The Association of Organizational, Environmental, and Staffing Characteristics of Residential Care Facilities and the Risk Rating of Statutory Notifications: A Cross-Sectional Study in Ireland.

OBJECTIVES: Safety incidents (SIs) are an indicator of quality in health and social care services. Safety incident research has largely focused on acute health care settings. We aimed to examine the association of organizational, environmental, and staffing characteristics of residential care facilities (RCFs) and severity of regulatory SI notifications. METHODS: This was a retrospective analysis of SI notifications to the regulator for social care in Ireland received in 2018 and 2019. The mean risk rating of SI notifications for each RCF was used as the outcome. Regression analysis was conducted for the association of RCF characteristics (beds, staff to bed ratio, staff full-time equivalent (FTE), nurse to bed ratio, nurse FTE, number of RCF operated by the service provider, non-statutory or statutory provider) and the outcome, separately for nursing homes and residential disability services. RESULTS: A total of 53,268 SI notifications were received. One thousand nine hundred RCFs were operational during the period: 594 (31.3%) for RCF-Nursing home and 1304 (68.7%) for RCF-Disability. For nursing homes, in the most adjusted model, the number of RCF operated by a provider ( ß coefficient [95% confidence interval] = 0.508 [0.223-0.793]) was positively associated with mean risk rating of SI. For disability services, the following characteristics were positively associated in the most adjusted model: beds (0.081; 0.060-0.101), staff to bed ratio (0.068; 0.017-0.120), nurse to bed ratio (0.356; 0.044-0.667), staff FTE (0.029; 0.015-0.042), and number of RCF operated by a provider (0.067; 0.050-0.084). CONCLUSIONS: Various modifiable organizational, environmental, and staffing characteristics and severity of SI notifications were associated in this study, most of which were related to RCF-Disability. Policymakers and providers of social care services should be cognizant of the relationship of these characteristics and severity of SI, when designing and planning residential care.

Contributing Factors to Adverse Events in Long-Term Care Facilities in Ireland, a Content Analysis.

OBJECTIVES: There is substantial research on contributing factors to adverse events (AEs) in acute settings. Little is known about AEs in long-term care facilities (LTCFs). Our aim was to identify contributing factors to AEs from LTCFs for older persons and people with disability to inform quality improvement. DESIGN: Content analysis of statutory notifications of AEs from LTCFs using a modified version of the Human Factors Analysis and Classifications System (HFACS) applied to health care. SETTING: A sample of high risk-rated notifications of AEs received by the regulator in 2018 and 2019 was drawn from the Database of Statutory Notifications from Social Care in Ireland (n = 156). METHODS: Two researchers independently analyzed notifications to identify contributing factors using our modified HFACS. The number of factors identified in each level, subcategory, and nanocode of the HFACS was calculated along with percentage representation of factors within notifications and percentage contribution of individual factors to the total number of factors identified. The number and percentage contributions of factors were also calculated, disaggregated by notification type. RESULTS: Contributing factors from all levels of the HFACS were identified. The most common contributing factor was "Resident factors" followed by "Unsafe acts." No contributing factors were attributed to 68 notifications (43.6%). Multiple contributing factors were attributed to 45 notifications (28.8%). The largest percentage of factors was identified in notifications of serious injuries (27.4%). CONCLUSION AND IMPLICATIONS: It is the responsibility of LTCFs to account for "Resident factors" in system design, risk management, and care plans. Developing systems and processes that identify where residents have higher risk of harm may reduce the occurrence of high-risk events and thus improve resident safety. The large proportion of notifications where no contributing factors were identified suggests the need for improved reflection and reporting from LTCFs and for more specific questions on notification forms.

Rational design of a SOCS1-edited tumor-infiltrating lymphocyte therapy using CRISPR/Cas9 screens.

