–Hochberg adjusted p-value cutoff of ≤ 0.05. The performance of discriminating VOCs was assessed using the area under the receiver operating characteristic (ROC) curve. Logistic regression analysis was used to evaluate the association between HNSCC and HCN and was adjusted for age and gender. Results are reported as odds ratios and 95% confidence intervals (CI). The type 1 error rate was set at p < 0.05.Breath samples were collected from patients with HNSCC (N = 23) and non-cancer volunteers (N = 21). The baseline characteristics of the participants are summarized in The 91 volatile organic compounds (VOCs) that had been previously associated with HNSCC and other malignancies were quantified in the breath of HNSCC and non-cancer groups by SIM scan methods. The median concentration of HCN was significantly higher in the HNSCC group  compared to the non-cancer group  . When HCA basic receiver operating curve (ROC) analysis was performed to investigate the optimum combination of sensitivity and specificity of HCN as a potential biomarker of HNSCC. This showed an area under the curve (AUC) of 0.801 , suggesting moderate accuracy of HCN in distinguishing HNSCC from non-cancer individuals . The cut3O+, NO+, or O2+ [This pilot study is the first study to demonstrate that SIFT-MS technology can identify VOCs in HNSCC and non-HNSCC patients. SIFT-MS is an analytical technique that was developed by David Smith and Patrik Spanel for precise and accurate real time quantification of trace gases in air . SIFT-MS, or O2+ . This re, or O2+ . The abi, or O2+ . SIFT-MSTo date, various other breath analysis technologies have been used in the detection of HNSCC. These techniques include off-line sampling analysis via Gas Chromatography-Mass Spectrometry (GC-MS) , and othOur results show that SIFT-MS technology could be used to identify potential breath biomarkers for the non-invasive detection of HNSCC. Using SIFT-MS SIM scan analysis, HCN was found at significantly higher concentrations in the breath samples of HNSCC patients compared to non-cancer controls. There were no other differences found between groups for the other breath VOCs measured in this study. VOCs previously associated with HNSCC in the literature ,4,8 (maiThe finding of elevated HCN in the HNSCC compared to the non-cancer group is a novel finding. HCN is found both in the environment and in human breath. In the environment, it is mainly a product of biomass burning, industrial processes, vehicle exhaust, and cigarette smoke . HCN is Pseudomonas aeruginosa infection [Pseudomonas bacteremia have been reported in patients with oral cavity SCCs undergoing chemo-radiotherapy [Pseudomonas aeruginosa presence in HNSCC patients could, in part, explain the observation of elevated HCN in HNSCC patients.HCN in exhaled breath may have also been produced by changes in the oral microbiome. In humans, HCN may be produced by microorganisms such as proteobacteria and fungi and is thought to be derived from the metabolism of methylene carbon of glycine . Elevatenfection . In HNSCotherapy . Hence, Age, gender, and smoking habits were significantly different between the HNSCC and non-cancer groups in this study. This is because HNSCC is primarily a disease which involves an older male population with major risk factors of tobacco and alcohol consumption . MatchinThis pilot study has demonstrated the feasibility of breath testing in a clinical environment using SIFT-MS. However, the small sample size and patient heterogeneity, particularly in smoking habits, tumor subsite, and stages of HNSCC, are acknowledged as limitations of this study. The challenge associated with matching smoking habits between non-cancer and HNSCC patient groups has been discussed above. Heterogeneity in tumor subsite and stage were accepted as potential confounding factors. The association between HCN and patient characteristics were not evaluated due to the small sample size. Hence, we are cautious to propose that HCN alone is suitable as a detection breath biomarker for HNSCC due to the small sample size and limitations in terms of matching the patient group to a non-cancer cohort. However, our study shows that SIFT-MS technology can be used to identify breath VOCs in HNSCC patients.Breath biomarkers are a promising non-invasive approach for the detection of HNSCC and surveillance after treatment. Further research with larger patient numbers and non-cancer subjects more closely matched to the patients is required to gain a deeper understanding of the confounding effects of patient characteristics to aid the development of a population-based detection test for HNSCC.


Clinically operated community-based residential rehabilitation units (Community Rehabilitation Units) are resource intensive services supporting a small proportion of the people with severe and persisting mental illness who experience difficulties living in the community. Most consumers who engage with these services will be diagnosed with schizophrenia or a related disorder. This review seeks to: generate a typology of service models, describe the characteristics of the consumers accessing these services, and synthesise available evidence about consumers’ service experiences and outcomes.A systematic review was undertaken to identify studies describing Community Rehabilitation Units in Australia, consumer characteristics, and evidence about consumer experiences and outcomes. Search strings were applied to multiple databases; additional records were identified through snowballing. Records presenting unique empirical research were subject to quality appraisal.The typology defined two service types, Community-Based Residential Care (C-BRC), which emerged in the context of de-institutionalisation, and the more recent Transitional Residential Rehabilitation (TRR) approach. Key differentiating features were the focus on transitional care and ‘recovery’ under TRR. Schizophrenia spectrum disorders were the most common primary diagnosis under both service types. TRR consumers were more likely to be male, referred from community settings, and less likely to be subject to involuntary treatment. Regarding outcomes, the limited quantitative evidence  indicated C-BRC was successful in supporting the majority of consumers transferred from long-term inpatient care to remain out of hospital. All qualitative research conducted in C-BRC settings was assessed to be of poor quality (3 records). No methodologically sound quantitative evidence on the outcomes of TRR was identified. Qualitative research undertaken in these settings was of mixed quality (9 records), and the four records exploring consumer perspectives identified them as valuing the service provided.While there is qualitative evidence to suggest consumers value the support provided by Community Rehabilitation Units, there is an absence of methodologically sound quantitative research about the consumer outcomes achieved by these services. Given the ongoing and increasing investment in these facilities within the Australian context, there is an urgent need for high-quality research examining their efficiency and effectiveness.CRD42018097326).PROSPERO (The online version of this article (10.1186/s12888-019-2019-5) contains supplementary material, which is available to authorized users. The provision of clinically-operated rehabilitation in a community residential setting (Community Rehabilitation Units) reflects one approach to supporting people with severe and persisting mental illness to manage in the community. Most of the consumers who engage with mental health rehabilitation services will be diagnosed with schizophrenia or a related psychotic disorder , 2. SchiCommunity Rehabilitation Units emerged in the context of de-institutionalisation. The initial goal was to assist long-stay inpatients in returning to community living in an appropriately supported ‘home-like’ environment . CommuniThis review aims to provide definitional clarity about the types of clinically operated Community Rehabilitation Units in the Australian context, and to examine the associated evidence base critically. Specifically, this review seeks to: (1) generate a typology of service models, (2) describe the characteristics of the consumers who access these services, and (3) synthesise the available evidence about consumers’ service experiences and outcomes.The systematic review followed the PRISMA guidelines . The proRecords were sought that described: (1) Australian Community Rehabilitation Units for people affected by severe and persisting mental illness, (2) the characteristics of the consumers engaging with these services, and (3) their service experiences and outcomes. Eligibility criteria for inclusion in the systematic review were a service focus on adults (18–65 years) with schizophrenia and related disorders. Rehabilitation units targeting consumers aged < 18 years or > 65 years, non-psychotic disorders  or specifically dual diagnosis consumers were excluded. These exclusion criteria related to the focus of the service model. There was no exclusion of consumer data from included records based on diagnosis or co-morbidity.Databases were searched from 1995 onwards. This limit was applied as these services emerged in the context of the deinstitutionalisation process  with theParallel strategies were