Predictive biomarkers and initial analysis of maternal immune alterations in postpartum preeclampsia reveal an immune-driven pathology.

Introduction: Postpartum preeclampsia (PPPE) is an under-diagnosed condition, developing within 48 hours to 6 weeks following an uncomplicated pregnancy. The etiology of PPPE is still unknown, leaving patients vulnerable and making the identification and treatment of patients requiring postpartum care an unmet need. We aimed to understand the immune contribution to PPPE at the time of diagnosis, as well as uncover the predictive potential of perinatal biomarkers for the early postnatal identification of high-risk patients. Methods: Placentas were collected at delivery from uncomplicated pregnancies (CTL) and PPPE patients for immunohistochemistry analysis. In this initial study, blood samples in PPPE patients were collected at the time of PPPE diagnosis (48h-25 days postpartum; mean 7.4 days) and compared to CTL blood samples taken 24h after delivery. Single-cell transcriptomics, flow cytometry, intracellular cytokine staining, and the circulating levels of inflammatory mediators were evaluated in the blood. Results: Placental CD163+ cells and 1st trimester blood pressures can be valuable non-invasive and predictive biomarkers of PPPE with strong clinical application prospects. Furthermore, changes in immune cell populations, as well as cytokine production by CD14+, CD4+, and CD8+ cells, suggested a dampened response with an exhausted phenotype including decreased IL1ß, IL12, and IFNγ as well as elevated IL10. Discussion: Understanding maternal immune changes at the time of diagnosis and prenatally within the placenta in our sizable cohort will serve as groundwork for pre-clinical and clinical research, as well as guiding clinical practice for example in the development of immune-targeted therapies, and early postnatal identification of patients who would benefit from more thorough follow-ups and risk education in the weeks following an uncomplicated pregnancy.

Social capital of families of children with neurodevelopmental disabilities in South India.

AIM: To investigate the social capital of families with children with neurodevelopmental disabilities in South India receiving a community-based early intervention (Enabling Inclusion®) program and to explore determinants and associations between social capital and program duration, socio-demographic factors, family empowerment, and caregiver burden. METHOD: Using purposive sampling in a cross-sectional study design, 217 families (n = 71 received short Enabling Inclusion [<5 months]; n = 146 received long Enabling Inclusion [>9 months]) were recruited and completed the Short Adapted Social Capital Tool (SASCAT: cognitive, structural), measures of family empowerment, and caregiver strain. Descriptive statistics, regression, and correlations were used for analyses. RESULTS: In 52.1% of participants, low cognitive and structural social capital was observed. Higher odds of low structural social capital were observed for mothers with primary versus secondary education (adjusted odds ratio [OR] = 0.35; 95% confidence interval [CI] 0.13-0.90; p = 0.029); and caregivers of children with cerebral palsy versus autism (OR = 4.66; 95% CI 1.02-21.21; p = 0.046). Significant associations were found between structural social capital, the child's age, and support group membership (χ2 = 6.29; 4.70; degrees of freedom [df] = 2; 1; p = 0.04; p = 0.02 respectively), as well as between cognitive social capital and other disability in the family (χ2 = 4.62, df = 1, p = 0.03). INTERPRETATION: While program duration was not found to mediate social capital, mother's education and child's diagnosis emerged as key influential factors, warranting their consideration in interventions supporting families of children with neurodevelopmental disabilities in low- and-middle-income countries and elsewhere.

Pregnant individuals with uncomplicated pregnancies display pro-inflammatory immune changes when exposed to the COVID-19 pandemic.

PROBLEM: The COVID-19 pandemic has been shown to have a detrimental impact on the mental health of pregnant individuals, and chronic stress can alter the immune profile. However, the effects of the COVID-19 pandemic on the immune system in pregnancy are still poorly understood. We aimed to evaluate the impact of pandemic exposure on the maternal immune profile in uncomplicated pregnancies. METHOD OF STUDY: We collected blood and placenta samples from pregnant individuals exposed and unexposed to the pandemic to compare their immune and inflammatory profiles. We performed co-culture with circulating maternal immune cells and endothelial cells to assess endothelial activation. Statistical analysis was performed using unpaired t-test, Mann-Whitney, or Fisher's exact test as appropriate. RESULTS: In exposed individuals, we observed a decreased proportion of Th2 cells (p < .0001) and Treg/Th17 ratio (p < .05), as well as an increased Th1/Th2 ratio (p < .0001). Levels of IL-1ß (p < .01) and IL-18 (p < .01) were increased in the circulation of exposed participants, whilst other mediators were significantly decreased (IFNγ, IL-8, MCP-1, amongst others). Furthermore, we observed increased production of ICAM, hallmark of endothelial activation, when we co-cultured endothelial cells with immune cells from exposed individuals. Vaccination status impacted the cellular profile with increased proportions of Th1 and B cells in vaccinated participants. CONCLUSION: Overall, we observed a pro-inflammatory bias in the circulation of pregnant individuals exposed to the COVID-19 pandemic, with otherwise uncomplicated pregnancies. Our work also supports an association between the increased risk of endothelial activation/hypertension and SARS-CoV2 infection, which might be driven in part by exposure to the pandemic and associated stressors.