Cell therapies such as tumor-infiltrating lymphocyte (TIL) therapy have shown promise in the treatment of patients with refractory solid tumors, with improvement in response rates and durability of responses nevertheless sought. To identify targets capable of enhancing the antitumor activity of T cell therapies, large-scale in vitro and in vivo clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 screens were performed, with the SOCS1 gene identified as a top T cell-enhancing target. In murine CD8+ T cell-therapy models, SOCS1 served as a critical checkpoint in restraining the accumulation of central memory T cells in lymphoid organs as well as intermediate (Texint) and effector (Texeff) exhausted T cell subsets derived from progenitor exhausted T cells (Texprog) in tumors. A comprehensive CRISPR tiling screen of the SOCS1-coding region identified sgRNAs targeting the SH2 domain of SOCS1 as the most potent, with an sgRNA with minimal off-target cut sites used to manufacture KSQ-001, an engineered TIL therapy with SOCS1 inactivated by CRISPR/Cas9. KSQ-001 possessed increased responsiveness to cytokine signals and enhanced in vivo antitumor function in mouse models. These data demonstrate the use of CRISPR/Cas9 screens in the rational design of T cell therapies.

To summarise the approach to and findings of the PPIE undertaken as part of a programme of secondary research with a vulnerable, hard to reach population during the COVID-19 pandemic.

BACKGROUND: Public and patient involvement and engagement (PPIE) is an important part of research. The inclusion of PPIE in research is becoming more widespread, however, there are some areas where it is still uncommon. For example, undertaking PPIE in secondary analysis projects is uncommon and PPIE with difficult to reach populations and vulnerable groups can be seen as being too difficult to facilitate. The aim was to summarise the approach to and findings of the PPIE undertaken as part of a programme of secondary analysis with a vulnerable, hard to reach population; residents of residential care facilities (RCFs), during the COVID-19 pandemic. METHODS: As part of a project to develop a publically available database of statutory notifications of adverse events from RCFs in Ireland, residents (n = 9) from RCFs for older people and people with disability were telephone interviewed. Residents were engaged through gatekeepers and posted participant information and consent forms. Themes were identified using content analyses of interview notes. RESULTS: Three parent themes were identified, each with two subthemes: privacy concerns, enthusiasm and dissemination of research findings. Residents highlighted the importance that no personal information be shared in the database. Once data were anonymized, residents thought that the database should be published and shared. Residents reported being happy about research being undertaken using the data and thought that publishing the database would help inform the public about RCFs. Completing a PPIE project with a vulnerable group during the global COVID-19 pandemic required planning and resources. Resources included finances, time and expertise. CONCLUSIONS: The involvement of residents informed the data inclusion in the published database and the approach taken in the protection of personal data. Enthusiasm for publication and research using the database by residents encouraged the developers as it was considered something that was wanted by residents. The benefits of PPIE can be achieved with vulnerable groups during unprecedented times with the appropriate planning. It requires dedication of time, finances and expertise. Overcoming the obstacles was achievable and worthwhile. The approach outlined can be used as an example to support PPIE in secondary analysis projects and or with vulnerable groups.

When doing research, it is important to involve the people that the research is going to impact. Research projects are increasingly including this involvement, however, there are some areas of research where it is not yet commonplace. For example, when undertaking projects with existing data or when the people of interest are considered a difficult to reach or vulnerable group. The LENS project (LEarning from Notifications in Social care) is a research project that developed and published a database using existing data on safety incidents in care homes. We carried out a consultation with people living in care homes as part of this project. People were asked for their input on the development of the database and the research that was being carried out on it. This work was completed during the COVID-19 pandemic and, as such, the people giving input were considered a vulnerable group. The people living in care homes were concerned about personal details being included in the database. Once they were reassured that no personal information would be included they were supportive of the database being made public. They also offered ideas about how the research that used the database could teach people working and living in care homes. The article describes how the researchers engaged the people and what was needed to achieve this. The article shows that involving people from vulnerable groups and in research relating to existing data, adds value even though there are obstacles to overcome. It is summarised here as an example for researchers undertaking similar work.