employed to identify relevant grey-literature using internet-based searches and published literature in academic databases .Full details of the search strategy are provided in Additional file Final extraction of records from all databases occurred on the 08/02/2018. Records were sequentially imported into an Endnote X8 database, and duplicates were removed. Two authors (SP & GH) independently screened records for eligibility at the title and abstract level. Additional records were identified through snowballing , with thRecords presenting unique quantitative and/or qualitative research data were subject to quality appraisal . Discrepancies were resolved through discussion to reach consensus. Relevant content was extracted into matrices. Data of interest included descriptive information outlining service models , service user characteristics , and quantitative and qualitative research findings . Descriptive data about service models were synthesised into a domains-based classification system , with thp ≤ .01 significance level was adopted to accommodate for the multiple comparisons and reduce the risk of Type 1 error. The absence of consistent documentation of standard deviations/standard errors for continuous variables  prohibited statistical comparison of the pooled means for these variables.Descriptive data regarding service user characteristics was pooled across studies, with means for service types and the associated models subsequently derived. Where data was available across both service types, differences in frequency of dichotomous variables was statistically compared using Chi-square or Fisher’s exact test. Fisher’s exact test was applied when the total sample size for pooled data was < 1000 cases  or if thIn relation to outcome data, no statistical synthesis was pre-specified or completed for the quantitative data. Findings from quantitative and qualitative studies were synthesised and tabulated.As shown in Fig. From the 24 records providing service descriptions, two types of Community Rehabilitation Units were identified– the original Community-Based Residential Care (C-BRC) type operating from the mid-1990s until the early 2000s, and the more recent Transitional Residential Rehabilitation (TRR) type  and to be referred from the community rather than an inpatient service . Schizophrenia spectrum disorders were the most common primary diagnosis across both service types, although this was significantly less frequent within the TRR service type . TRR consumers were also significantly less likely to be subject to an involuntary treatment order . C-BRC and TRR consumers did not differ significantly with respect to the frequency of being born in Australia , or rates of comorbid disorders (substance use (Fisher exact test p = 0.78), developmental disorders , and physical illness .Differences arose in the characteristics of consumers from the C-BRC and TRR service types. TRR consumers were significantly more likely to be male , and on lower total chlorpromazine dose equivalence of antipsychotic medication .With regards to quantitative research, only six records were identified. Findings from these studies are detailed in Table Twelve records presented qualitative research findings that considered a range of stakeholder perspectives . Findings are detailed in Table This systematic review identified core features of Australian Community Rehabilitation Units as the provision of 24-h rehabilitation focused support in a community-based residential setting to mental health consumers primarily diagnosed with a schizophrenia spectrum disorder. Two distinct service types were identified: the original C-BRC type that emerged in the context of deinstitutionalisation, and the more recent TRR type which replaced this from the early 2000s. TRR services differed from C-BRC in their transitional (time-limited) focus and emphasis on recovery-oriented care. Significant differences were present in the profile of consumers engaged with TRR and the earlier C-BRC services. Specifically, TRR consumers are more likely to be male, referred from the community and treated voluntarily, and less likely to have a primary diagnosis of a schizophrenia spectrum disorder. The extent to which these changes relate to shifts in relevant mental health policy needs to be considered.Quantitative research exploring the outcomes of Community Rehabilitation Units is limited. There is evidence to suggest that C-BRC services met their original goal of avoiding hospitalisation for most consumers initially transferred from long-stay inpatient care. Additionally, the need for 24-h supervision declined over time. The transition to community-based care was associated with improvements in quality of life. There is an absence of methodologically sound quantitative evidence considering the outcomes achieved for consumers engaged with the current TRR service type.Methodological concerns in qualitative research conducted in these settings were commonly identified. All qualitative research conducted in C-BRC settings and in non-Community Care Unit TRR settings was assessed to be of ‘poor’ quality. Qualitative research consistently reported favourable expectations and experiences of care at Community Rehabilitation Units by consumers and their families across both service types. Consumers and staff of TRR services articulate understandings of the service consistent with the designated service models. However, there is an absence of follow-up qualitative data from former TRR consumers, and that available for the original C-BRC cohort suggests consumers may continue to struggle with issues such as social isolation, accommodation instability and disability following the receipt of intensive rehabilitation support.The typology enhances understanding of the nature and function of Australian Community Rehabilitation Units for people affected by severe and persisting mental illness. Within the Australian context the typology identified potential bases of service non-comparability, whereby even identically named services were discrepant from each other. The matrix conceptually grouping the key emphases of services models supports the appropriateness of comparing extant Australian service models in future research. Additionally, differential features associated with sub-types and specific service models will facilitate the exploration of differences in service outcomes that may emerge. A relevant example of this may be the impact of novel staffing models being trialled, such as the integration of peer support work within the multidisciplinary team and non-government organisation partnerships.The availability of domains-based classification presents an opportunity to synthesise existing research internationally, and for future research collaboration. By identifying the key emphases of Australian service models, the typology will allow identification of the extent to which these models are similar, and the appropriateness of comparing and synthesising current and future quantitative and qualitative research findings through meta-analytic methods. One potential opportunity for comparison is the overlap identified between the two Australian Community Rehabilitation Unit types, and two of the five types of supported accommodation emerging in the recent English classification system of supported accommodation - ‘The Simple Taxonomy for Supported Accommodation’ (STAX-SA) . C-BRC aThe limitations in research exploring the outcomes for TRR consumers are concerning given the increasing investment in these services , 10, 12 The consistent finding of positive expectations and reflections on the experience of Community Rehabilitation Units by consumers across qualitative studies provides some support for the value and acceptability of these services. Additionally, available research exploring consumer’s commencement expectations of TRR services found they understood the model , 40, andThis review deliberately focused on Community Rehabilitation Units for people affected by severe and persisting mental illness in the Australian context. The review did not consider other types of accommodation and support that may be provided to this group, including substance use rehabilitation, non-clinical psychosocial rehabilitation services delivered by non-government organisations, and non-rehabilitation focussed supported accommodation. While these alternative residential services are outside the scope of the present review, a comprehensive understanding of the service array is critical for answering the complex questions of what works for whom, under what circumstances, and why.The two defined service types (C-BRC and TRR) reflect changes in the approach to these services over time, rather than two distinct types that are currently operating. This limits the utility of the C-BRC type to efforts directed towards understanding historical aspects of care.While the process of pooling service user data facilitated statistical comparison between the C-BRC and TRR types, there are several limitations associated with this approach. At least partial overlap of consumer characteristic data is anticipated due to the combination of cross-sectional and service commencement data covering overlapping time periods. Additionally, the use of cross sectional data may create bias towards