Mortality in residential care facilities for people with disability: a descriptive cross-sectional analysis of statutory notifications in Ireland.

OBJECTIVES: To determine incidence of death in residential care facilities for people with disability in Ireland, primary cause of death, associations of facility characteristics and deaths, and to compare characteristics of deaths reported as expected and unexpected. DESIGN: Descriptive cross-sectional study. SETTING: All residential care facilities for people with disability operational in Ireland in 2019 and 2020 (n=1356). PARTICIPANTS: n=9483 beds. MAIN OUTCOME MEASURES: All expected and unexpected deaths notified to the social services regulator. Cause of death as reported by the facility. RESULTS: 395 death notifications were received in 2019 (n=189) and 2020 (n=206). 45% (n=178) were for unexpected deaths. Incidence of death per 1000 beds per year was 20.83 for all, 11.44 for expected and 9.39 for unexpected deaths. Respiratory disease was the most common cause of death, accounting for 38% (n=151) of all deaths. In adjusted negative binomial regression analysis, congregated settings versus non-congregated (incidence rate ratio (95% CI): 2.59 (1.80 to 3.73)) and higher bed numbers (highest vs lowest quartile) (4.02 (2.19 to 7.40)) were positively associated with mortality. There was also a positive n-shaped association with category of nursing staff-to-resident ratio when compared with zero nurses. Emergency services were contacted for 6% of expected deaths. Of the deaths reported as unexpected, 29% were receiving palliative care and 10.8% had a terminal illness. CONCLUSION: Although incidence of death was low, residents of congregated and larger settings had higher incidence of death than residents of other settings. This should be a consideration for practice and policy. Given the high contribution of respiratory diseases to deaths and the potential avoidability of these, there is a need for improved respiratory health management in this population. Nearly half of all deaths were reported as unexpected; however, overlap in the characteristics of expected and unexpected deaths highlights the need for clearer definitions.

Determinants of regulatory compliance in health and social care services: A systematic review using the Consolidated Framework for Implementation Research.

BACKGROUND: The delivery of high quality care is a fundamental goal for health systems worldwide. One policy tool to ensure quality is the regulation of services by an independent public authority. This systematic review seeks to identify determinants of compliance with such regulation in health and social care services. METHODS: Searches were carried out on five electronic databases and grey literature sources. Quantitative, qualitative and mixed methods studies were eligible for inclusion. Titles and abstracts were screened by two reviewers independently. Determinants were identified from the included studies, extracted and allocated to constructs in the Consolidated Framework for Implementation Research (CFIR). The quality of included studies was appraised by two reviewers independently. The results were synthesised in a narrative review using the constructs of the CFIR as grouping themes. RESULTS: The search yielded 7,500 articles for screening, of which 157 were included. Most studies were quantitative designs in nursing home settings and were conducted in the United States. Determinants were largely structural in nature and allocated most frequently to the inner and outer setting domains of the CFIR. The following structural characteristics and compliance were found to be positively associated: smaller facilities (measured by bed capacity); higher nurse-staffing levels; and lower staff turnover. A facility's geographic location and compliance was also associated. It was difficult to make findings in respect of process determinants as qualitative studies were sparse, limiting investigation of the processes underlying regulatory compliance. CONCLUSION: The literature in this field has focused to date on structural attributes of compliant providers, perhaps because these are easier to measure, and has neglected more complex processes around the implementation of regulatory standards. A number of gaps, particularly in terms of qualitative work, are evident in the literature and further research in this area is needed to provide a clearer picture.

Incidence and type of restrictive practice use in nursing homes in Ireland.

BACKGROUND: Use of restrictive practices (RP) in care settings may sometimes be warranted but can also conflict with human rights. Research to date has focused primarily on physical and chemical RP, however other forms are also used. Better understanding of practice can inform RP reduction. This study describes the incidence of all types of RP use reported from nursing homes in Ireland. METHODS: RP notifications from nursing homes reported in 2020 were extracted from the Database of Statutory Notifications from Social Care in Ireland. The primary outcome measurement was the national incidence of use (frequency of RP/occupancy per 1000 residents) of categories and types of RP. Secondary outcome measurements such as percentage of facilities reporting use and quarterly median incidence of use in these facilities were calculated. RESULTS: Seventy thousand six hundred sixty-three RP uses were notified from 608 facilities (33,219 beds). National incidence of RP use per 1000 residents was, all categories: 2465.1, environmental: 1324.5, physical: 922.5, chemical: 141.1; 'other': 77.0. The most frequently used RPs per category were, environmental: door locks; physical: bedrails; chemical (where drug specified): antipsychotics; 'other': privacy. 90.5% of nursing homes reported using at least one type of RP in the 12-month period. Quarterly incidence of any RP use in these facilities was median 1.642 (IQR: 0.018 to 18.608) per bed. CONCLUSIONS: Nursing homes in Ireland regularly use RP; only 9.5% reported no RP use in the 12-month period. A wide variety of types of RP were reported. Environmental and 'other' (largely psychosocial) RP contributed notably to total RP use and warrant attention alongside the traditional focus on physical and chemical RP. Policy implications include the need for more comprehensive RP definitions.

Incidence and type of restrictive practice use in residential disability facilities in Ireland, a cross-sectional study.

Restrictive practices (RPs) are a contentious issue in health and social care services. While use may be warranted in some instances, there are risks and concerns around human rights infringements. There are limited data available on the types and incidences of RPs used in health and social care services internationally. The objective of this study is to describe the type of RPs and incidence of use in disability residential care facilities (RCFs) in Ireland. RP notifications from disability RCFs reported from November 2019 to October 2020 were extracted from the Database of Statutory Notifications from Social Care in Ireland. National frequency and incidence of use of categories and type of RPs were calculated. The number and percentage of disability RCFs reporting RP use, along with the mean annual incidence of use, were also calculated. A total of 48,877 uses of RPs were notified from 1387 disability RCFs (9487 beds) during the 12-month period. The national incidence of RPs use per 1000 beds was as follows: all categories: 5152.0, environmental: 2988.2, physical: 1403.0, other: 527.0 and chemical: 233.8. The most frequently used RPs for each category was as follows: environmental: door locks, physical: other physical, other: liberty and autonomy and chemical: anxiolytics. Most RCFs (81.7%) reported at least one RPs use. The median incidence of any RPs per 1000 beds in these RCFs was 4.75 (IQR: 2.00 to 51.66). Usage of RPs was generally low, although some RCFs reported relatively high usage. Nationally, on average, five RPs were applied per resident over 12 months; environmental contributing to more than half. These findings can be used to inform policy, measure progress in reducing RPs use and for cross-jurisdiction comparisons.

Management and reporting of safety incidents by residential care facilities in Ireland: A thematic analysis of statutory notifications.

The prevention of safety incidents (SI) in health and social care settings is an ongoing undertaking. Limited research has been conducted on SIs outside of acute care. Internationally residential care facilities (RCFs) are typically regulated to promote quality and safeguarding. A part of this regulation is the statutory responsibility of RCFs to notify the regulator about SIs. Notifications include details surrounding SIs and are used to inform the regulatory monitoring approach. The recent development of the Database of Statutory Notifications from Social Care in Ireland facilitates in-depth analysis of notifications which can be used to inform the management of SIs and thus, improve quality and safety. The aim of this study was to analyse narratives provided in statutory notifications for older persons and people with disability, in order to identify current management of SIs, system vulnerabilities and reporting practices. A Qualitative Descriptive approach was taken. A random sample of notifications received in 2018 was drawn and stratified by service-type and notification-type. Data extraction was conducted against priori agreed target areas of management, system vulnerabilities and reporting practices. Inductive thematic analysis was used identifying two parent themes: 'chronology' and 'regulatory input'. 'Chronology' subthemes included 'pre-event', 'immediate response' and 'continued response'. Measures that are resident focused and follow policies and protocols in RCFs to prevent or mitigate the seriousness of SIs were evident in the immediate response and continued response. The actions taken in the immediate and continued response in turn became part of the pre-event of future SIs. Under 'regulatory input' subthemes included 'inaccurate reporting', 'lines of inquiry', 'requests for further information', 'identification of repetitive patterns' and 'satisfactory conclusion'. In conclusion, RCFs manage SIs with short and longer term actions focused on resident wellbeing. These actions in turn become part of the pre-event of future SIs. Regulatory input highlighted regulatory burden.