more severely impaired consumers who received longer durations of residential care.Significant gaps and methodological limitations in the literature were identified, particularly with regards to qualitative research for C-BRC services and quantitative research for TRR services. There were no randomised controlled trials, and naturalistic observational designs predominated. Given the socially complex nature of these services the absence of studies involving randomisation, blinding and controls was anticipated. Moreover, there are ethical and practical barriers to attempting randomized controlled trials of such services .Community Rehabilitation Units in Australia fulfilled their original purpose of supporting de-institutionalised consumers to avoid hospitalisation. However, the focus of these units has shifted to the provision of transitional recovery-oriented care since the early 2000s. The profile of consumers currently accessing these services differs significantly from the original cohort. Although there is qualitative evidence to suggest that consumers value the support provided, there is no methodologically sound research quantifying the outcomes achieved. Given the ongoing and increasing investment in these services in the Australian context, there is an urgent need for high-quality research to examine the efficiency and effectiveness of these services. Such an evidence-base would be invaluable to informing policy decisions regarding the allocation of funding within the mental health service array.Additional file 1: Literature Search Strategy. (PDF 403 kb)Additional file 2: Quality appraisal. (PDF 156 kb)Additional file 3: Service types and models. (PDF 99 kb)Additional file 4: Consumer characteristics. (PDF 457 kb)Additional file 5: Included research relating to community-based and clinically operated residential rehabilitation for people affected by schizophrenia and related disorders in Australia. (PDF 559 kb)


Macroautophagy is an evolutionarily conserved process of the lysosome-dependent degradation of damaged proteins and organelles and plays an important role in cellular homeostasis. Macroautophagy is upregulated after myocardial infarction (MI) and seems to be detrimental during reperfusion and protective during left ventricle remodeling. Identifying new regulators of cardiac autophagy may help to maintain the activity of this process and protect the heart from MI effects. Recently, it was shown that noncoding RNAs (microRNAs and long noncoding RNAs) are involved in autophagy regulation in different cell types including cardiac cells. In this review, we summarized the role of macroautophagy in the heart following MI and we focused on the noncoding RNAs and their targeted genes reported to regulate autophagy in the heart under these pathological conditions. Myocardial infarction (MI) is a cardiovascular event caused by obstruction of one or more arteries supplying the heart. This area of the heart is therefore no longer supplied with oxygen and nutrients leading to the death of cardiomyocytes. Coronary reperfusion is the only recognized method to reduce the size of the infarct if it is performed within hours after MI. Despite its beneficial effect, several deleterious events such as increased oxidative stress and cell death are observed during the reperfusion process. If the infarcted zone is very extensive, there is a decrease in the contractile function of the heart. In order to compensate for this loss and maintain normal blood flow, the heart will undergo structural changes such as thinning of the infarcted zone, fibrosis, cardiomyocyte hypertrophy, and left ventricle (LV) dilatation . Left veMacroautophagy is an important and nonselective proteolytic mechanism that regulates the homeostasis of long-lived proteins, macromolecules including lipids and cell organelles, by surrounding them in a double-membrane vesicle known as autophagosome in order to deliver them to the lysosome for degradation . It playMacroautophagy proceeds in several successive steps and involves different proteins as previously described . In summThe regulation of autophagy is different during ischemia and reperfusion . During The activity of autophagy and its role in LVR post-MI have been studied in murine models with permanent ligation of the left coronary artery. Autophagy is induced in noninfarcted area of the heart during the subacute (1 week) and chronic (3 weeks) stages after MI . InhibitAbout 99% of the human genome do not encode proteins but are transcriptionally highly active and give rise to a broad spectrum of noncoding RNAs (ncRNAs) with regulatory and structural functions. Based on the size criteria of 200 nucleotides (nt), ncRNAs are divided into long (>200 nt) and short ncRNAs (<200 nt).The ncRNAs are modulated in some cardiovascular diseases including MI , 23. TheMiRNAs are defined as single-stranded noncoding RNAs around 22 nucleotides and are highly conserved between species [Several miRNAs were modulated during I/R and seem to have a protective effect by decreasing excessive autophagy-induced cell apoptosis by targeting one of the ATG genes. MiR-188-3p levels are reduced in cardiomyocytes treated with anoxia/reoxygenation and in MI mice. Overexpression of miR-188-3p in MI mice attenuated autophagy by targeting autophagy mediator Atg7 and decreased the infarcted area size . It was α expression resulting in reduced autophagy and apoptosis levels on NRCMs after H/R [β-1/Smad3 pathway [Other miRNAs play their protective effect by regulating one of the pathways involved in autophagy regulation. The levels of miR-223 are significantly upregulated in the heart of post-MI HF rats and in hypoxia-treated neonatal rat cardiomyocytes (NRCMs) and H9c2 cells. The increased miR-223 levels protect NRCMs and H9c2 cells from hypoxia-induced apoptosis whereas decreasing miR-223 expression had contrasting effects. This protective effect of miR-223 is explained by the decrease of its target gene expression PARP-1 (poly(ADP-ribose) polymerase 1) resulting in inhibition of excessive autophagy via the Akt/mTOR pathway . Howeverfter H/R . Lower m pathway .Some miRNAs contribute to ischemic/reperfusion injury by inhibiting the autophagy process. miR-497 is dramatically downregulated in the infarcted heart and in hypoxic cardiomyocytes, and its overexpression in murine MI model increased the infarcted size. It was shown that miR-497 inhibited autophagy by targeting the LC3B gene and induced cell apoptosis by targeting the Bcl-2 gene suggesting that decreasing miR-497 levels is a protective mechanism of the heart in response to MI . The expHigashi et al.  showed tlncRNAs are noncoding RNAs longer than 200 nucleotides that regulate both gene expression and protein translation . Nuclear2O2. Conversely, overexpression of CAIF inhibited autophagy inducing cardiomyocyte cell death and cardiac dysfunction caused by I/R. In this study, the authors demonstrate that CAIF directly binds to p53 protein and blocks its interaction with the myocardin promotor. Myocardin, a smooth muscle and cardiac muscle-specific transcriptional activator, is upregulated after I/R and H2O2 treatment and is involved in autophagy regulation in cardiomyocytes by increasing Beclin-1 expression. These data suggest CAIF-P53-myocardin pathway as a novel regulator of autophagy in cardiomyocytes and as a potential therapeutic target in order to inhibit excessive autophagy and improve cardiac function after I/R [Liu et al.  showed tfter I/R .On the other hand, it was shown that the lncRNA H19 expression was decreased in a mice model of acute MI and that its overexpression decreased infarcted size and improved cardiac function associated with autophagy upregulation; however, the mechanisms by which autophagy is regulated by H19 are still unknown. These results suggest that H19 protects the heart from MI by increasing cardiac autophagy .Some lncRNAs are upregulated after I/H and enhanced autophagy target gene expression by inhibiting miRNA expression. Yin et al.  showed tlncRNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) is expressed at high levels in patients with acute MI  and is cDespite current therapies, acute MI and HF which often follows remain the leading causes of death and disability worldwide. New therapeutic strategies are therefore required to protect the heart against the detrimental effects of acute ischemia/reperfusion injury. Inhibition of macroautophagy during reperfusion prevented cardiomyocyte death and reduced myocardial infarct size; however, its induction during LVR preserved LV function and prevented the onset of HF. Most pharmacological agents used up to date for regulating macroautophagy are not specific and may interfere with other cellular processes, so it will be necessary to identify new therapeutic approaches to regulate autophagy. Several noncoding RNAs were shown to be modulated during I/R and involved on cardiac autophagy regulation. The tissue-specific expression of some noncoding RNAs and their easy manipulation show their potential as novel targets for clinical developments to treat autophagy-related diseases. Identification of specific cardiac noncoding RNAs that regulate autophagy could be a good opportunity to protect the heart from MI injury without affecting the autophagy activity in other organs.