Public Reporting of Adverse Events From Long-Term Care Facilities for Older Persons and People With Disability in Ireland 2013-2019: Development of an Openly Accessible Database and Descriptive Analyses.

OBJECTIVES: To describe the development of an analyzable database of statutory notifications received from long-term care facilities (LTCFs) and to describe trends in receipt of notifications from 2013 to 2019. DESIGN: Description of database development with descriptive and trend analyses. SETTING AND PARTICIPANTS: LTCFs for older persons and for people with disability in Ireland. METHODS: Data on notifications received and on centers were extracted from a system internal to the health and social services regulator and combined into an analyzable database. Variables were screened for personal information, cleaned, transformed, or redacted and combined into a database suitable for open access publication. Descriptive analyses of the volume of notifications, trends over time and breakdown by service type, notification type, and risk-rating were conducted. RESULTS: The Database of Statutory Notifications from Social Care in Ireland was developed and an open access version published in February 2021. Protection of personal data was an important consideration in publishing the data publicly. Uses of the database include examination of national trends and identification of determinants of adverse events and areas for quality improvement. The number of notifications received increased over time. Quarterly notifications contributed to the largest proportion of notifications (older persons, 36.7%; disability, 39.1%). This was followed by serious injury notifications in LTCFs for older persons (33.3%) and abuse allegation notifications in LTCFs for people with disability (36.0%). Less than 1% of individual notifications were risk-rated red (highest severity level of impact on resident welfare). The types of notifications that were collectively risk-rated highest were staff misconduct, abuse allegations, and outbreaks of infectious disease. CONCLUSIONS AND IMPLICATIONS: The methodology and findings can inform publications of notifications, planning and resourcing for receipt and submission of notifications, target areas for quality improvement initiatives, mandating of timelines for receipt of notifications, and the mandating of notifications in legislation.

Determinants of regulatory compliance in health and social care services: a systematic review protocol.

Background: The delivery of high quality health and social care services is a fundamental goal for health systems worldwide. The measurement of quality in health and social care services is a complex task as there are a myriad of determinants and outcome measures to choose from. Researchers in this field have assessed a range of organisational and environmental factors (for example: staff composition, facility ownership, facility size) for an association with various measurements for quality. Compliance with regulations is one such quality measure. Compliance with regulations is variable and the determinants of this variability are under-investigated. Identifying the determinants of compliance has the potential to improve regulatory processes and can inform quality improvement initiatives undertaken by service providers and policy makers. This protocol describes a systematic review which will review literature from a wide range of study designs and sources to develop an overview of the determinants of regulatory compliance in health and social care services. Methods: A wide range of study designs and grey literature will be sought for this review. Searches will be conducted using PubMed, MEDLINE, PsycInfo, SocINDEX and CINAHL databases. The studies included in the review will be subject to quality appraisal with reference to the collection of tools available from the Joanna Briggs Institute. Data extraction will be informed by the Consolidated Framework for Implementation Research (CFIR). A narrative synthesis will be conducted with reference to the CFIR and Normalisation Process Theory (NPT). GRADE-CERQual will be used to grade the overall body of evidence. Conclusion: The findings of this review will be useful to regulators to inform regulatory policy and practice. Service providers and policy makers may also use the findings to inform quality improvement initiatives aimed at improving compliance and quality across a range of health and social care services.

Pulmonary monocytes interact with effector T cells in the lung tissue to drive TRM differentiation following viral infection.

Lung resident memory CD8 T cells (TRM) are critical for protection against respiratory viruses, but the cellular interactions required for their development are poorly understood. Herein we describe the necessity of classical monocytes for the establishment of lung TRM following influenza infection. We find that, during the initial appearance of lung TRM, monocytes and dendritic cells are the most numerous influenza antigen-bearing APCs in the lung. Surprisingly, depletion of DCs after initial T cell priming did not impact lung TRM development or maintenance. In contrast, a monocyte deficient pulmonary environment in CCR2-/- mice results in significantly less lung TRM following influenza infection, despite no defect in the antiviral effector response or in the peripheral memory pool. Imaging shows direct interaction of antigen-specific T cells with antigen-bearing monocytes in the lung, and pulmonary classical monocytes from the lungs of influenza infected mice are sufficient to drive differentiation of T cells in vitro. These data describe a novel role for pulmonary monocytes in mediating lung TRM development through direct interaction with T cells in the lung.

CXCR6 regulates localization of tissue-resident memory CD8 T cells to the airways.

Resident memory T cells (TRM cells) are an important first-line defense against respiratory pathogens, but the unique contributions of lung TRM cell populations to protective immunity and the factors that govern their localization to different compartments of the lung are not well understood. Here, we show that airway and interstitial TRM cells have distinct effector functions and that CXCR6 controls the partitioning of TRM cells within the lung by recruiting CD8 TRM cells to the airways. The absence of CXCR6 significantly decreases airway CD8 TRM cells due to altered trafficking of CXCR6-/- cells within the lung, and not decreased survival in the airways. CXCL16, the ligand for CXCR6, is localized primarily at the respiratory epithelium, and mice lacking CXCL16 also had decreased CD8 TRM cells in the airways. Finally, blocking CXCL16 inhibited the steady-state maintenance of airway TRM cells. Thus, the CXCR6/CXCL16 signaling axis controls the localization of TRM cells to different compartments of the lung and maintains airway TRM cells.

IL-36γ Protects against Severe Influenza Infection by Promoting Lung Alveolar Macrophage Survival and Limiting Viral Replication.

Although influenza virus infection remains a concerning disease for public health, the roles of individual cytokines during the immune response to influenza infection are not fully understood. We have identified IL-36γ as a key mediator of immune protection during both high- and low-pathogenesis influenza infection. Il36g mRNA is upregulated in the lung following influenza infection, and mice lacking IL-36γ have greatly increased morbidity and mortality upon infection with either H1N1 or H3N2 influenza. The increased severity of influenza infection in IL-36γ-knockout (KO) mice is associated with increased viral titers, higher levels of proinflammatory cytokines early in infection, and more diffuse pathologic conditions late in the disease course. Interestingly, the increased severity of disease in IL-36γ-KO mice correlates with a rapid loss of alveolar macrophages following infection. We find that the alveolar macrophages from naive IL-36γ-KO mice have higher expression of M2-like surface markers compared with wild-type (WT) mice and show increased apoptosis within 24 h of infection. Finally, transfer of WT alveolar macrophages to IL-36γ-KO mice restores protection against lethal influenza challenge to levels observed in WT mice. Together, these data identify a critical role for IL-36γ in immunity against influenza virus and demonstrate the importance of IL-36γ signaling for alveolar macrophage survival during infection.

Pulmonary antigen encounter regulates the establishment of tissue-resident CD8 memory T cells in the lung airways and parenchyma.