Small bowel obstruction (SBO) is associated with high morbidity and mortality in acute care surgery practice, with hernias constituting a significant portion of the underlying etiology. Physical examination and maneuvers such as changing the extremity position of the patient can further improve clinician's diagnostic acumen to identify the cause of the disease. We present a case of SBO in an 83-year-old female whose physical exam was consistent with an underlying obturator hernia. The Howship-Romberg sign is an indication of obturator nerve irritation resulting in inner thigh pain that may extend to the knee on internal rotation of the hip . ObturatAn 83-year-old female patient presented to our emergency room with a two-day history of right thigh and knee pain, nausea, and obstipation. The initial evaluation was concerning for hip pathology, as she was avoiding right hip extension Figure . Her famHer laboratory findings were within normal limits, except for elevated blood urea nitrogen 40 mg/dl  and creatinine 1.48 mg/dl , consistent with dehydration. A plain X-ray of her abdomen and pelvis revealed mild hip degenerative disease but raised concerns for dilated small bowel loops. A computed tomography (CT) scan of the abdomen and pelvis was done, which revealed a high-grade mid-ileal small bowel obstruction secondary to right obturator hernia (Figure Emergent abdomen exploration along with reduction and resection of the herniated ischemic small bowel loop with perforation was performed Figure .The hernia defect Figure  was closThe patient recovered and was discharged from the hospital four days later.The Howship-Romberg sign was initially described by John Howship back in 1840 , and MorElderly female patients presenting with a positive Howship-Romberg sign and symptoms suggestive of small bowel obstruction should always raise concerns for an obturator hernia. A CT scan of the abdomen and pelvis can be very helpful, and early surgical management is the mainstay of therapy.


We assessed the unintended effects on rooting of pear semi-hardwood cuttings and evaluated the stability of transgene expression in progeny produced by generative (seedlings) and vegetative  means up to four years. Our investigation revealed that: (1) The single and repeated transformations of clonal pear rootstocks did not result in unintended effects on adventitious root formation in cuttings; (2) stability of the transgene expression was confirmed on both generative and vegetative progeny, and no silenced transgenic plants were detected; (3) yearly variation in the gene expressions was observed and expression levels were decreased in extremely hot and dry summer; (4) the intron enhanced the expression of uidA gene in pear plants approximately two-fold compared to gene without intron. The current study provides useful information on transgene expression in progeny of fruit trees under natural environmental conditions.Adventitious rooting plays an important role in the commercial vegetative propagation of trees. Adventitious root formation is a complex biological process, but knowledge of the possible unintended effects induced by both the integration/expression of transgenes and in vitro conditions on the rooting is limited. The long-term stability of transgene expression is important both for original transformants of woody plants and its progeny. In this study, we used field-grown pear rootstock GP217 trees transformed with the reporter ß-glucuronidase ( Pear is one of the most important fruit species in the temperate-zone countries (temperate climate zone). The world production of pear occupies the second place after apple among the deciduous fruit trees, and about 24–26 million tons of pears were produced annually in the 2010s , and mosSelf-rooted fruit trees have a long juvenile period—for example, in an apple, tree it can take five to ten or even twelve years . In orderol genes from Agrobacterium rhizogenes were used to enhance rooting competence of rootstocks, including rolC to pear  was 9–12 cm. A significant decrease in the rooting frequency of non-transgenic control in the MR may be due to the increased diameter of the cuttings. This characteristic is an important factor as it may be associated with the endogenous auxin and carbohydrate contents of the tissues [The length and diameter of cuttings can affect the rooting efficiency. The average length of the cuttings in all experiments varied slightly from 123 to 134 mm, except for 2010 (MR), when it was 103 mm. Such small variations in length have practically no effect on rooting. For example, cuttings of ing rate . OuYang ing rate  reported tissues . Exadakt tissues  investig tissues .The correlation between the cutting diameter and the number of roots >2 mm was found in 2009, when the thickness of cuttings was most variable . Thus, tA. rhizogenes were used, and results of these studies are inconsistent. Transgenic pear rootstock lines with the rolB gene rooted much better than control and did not differ between themselves [Populus × canescens × P. grandidentata expressing rolB gene, with a range of 12.5–88.9% for the gene under 35S promoter, and a range of 20–100% for the gene under heat shock promoter [rolB gene significantly differed in their rooting rate (67% and 43%) [rolC gene in the field, but not in plants with 35S-rolC gene, although shoot formation from roots was easy induced under in vitro conditions. Possibly, the constitutive expression of rolC gene induces pleiotropic changes in the whole plant, including the root system as a consequence of the altered phytohormonal balance.In sum, the single and repeated transformations of pear rootstocks apparently did not lead to the unintended effects on rooting ability, as we did not find transgenic lines demonstrating stable enhancement or reduction of rooting rate. Two original (HB-1 and T-BO lines) and one double (the P-BK line) transformants showed a significant decrease in rooting of microshoots in vitro , but thiemselves . Howeverand 43%) . At lastand 43%) . Moreoveand 43%)  observedin vitro  was performed using ter gene . The pren intron  allowed ® apples. Resistance to glyphosate in transgenic P. trichocarpa × P. deltoides lines was maintained after propagation by cuttings [MdTFL1 gene, two flowered in 2.5 and 7 months, and the rest did not bloom after 36–45 months. This may serve as an indirect confirmation of a large variation in the blocking expression in seed progeny. On the other hand, seedlings of apple with RNAi suppressed the MdTFL1-1 gene [BpMADS4 gene [rolB gene did not have a negative effect on the budding of the apple rootstock. As for the seedlings from the harvest of 2006, the GUS activity in cutting-derived plants was lower in the year of 2010, apparently due to less favorable weather conditions.We also evaluated the expression stability in vegetative progeny obtained by grafting or cutting . Graftincuttings , but quacuttings  reported1-1 gene  or overeDS4 gene  bloomed DS4 gene  showed tPyrus communis L.) plants and untransformed control were used in this study. The first group of transgenic plants was generated by Agrobacterium-mediated transformation of leaf explants with the binary plasmid pBI121 (35S-uidA and nos-nptII genes) or p35SGUSint (35S-uidA with intron IV2 of the potato ST-LS1 gene and nos-hpt gene) as described by Lebedev and Dolgov [in vitro rooted shoots were inoculated with agrobacterial suspension for 40–50 min and co-cultivated in the dark on regeneration medium without antibiotics for 3–4 days. For shoot regeneration explants cultured on media with 500 mg/L cefotaxim and 25 mg/L kanamycin or 5 mg/L hygromycin. The plasmid pBIBar containing the 35S-bar and the nos-nptII genes was used to produce the second group of plants. Both wild-type plants and transgenic lines expressing uidA and nptII genes were used for the transfer of the herbicide resistance gene as described by Lebedev et al. [uidA-intron (line HB-1 and HB-4), transgenic GP217-uidA (line NII-1 and NIII-2), transgenic GP217-bar (line P-BK and P-BU), and re-transformants  were chosen. Two groups of transgenic pear rootstock GP217  and transgenic pear rootstock lines carrying reporter and herbicide resistance genes were planted in accordance with the permission of the Russian Inter-Agency Committee on Genetic Engineering Activity in 2000 and 2001, respectively . RootinguidA gene (line NII-1) and uidA-intron gene (line HA-6) in 2006. Seeds were removed from the fruits, stored at 4 °C for three months to break dormancy and were germinated in the greenhouse in the following spring. 