Resident memory CD8 T (TRM) cells in the lung parenchyma (LP) and airways provide heterologous protection against influenza virus challenge. However, scant knowledge exists regarding factors necessary to establish and maintain lung CD8 TRM. Here we demonstrate that, in contrast to mechanisms described for other tissues, airway, and LP CD8 TRM establishment requires cognate antigen recognition in the lung. Systemic effector CD8 T cells could be transiently pulled into the lung in response to localized inflammation, however these effector cells failed to establish tissue residency unless antigen was present in the pulmonary environment. The interaction of effector CD8 T cells with cognate antigen in the lung resulted in increased and prolonged expression of the tissue-retention markers CD69 and CD103, and increased expression of the adhesion molecule VLA-1. The inability of localized inflammation alone to establish lung TRM resulted in decreased viral clearance and increased mortality following heterosubtypic influenza challenge, despite equal numbers of circulating memory CD8 T cells. These findings demonstrate that pulmonary antigen encounter is required for the establishment of lung CD8 TRM and may inform future vaccine strategies to generate robust cellular immunity against respiratory pathogens.

Species-specific differences in the expression and regulation of α4ß7 integrin in various nonhuman primates.

Among nonhuman primates, SIV-infected Asian pigtailed macaques (PM) are relatively more susceptible to infection and disease progression than SIV-infected rhesus macaques (RM). In addition, SIV-infected African natural hosts such as the sooty mangabeys (SM) are resistant to disease. The mechanisms associated with such species-related variable clinical outcomes remain ill-defined but hold the potential to provide insights into the underlying mechanisms surrounding HIV pathogenesis. Recent findings indicate that the expression of the heterodimeric gut homing integrin α4ß7 can influence both susceptibility and disease progression in RM. It was reasoned that differences in the frequencies/surface densities of α4ß7-expressing lymphocytes might contribute to the differences in the clinical outcome of SIV infection among NHPs. In this article, we report that CD4(+) T cells from PM constitutively express significantly higher levels of α4ß7 than RM or SM. Retinoic acid, a key regulator of α4ß7 expression, was paradoxically found at higher levels in the plasma of SM versus RM or PM. We also observed pairing of ß7 with αE (αEß7) on CD4(+) T cells in the peripheral blood of SM, but not PM or RM. Finally, the differential mean density of expression of α4ß7 in RM versus SM versus PM was predominantly dictated by species-specific sequence differences at the level of the ß7 promoters, as determined by in vitro reporter/promoter construct transfection studies. We propose that differences in the regulation and expression of α4ß7 may explain, in part, the differences in susceptibility and SIV disease progression in these NHP models.

Blocking αVß3 integrin ligand occupancy inhibits the progression of albuminuria in diabetic rats.

This study determined if blocking ligand occupancy of the αVß3 integrin could inhibit the pathophysiologic changes that occur in the early stages of diabetic nephropathy (DN). Diabetic rats were treated with either vehicle or a monoclonal antibody that binds the ß3 subunit of the αVß3 integrin. After 4 weeks of diabetes the urinary albumin to creatinine ratio (UACR) increased in both diabetic animals that subsequently received vehicle and in the animals that subsequently received the anti-ß3 antibody compared with control nondiabetic rats. After 8 weeks of treatment the UACR continued to rise in the vehicle-treated rats; however it returned to levels comparable to control nondiabetic rats in rats treated with the anti-ß3 antibody. Treatment with the antibody prevented the increase of several profibrotic proteins that have been implicated in the development of DN. Diabetes was associated with an increase in phosphorylation of the ß3 subunit in kidney homogenates from diabetic animals, but this was prevented by the antibody treatment. This study demonstrates that, when administered after establishment of early pathophysiologic changes in renal function, the anti-ß3 antibody reversed the effects of diabetes normalizing albuminuria and profibrotic proteins in the kidney to the levels observed in nondiabetic control animals.

Targeting α4ß7 integrin reduces mucosal transmission of simian immunodeficiency virus and protects gut-associated lymphoid tissue from infection.

α4ß7 integrin-expressing CD4(+) T cells preferentially traffic to gut-associated lymphoid tissue (GALT) and have a key role in HIV and simian immunodeficiency virus (SIV) pathogenesis. We show here that the administration of an anti-α4ß7 monoclonal antibody just prior to and during acute infection protects rhesus macaques from transmission following repeated low-dose intravaginal challenges with SIVmac251. In treated animals that became infected, the GALT was significantly protected from infection and CD4(+) T cell numbers were maintained in both the blood and the GALT. Thus, targeting α4ß7 reduces mucosal transmission of SIV in macaques.