15–20 seedlings were grown for 1–2 months in pots and evaluated by histochemical GUS assay. Three or four individuals were randomly selected from GUS-positive plants for each line and grown in the field up to four years. In total, almost 100 transgenic pear hybrids were studied. Wild-type pear rootstock and four transgenic lines with reporter genes  were vegetative propagated by grafting on field-grown pear seedlings in the summer of 2008. The ten plants were grafted for each genotype using T-budding method. The flowers of untransformed plants and transgenic lines of pear rootstock GP217 were used for pollination in 2006–2009. Pollen was collected from field-grown plants of different pear cultivars. Several tens of flowers for each transgenic line and wild-type plants were pollinated with non-transgenic pollen every year, and several tens of hybrid seeds were sown. The old local pear cultivar Bessemyanka was pollinated with two transgenic lines carrying The progenies resulting from the crosses with transgenic pear plants were screened for GUS expression by a qualitative histochemical GUS assay . Young lData were analyzed by analysis of variance (ANOVA) and Duncan’s multiple range test at a significance level of 0.05 using the Statistica software .uidA gene increased the GUS activity in pear plants approximately two-fold compared to the no-intron construction. The current study provides useful information on transgene expression in progeny of fruit trees under natural environmental conditions.In summary, the single and repeated transformations of clonal pear rootstocks by marker and herbicide resistance genes did not result in the unintended effects on adventitious root formation in semi-hardwood cuttings from field-grown trees. We demonstrate the stable expression of reporter ß-glucuronidase genes and absence of gene silencing in the generative and vegetative progeny of pear up to four years under field conditions. Year-dependent variation in the foreign gene expression was observed, and expression levels were decreased in extremely hot and dry summer. The intron in the


In their recent article assessing the predictive ability of urinary liver-type fatty-acid binding protein and serum N-terminal pro-B-type natriuretic peptide for acute kidney injury (AKI) in patients treated at a medical cardiac intensive care unit (ICU), Naruse et al.  did not Furthermore, it was unclear whether the serum creatinine levels used for diagnosis of AKI had been corrected based on fluid balance. It has been shown that not adjusting serum creatinine levels for fluid balance can underestimate the incidence and severity of AKI in the ICU patients, as a positive fluid balance can dilute serum creatinine .P < 0.05 indicates poor calibration of the prediction model or a lack of fit between two models [Finally, the discriminative ability of risk prediction models for AKI was assessed by c-statistic, but the calibration was not performed with the Hosmer-Lemeshow test. The calibration assesses the ability of a prediction model to match the number of actual events across deciles of risk-stratified subgroups. A


As eye tracking-based assessment of cognition becomes more widely used in older adults, particularly those at risk for dementia, reliable and scalable methods to collect high-quality data are required. Eye tracking-based cognitive tests that utilize device-embedded cameras have the potential to reach large numbers of people as a screening tool for preclinical cognitive decline. However, to fully validate this approach, more empirical evidence about the comparability of eyetracking-based paradigms to existing cognitive batteries is needed.Using a population of clinically normal older adults, we examined the relationship between a 30-minute Visual Paired Comparison (VPC) recognition memory task and cognitive composite indices sensitive to a subtle decline in domains associated with Alzheimer disease. Additionally, the scoring accuracy between software used with a commercial grade eye tracking camera at 60 frames per second (FPS) and a manually scored procedure used with a laptop-embedded web camera (3 FPS) on the VPC task was compared, as well as the relationship between VPC task performance and domain-specific cognitive function.A group of 49 clinically normal older adults completed a 30-min VPC recognition memory task with simultaneous recording of eye movements by a commercial-grade eye-tracking camera and a laptop-embedded camera. Relationships between webcam VPC performance and the Preclinical Alzheimer Cognitive Composite (PACC) and National Institutes of Health Toolbox Cognitive Battery (NIHTB-CB) were examined. Inter-rater reliability for manually scored tests was analyzed using Krippendorff’s kappa formula, and we used Spearman’s Rho correlations to investigate the relationship between VPC performance scores with both cameras. We also examined the relationship between VPC performance with the device-embedded camera and domain-specific cognitive performance.P=.007) and NIHTB-CB  composite scores, and additional individual neurocognitive task scores including letter fluency , category fluency , and Trail Making Test A . Robust relationships were observed between the 60 FPS eye tracker and 3 FPS webcam on both trial-level VPC novelty preference  and overall mean VPC novelty preference (r=.92 P<.001). Inter-rater agreement of manually scored web camera data was high (kappa=.84).Modest relationships were seen between mean VPC novelty preference and the PACC (r=.39, In a sample of clinically normal older adults, performance on a 30-minute VPC task correlated modestly with computerized and paper-pencil based cognitive composites that serve as preclinical Alzheimer disease cognitive indices. The strength of these relationships did not differ between camera devices. We suggest that using a device-embedded camera is a reliable and valid way to assess performance on VPC tasks accurately and that these tasks correlate with existing cognitive composites. Alzheimer disease (AD) and other forms of dementia, broadly characterized by declines in mental ability severe enough to interfere with daily life, pose serious challenges to patients, caregivers, and healthcare systems worldwide. As populations age, the global prevalence of dementia is expected to triple to 132 million between 2015 and 2050 [Current detection methods for preclinical AD include the use of biomarkers, such as neuroimaging and cerebrospinal fluid tests for amyloid-β and tau proteins ,4. IncreAnother method for detecting presymptomatic cognitive decline is through the use of eye tracking systems that assess eye movement behavior . For exaCommercial-grade eye-tracking cameras have traditionally been used to collect VPC data. These high frame rate cameras can capture a variety of complex visual features, including saccades, smooth pursuit (consistent tracking movements of the eyes), and fixation distributions (eyes focusing on particular areas or items), which can all be assessed for abnormal patterns indicative of a variety of pathologies ,20. DataEmerging research indicates that when used for cognitive tests sensitive to early signs of decline, embedded webcams in laptops and mobile devices produce data of similar quality to that collected by commercial-grade cameras . It remaThe purpose of this study is (1) to investigate the relationships between performance on a 30-minute webcam-based digital VPC task and two cognitive composite indices sensitive to subtle impairment in AD-relevant cognitive domains, (2) to examine the relationship between performance on the VPC task with a device-embedded camera and domain-specific cognitive scores, and (3) to investigate the accuracy of human-coded gaze positions on a thirty-minute VPC using a laptop-embedded camera when compared to an automatically scored gold standard high frame rate eye-tracking camera.All subjects underwent informed consent procedures approved by the Partners Human Research Committee, the Institutional Review Board for Brigham and Women’s Hospital and Massachusetts General Hospital. A total of 49 clinically normal, community-dwelling older adults were recruited from a cohort of volunteers interested in participating in research studies at the Center for Alzheimer Research and Treatment at Brigham and Women’s Hospital and the Massachusetts Alzheimer Disease Research Center at Massachusetts General Hospital. Subjects were excluded if they had a history of alcoholism, drug abuse, head trauma, or current serious medical or psychiatric illnesses. All subjects above the age of 50 years and within age-specified norms on the Telephone Interview of Cognitive Status  were eliThe PACC is a paper-pencil cognitive composite that includes 2 tasks of episodic memory, a task of speeded executive functioning, and a global cognitive screen. The Logical Memory-delayed recall score and the Free and Cued Selective Reminding Test total score comprised the episodic memory tests, with the Wechsler Adult Intelligence Scale-Revised Digit Symbol Coding Test total score representing the speeded executive functioning measure, and the Mini-Mental State Exam total score serving as the global cognitive screen .Additionally, a measure of attention and processing speed (Trail Making Test A) and 2 measures of executive functioning  were administered. All tests were z-transformed using the performance means and standard deviations of clinically normal older adults  ,25. All The NIHTB-CB is a computerized cognitive composite comprised of the Picture Vocabulary Test (PVT), the Flanker Inhibitory Control and Attention Test (Flanker), the Dimensional Change Card Sort Test (DCCS), the Pattern Comparison Processing Speed Test (PCPST), and the Picture Sequence Memory Test (PSMT) . The PVTA 30-minute VPC task developed by Neurotrack Technologies Inc  was used in this study. VPC tasks quantify how the test subject splits attention between familiar and novel visual stimuli, with a familiarization phase preceding a testing phase. During the familiarization phase, subjects were presented with pairs of identical visual stimuli for a fixed period (5 seconds). During the test phase, which follows a delay of either 2 seconds or 2 minutes to assess immediate and delayed recognition memory, subjects were presented with additional pairs of visual stimuli, including 1 from the familiarization phase (familiar stimulus) and 1 novel stimulus. The ratio of time a subject spends gazing at the novel stimulus relative to the total viewing time produces a novelty preference (NP) score, with higher scores representing better declarative memory function and lower scores indicating impaired function ,26,27.Eye movements during the VPC task were simultaneously recorded with a commercial-grade Tobii X2-60 eye tracker camera system  and an embedded web camera on a 13-inch Apple MacBook Air laptop . The Tobii camera sampled at 60 Hz, with corneal and pupil centers determining the gaze angle. Eye data were recorded using the Tobii SDK and API software. Participants were seated approximately 27 inches from the 13-inch laptop monitor that displayed the visual stimuli. The Apple MacBook Air laptop processor was a 1.4 GHz Intel Core i5 with 4 GB 1,600 MHz DDR3 memory and a 1,536 MB Intel HD Graphics 5,000 Graphics card. Video resolution of the laptop during test recording was 640 by 480.Explanations regarding the validation of camera calibration, data acquisition, and fixation filters for device-embedded cameras have previously been reported . BrieflyUsing the Tobii Pro Analytics software development kit default Tobii Pro Studio settings, we utilized the Active Display Coordinate System and the User Coordinate System to determine gaze location. Each data point consisted of an estimated gaze point for both the left and right eye. For each data point, the midpoint of the 2 gaze points was used as the definitive gaze estimate. Test trials were automatically excluded if more than 4s of data was missing due to the Tobii failing to find the eyes of the subject. In a previous study, Zola and colleagues used an Applied Science Laboratories eye tracker that recorded gaze data at 120 Hz (120 frames per second) . Three rIn addition to the commercial eye tracker, subjects were simultaneously recorded with a device embedded camera during the calibration and test phases. A high definition Flash video recorder recorded the subject, and the resulting Flash video (FLV) footage was streamed to Neurotrack’s Wowza Amazon Web Services instance. Metadata, such as calibration phase timing and timing of task image presentation, was injected into the FLV video to ensure correspondence between frames of the video and events of the test.Performance on preferential looking VPC tasks is quantified as novelty preference. In the present study, novelty preference was defined as the percentage of time the participant spent looking at the novel image compared with the familiar image. For each test trial, NP was calculated as (time viewing novel image) divided by . Mean novelty preference for each of the 20 test trials yielded the overall novelty preference score. Using the commercial grade eye-tracking camera, a rectangular area of interest perimeter slightly larger than each image was defined. Gaze time on each image was calculated based on the total gaze fixation time recorded by the Tobii X2-60 software.For the device-embedded camera data, individual processed video frames were evaluated on a frame by frame basis down-sampled to 3 frames per second (FPS) by 3 independent human coders to determine whether the subject was looking to the left, right, or neither side of the screen. Coding of the “neither” option was intended for frames when the participant was blinking, or when the image was of poor enough quality that the iris was indistinguishable from the rest of the eye. For each image, the majority decision was taken by the individual ratings. The NP score for each trial was the percentage of frames that the participant was rated as looking at the novel side (no. of “novel” frames) divided by .Analyses of VPC test data were conducted with IBM SPSS version 24.0 using non-parametric statistical procedures due to the non-normal distribution of VPC test performance. Inter-rater agreement of web camera data scoring was assessed using Krippendorff’s kappa calculation . RelatioSubjects were all cognitively normal community-dwelling older adults. The age range of the study cohort was 54-97 years and the level of education ranged from 12-20 years. .P>.10; To further investigate the data from the commercial-grade eye-tracking camera and the laptop-embedded camera, we compared the strength of the correlations between the Tobii X2-60 VPC and the PACC and NIHTB-CB composites with the strength of the correlations between the laptop embedded camera and the PACC and NIHTB-CB composites. Fisher r to z transformation revealed no significant differences in the strength of correlation between each modality of data acquisition P>.10; .P<.001), which is in line with what has been published previously [P=.007) and the NIHTB-CB  across 46 subjects. Three subjects were excluded from the analysis due to insufficient data quality.Performance on the NIHTB-CB was moderately correlated with scores on the PACC , Trails A , letter fluency , and category fluency . A trend relationship was seen on Logical Memory Delayed Recall . On the NIHTB-CB, significant relationships were observed on PSMT  and DCCS , with a trend relationship for PVT .We then analyzed the correlations between VPC performance and domain-specific cognitive functions . SignifiP<.001) among study participants  will greatly increase the availability of these assessments.This study has a few limitations. For one, the small study sample comprised of clinically normal older adults restricts the generalizability of the results to broader populations. However, we were able to recruit a diverse group of participants and will strive to do so in larger studies in the future to maximize the external validity of the results. Also, the collection of the webcam-based VPC data within a clinic setting is not ideal for approximating in-home performance, but the validation of webcam-based data in a research setting is a necessary precursor to remote data collection.These results set the stage for many future directions. We demonstrated here that manual scoring of the webcam-based VPC task had high inter-rater reliability, indicating that this method of data quantification produces consistent results across different scorers. The future development of an automated scoring system for device-embedded camera data would be extremely valuable, allowing for faster scoring and deployment on a larger scale. Additionally, although outside of the scope of this study, future studies will need to examine the test-retest reliability of the webcam-based VPC tests to ensure high internal validity.In conclusion, this study showed strong convergence in data accuracy between commercial-grade eye tracking cameras and device-embedded cameras on a 30-min VPC task. Results demonstrated modest to moderate correlations on 30-minute VPC task performance using device-embedded cameras and performance on gold standard digital and paper-pencil cognitive composites. Eye tracking through device-embedded cameras can provide efficient and scalable evaluation of cognitive performance and support the growing number of individuals at risk for cognitive decline.