Blocking ligand occupancy of the αVß3 integrin inhibits the development of nephropathy in diabetic pigs.

Hyperglycemia stimulates secretion of αVß3 ligands from vascular cells, including endothelial cells, resulting in activation of the αVß3 integrin. This study determined whether blocking ligand occupancy of αVß3 would inhibit the development of diabetic nephropathy. Ten diabetic pigs received an F(ab)2 fragment of an antibody directed against the extracellular domain of the ß3-subunit, and 10 received a control IgG F(ab)2 for 18 weeks. Nondiabetic pigs excreted 115 ± 50 µg of protein/mg creatinine compared with control F(ab)2-treated diabetic animals (218 ± 57 µg/mg), whereas diabetic animals treated with the anti-ß3 F(ab)2 excreted 119 ± 55 µg/mg (P < .05). Mesangial volume/glomerular volume increased to 21 ± 2.4% in control-treated diabetic animals compared with 14 ± 2.8% (P < .01) in animals treated with active antibody. Diabetic animals treated with control F(ab)2 had significantly less glomerular podocin staining compared with nondiabetic animals, and this decrease was attenuated by treatment with anti-ß3 F(ab)2. Glomerular basement membrane thickness was increased in the control, F(ab)2-treated diabetic animals (212 ± 14 nm) compared with nondiabetic animals (170 ± 8.8 nm), but it was unchanged (159.9 ± 16.4 nm) in animals receiving anti-ß3 F(ab)2. Podocyte foot process width was greater in control, F(ab)2-treated, animals (502 ± 34 nm) compared with animals treated with the anti-ß3 F(ab)2 (357 ± 47 nm, P < .05). Renal ß3 tyrosine phosphorylation decreased from 13 934 ± 6437 to 6730 ± 1524 (P < .01) scanning units in the anti-ß3-treated group. We conclude that administration of an antibody that inhibits activation of the ß3-subunit of αVß3 that is induced by hyperglycemia attenuates proteinuria and early histologic changes of diabetic nephropathy, suggesting that it may have utility in preventing the progression of this disease complication.

In vivo administration of a JAK3 inhibitor during acute SIV infection leads to significant increases in viral load during chronic infection.

The studies reported herein are the first to document the effect of the in vivo administration of a JAK3 inhibitor for defining the potential role of NK cells during acute SIV infection of a group of 15 rhesus macaques (RM). An additional group of 16 MHC/KIR typed RM was included as controls. The previously optimized in vivo dose regimen (20 mg/kg daily for 35 days) led to a marked depletion of each of the major NK cell subsets both in the blood and gastro-intestinal tissues (GIT) during acute infection. While such depletion had no detectable effects on plasma viral loads during acute infection, there was a significant sustained increase in plasma viral loads during chronic infection. While the potential mechanisms that lead to such increased plasma viral loads during chronic infection remain unclear, several correlates were documented. Thus, during acute infection, the administration of the JAK3 inhibitor besides depleting all NK cell subsets also decreased some CD8⁺ T cells and inhibited the mobilization of the plasmacytoid dendritic cells in the blood and their localization to the GIT. Of interest is the finding that the administration of the JAK3 inhibitor during acute infection also resulted in the sustained maintenance during chronic infection of a high number of naïve and central memory CD4⁺ T cells, increases in B cells in the blood, but decreases in the frequencies and function of NKG2a⁺ NK cells within the GIT and blood, respectively. These data identify a unique role for JAK3 inhibitor sensitive cells, that includes NK cells during acute infection that in concert lead to high viral loads in SIV infected RM during chronic infection without affecting detectable changes in antiviral humoral/cellular responses. Identifying the precise mechanisms by which JAK3 sensitive cells exert their influence is critical with important implications for vaccine design against lentiviruses.