Metabolic syndrome including diabetes and its complications  are common diseases and frequently occur in combination. The animal models of metabolic diseases are essential tools to reveal the pathophysiology and provide novel insights to develop new therapies and drugs. To this day, many animal models such as hereditary models, chemical- or diet-induced models, and gene-engineered models have been developed and studied to elucidate molecular mechanisms and functional alterations associated with metabolic diseases. In this special issue, we aimed to provide information on recent developments on experimental animal models in this field and up-to-date information on the pathophysiology, therapeutic drugs/strategies, and diagnosis of metabolic diseases. Here, we bring together 6 excellent articles related to diabetes and related metabolic diseases from all over the world.The review article “Focusing on Sodium Glucose Cotransporter-2 and the Sympathetic Nervous System: Potential Impact in Diabetic Retinopathy” by L. Y. Herat et al. comprehensively covers the etiology of diabetic retinopathy (DR) and highlights novel targets, SGLT2 and the sympathetic nervous system, for the management of this pathology. DR is a serious microvascular complication observed in many diabetic patients that can ultimately lead to vision loss. Prevention of DR and other diabetes-related microvascular complications is a major treatment goal. Today, SGLT2 inhibitors provide a new therapeutic option to control blood glucose levels and prevent the subsequent development of diabetic complications in retinal microvasculature. This in-time review summarizes current evidence on the use of SGLT2 inhibitors and identifies gaps that need to be addressed.In the article entitled “Spontaneously Diabetic Torii (SDT) Fatty Rat, a Novel Animal Model of Type 2 Diabetes Mellitus, Shows Blunted Circadian Rhythms and Melatonin Secretion,” K. Sakimura et al. demonstrate the deficits in the circadian rhythms and dysregulation of melatonin secretion in SDT fatty rat, a new animal model of type 2 diabetic obesity. Since hyperglycemia, hyperlipidemia, and insulin resistance are all observed in these SDT fatty rats from a young age, this exciting new animal model will undoubtedly be useful for future studies investigating the relationship between deficits in the circadian rhythm and metabolic dysfunction in obese type 2 diabetics.Nitric oxide (NO) is a potent vasodilator released from vascular endothelial cells and plays a crucial role in vascular homeostasis. In many cardiovascular diseases and type 2 diabetes, NO bioavailability is reduced primarily due to endothelial dysfunction. It is also known that metabolic syndrome including obesity and glucose tolerance is associated with impairment of NO signaling. Dietary supplementation of nitrate is an alternate source of NO when the endothelium-dependent, endogenous NO synthesis system is compromised. V. B. Matthews et al. examined whether the dietary supplementation of nitrate prevents the development of the metabolic syndrome in mice fed a high-fat diet, in their paper “Long-Term Dietary Nitrate Supplementation Does Not Prevent Development of the Metabolic Syndrome in Mice Fed a High-Fat Diet.” The authors also discuss the importance of short-chain fatty acids in the context of metabolic syndrome.Abnormal platelet function such as platelet hyperreactivity and hyperaggregability is commonly observed in metabolic syndrome. It has been reported that arginine supplementation and aerobic exercise training enhance vascular NO activity, resulting in the inhibition of platelet hyperaggregability. However, the mechanisms underlying these beneficial effects remain unclear. In the article entitled “Aerobic Training Associated to Arginine Supplementation Reduces Platelet Hyperaggregability Collagen-Induced in Rats under High Risk to Develop Metabolic Syndrome,” Motta et al. examined the impact of aerobic training and/or arginine supplementation on platelet hyperaggregability, inflammatory mediators , serum lipid profile, and serum lipid peroxidation in fructose-administered rats. The authors demonstrate that the combination of aerobic training and arginine supplementation provides benefit by prevention of collagen-induced platelet hyperaggregability and reduction of inflammatory markers that are not observed animal groups receiving either only aerobic training or only arginine supplementation. These findings suggest that the combination of currently available therapeutic options has greater benefit than monotherapy to delay the onset of cardiovascular diseases in patients with metabolic syndrome.Vanadium derivatives have hypoglycemic effects in animal models and humans. Due to their role on insulin signaling and enzymatic processes regulation, these compounds are clinically used to patients with poorly controlled type 2 diabetes. “Vanadyl Sulfate Effects on Systemic Profiles of Metabolic Syndrome in Old Rats with Fructose-Induced Obesity” written by Ortega-Pacheco et al. describes the antiobese, hypoglycemic, and hypolipidemic effects of vanadyl sulfate on fructose-induced metabolic syndrome in aged rats. In addition to an antiobesity effect in aged obese rats, vanadyl sulfate improved insulin sensitivity and oral glucose tolerance tests in rats with fructose-induced chronic obesity. Vanadyl sulfate may be a valuable therapeutic agent in preventing insulin resistance, the development and progression of obesity, and metabolic syndrome complications in aged patients with obesity or type 2 diabetes.N. Babaya et al. demonstrate that NSY-Chr14 is a streptozotocin- (STZ-) susceptible chromosome and that the STZ-susceptible region is located in the distal segment of NSY-Chr14 in their paper “Verification That Mouse Chromosome 14 Is Responsible for Susceptibility to Streptozotocin in NSY Mice.” Construction of new congenic strains will lead to fine mapping and identification of causal variants of the genes responsible for STZ susceptibility in the NSY mouse.We hope these articles bring further light in the research field of diabetes and related metabolic diseases and contribute to the development of new therapeutic strategies and drugs in the future.


Mobilization and activation of natural killer cells (NK cells) have been hypothesized to contribute to observed protective effects of exercise on cancer development and progression. Some evidence exists for acute effects of aerobic exercise on NK cell mobilization and function, i.e., alteration of the gene expression profile of NK cells. Yet, the chronic effects of exercise training, and effects of other modalities than endurance exercise are still understudied. Here, we investigated the chronic effects of a 12-week resistance exercise program on NK cell gene expression in breast cancer patients undergoing adjuvant chemo- or radiotherapy.Breast cancer patients were randomly assigned to either a 12-week resistance exercise program or a relaxation control group concomitant to adjuvant therapy. In a subsample of 19 participants, RNA was extracted from magnet bead isolated NK cells and subsequently analyzed for differential gene expression using microarray Illumina HumanHT-12 v4 before and after the intervention.After chronic exercise intervention several genes showed higher differential expression compared to the control group. However, after correction for multiple testing, baseline-adjusted analyses of covariance indicated no significant differences between the intervention and the control group with regard to the gene expression profile.Our findings suggest that 12-week resistance-exercise did not alter the gene expression profile of NK cells in breast cancer patients undergoing adjuvant therapy on the long term. Further studies with larger sample sizes and specifically designed to investigate whether exercise-induced changes in NK cell function are attributed to acute effects are warranted. An active lifestyle is associated with reduced breast cancer risk and improved survival in breast cancer patients . BesidesStudies have revealed that an acute bout of exercise affect the NK cell distribution and function. In detail, NK cells are elevated immediately after exercise, strongly decrease in the subsequent hours and return to baseline within 24 h , dependiIn contrast to acute effects of exercise on NK cell mobilization and function, the knowledge about training effects on baseline NK cell function is still sparse. Although inconsistent, some studies reported changes of resting NK cell numbers and proportions as well as altered NK cell cytotoxicity after longer training periods .Since acute effects of exercise on NK cell cytotoxicity are accompanied by changes of the transcriptome we hypothesized that chronic physical exercise may have a similar effect. Thus, in this pilot study we investigated the chronic effect of 12-week resistance exercise on NK-cell gene expression in breast cancer patients undergoing chemotherapy or radiation therapy.ClinicalTrials.gov . Details of the study designs and primary results are already published , and after the end of intervention (T2), endpoints and patients characteristics were assessed and blood samples taken. The studies were approved by the ethics committee of the University of Heidelberg and registered at ublished . Here weThe consent obtained from all participants was both informed and written. General exclusion criteria for the exercise trials comprised contra-indications for progressive resistance training and patients performing already a systematic intense resistance training (at least twice a week) were excluded. In order to investigate a homogenous sample, 10 participants of each trial (BEATE and BEST) were carefully selected for immunological analysis. Participants were chosen by indicating similar baseline values of BMI, age, and fitness levels between both trials (BEATE and BEST) as well as between participants of the intervention and the control groups. Participants of the exercise groups were only considered for inclusion if they attended >80% of training sessions. Moreover, participants who reported acute infections prior or during blood sampling were excluded.Both interventions were performed group-based for 60 min twice weekly over 12 weeks under the supervision and guidance of experienced therapists in specific training facilities. Exercise comprised eight different machine-based progressive resistance exercises  without any specific aerobic exercise. The control group encompassed progressive muscle relaxation according to Jacobson without any aerobic or muscle strengthening exercise .* 107 cells/ml and were re-suspended in 1 l phosphate buffer solution (PBS). NK cells were isolated from peripheral blood mononuclear cells (PBMCs) using EasySep Human NK-Cell Enrichment Kit, StemCell Technologies (Cat# 19055).PBMCs were isolated from freshly collected blood. After PBMC isolation with Ficoll, the cells were adjusted to a maximum of 5 Total RNA for gene and miRNA analysis was extracted using TRIzol (Ambion by Life Technologies). For gene expression study only, RNA was purified using Qiagen-RNeasy Mini Kit. RNA pellets were re-suspended in diethyl pyrocarbonate-treated water. RNA integrity was assessed (before beginning target processing) using Agilent Bioanalyzer 2100 .TM Labeling Kit. Labeled RNA was detected by hybridization to the probes on the BeadChip. After washing and staining steps, BeadChips are scanned on a iScanTM. The experiment was carried out in adherence to the protocol provided by Illumina Technologies®.Microarray analysis using Illumina HumanHT-12 v4 Expression BeadChip was conducted with the extracted RNA of NK cells. Each array on the HumanHT-12 v4 Expression BeadChip targets >47,000 probes. A microarray is used to detect the expression levels of thousands of genes at the same time. BeadChips microarray consists of oligonucleotides immobilized to beads held in microwells on the surface of an array substrate. RNA collected from isolated NK cells was labeled using the TargetAmp-NanoTM array scanner. Data extraction was done for all beads individually, and outliers were removed when the absolute difference to the median was >2.5 times median absolute deviation (MAD) (2.5 Hampel’s method). All remaining bead level data points were then background corrected and quantile normalized  bead expression values of the two groups of interest. In the case of significance of expression against background we tested for greater than all negative beads for this sample and in the case of comparing separate groups we tested for inequality of the means of the groups. In the case of comparing groups we additionally calculated p-values using averaged expression values for each sample in the group. For the differential expression analysis, Benjamini–Hochberg correction was applied to the complete set of p-values of all ProbeIDs on the chip. The average expression value was calculated as mean of the measured expressions of beads together with the standard deviation of the beads. The test for baseline-adjusted differences between exercise vs. non-exercise after oncological treatment was done using analysis of covariance (ANCOVA) expression after treatment as dependent variable and expression at baseline as well as medical treatment as covariate. Testing several thousands of genes individually requires adjustment for multiple testing in order to control for false-positive findings. We adjust p-values using the Benjamini–Hochberg method, which controls the false discovery rate  was not successful; hence, the total sample size is 19. Participant’s characteristics are shown in p-values > 0.9). However, we could explore the top candidates, e.g., the attached heat map contains the genes with raw p < 0.001 .One of the interesting candidates is the TET1 gene (10–11 translocation methyl cytosine dioxygenase 1). The expression levels after the treatment tend to be higher in the exercise group compared to the non-exercise group .FXYD4 is an ion transport regulator gene expression and has a significant difference in expression between exercise and non-exercise groups with a higher expression in exercise group (raw Homo sapiens vesicle-associated membrane protein (VAMP)-associated protein A was higher in exercise group compared to the non-exercise group after treatment .The expression of VAPA, Homo sapiens WD repeat domain 68 (WDR68) after treatment tend to be higher in the exercise group compared to the non-exercise group. This effect was still visible when analysis was performed without the “outlier” sample in the non-exercise group with very low expression before treatment .The expression levels of Homo sapiens chromosome 20 open-reading frame 199 (C20orf199) has a significantly higher expression in exercise group compared to the non-exercise group after treatment .p = 0.0002, adjusted p = 0.990911).The gene expression of SLC22A10 is significantly higher in exercise groups compared to the non-exercise group after treatment  activation at the cell surface  is an epigenetic marker responsible for the conversion of the modified DNA base 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC) and is the initial step for active DNA demethylation in mammals. Reduced levels of TET1 have been associated with higher proliferation levels . The oth surface . Homo saferation . C20orf1Physical exercise indeed disturbs the immune system homeostasis. However, our study together suggests that these changes are probably driven by acute rather than chronic exercise effects. Additionally, chronic exercise may not induce any changes in NK-cell gene expression in breast cancer patients undergoing medical treatment.One of the possible explanations for our findings can be, since medical treatments (chemotherapy or radiation therapy) strongly influence gene expression in various tissues ; this caIt is of importance to note that similar to other investigations in this field our study was limited by small number of participants and should thus be considered a pilot study. Another limitation is that we did not measure NK cell functions or the change in NK cell number or proportions. However, ours is the first study that explored effects of chronic resistance training program as well as cancer therapy effects on NK cell gene expression of breast cancer patients. Further research in this context should include acute and chronic assessments of NK cell function, transcriptomics, and epigenomics in larger sample sizes with different exercise modalities.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.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.