Enabling local provision of assistive products in rural South India: an organisational survey of needs, barriers, and facilitators.

Objective: Access to assistive products (APs) is essential to maximising function, participation, and inclusion of persons with disabilities. Challenges to AP access in low- and middle-income countries include stigma, costs, supply, and rehabilitation capacity gaps. This study aimed to examine AT access in the context of a low-resource setting in rural South India. Objectives were to examine rehabilitation professionals' perceptions of AP needs, barriers and facilitators of AP provision, and AT knowledge.Methods: A descriptive study design with a 2-part online survey methodology was utilized. This study was conducted in April-September 2020 at a non-governmental organization (NGO) serving children and adults with disabilities in 3 districts of rural South India. Purposive sampling of NGO's multidisciplinary rehabilitation professionals (N=62) was used. The survey was developed based on WHO's Assistive Products List (APL). Barriers and facilitators were classified according to the principles of AT access. Analyses revealed acceptability, affordability, and availability as the top three barrier themes across disciplines, including poor acceptance by clients/families due to stigma, high AP costs, and a long waitlist for government-provided devices. Acceptability, affordability, and accessibility were the top three facilitator themes, including community awareness, availability of AP funding, client/family education, and AT service provision training.Impact: Our study identified key enabling strategies for AT access, aimed at reducing reported barriers. Enabling AP provision was determined to be multi-factorial, aimed at users/ families, service providers, organizations, communities, and policymakers. Local stakeholder groups are crucial to understanding challenges and opportunities to AP provision within a low-resource context.

Identified barriers to assistive product (AP) provision in rural South India include poor acceptance by clients/families due to stigma, high AP costs, limited AP availability, and rehabilitation capacity gaps.Suggested facilitators to AP provision in rural South India include improving AP acceptability, affordability, and accessibility through community awareness, client/family education, AP funding and supply, and assistive technology (AT) service provision capacity building.An organisational-level survey based on the WHO's Priority Assistive Products List and the Principles of AT Access can identify local needs, barriers and facilitators.An AT access strategies in resource-limited areas may be developed based on barriers and facilitators identified by local/regional rehabilitation professionals.

Placenta analysis of Hofbauer cell profile according to the class of antiretroviral therapy used during pregnancy in people living with HIV.

INTRODUCTION: The use of antiretroviral therapy drastically reduces vertical transmission of Human Immunodeficiency Virus. However, recent studies demonstrate associations between ART use during pregnancy and placental inflammation, particularly within protease inhibitor (PI)-based regimens. We sought to characterize placental macrophages, namely Hofbauer cells, according to the class of ART used during pregnancy. METHODS: Using immunofluorescence and immunohistochemistry, placentas from 79 pregnant people living with HIV (PPLWH) and 29 HIV-uninfected people were analyzed to quantify the numbers and frequencies of leukocytes (CD45+) and Hofbauer cells (CD68+ and/or CD163+). PPLWH were stratified into three groups based on class of ART: non-nucleoside reverse transcriptase inhibitor (NNRTI)-based, integrase strand-transfer inhibitor (INSTI)-based, and PI-based regimens. RESULTS: Placentas of PPLWH contained significantly more leukocytes and Hofbauer cells than controls. Multivariable analyses revealed that this increase in immune cells was associated with a predominantly CD163+ profile in all ART subgroups compared to the HIV-negative group. This was characterized by an increase in total CD163+ cells in the PI and INSTI subgroups, and a higher frequency of CD163+ cells and CD163+/CD68+ ratio in the NNRTI and PI subgroups. DISCUSSION: Placentas of PPLWH treated with any ART regimen during their entire pregnancy displayed a selection for CD163+ cells compared to the HIV-negative group, regardless of class of ART, suggesting that class of ART does not intrinsically affect selection of CD163+ and CD68+ Hofbauer cells. Further investigations into the role of Hofbauer cells in ART-associated placental inflammation are warranted to identify the mechanisms behind their potential involvement in maternal-fetal tolerance maintenance.

Proinflammatory changes in the maternal circulation, maternal-fetal interface, and placental transcriptome in preterm birth.

BACKGROUND: Preterm birth remains a leading obstetrical complication because of the incomplete understanding of its multifaceted etiology. It is known that immune alterations toward a proinflammatory profile are observed in women with preterm birth, but therapeutic interventions are still lacking because of scarcity of evidence in the integration of maternal and placental interrelated compartments. OBJECTIVE: This study aimed to obtain an integrated view of the maternal and placental contribution to preterm birth compared with normal term pregnancies for an in-depth understanding of the immune/inflammatory involvement, intending to identify novel strategies to mitigate the negative impact of inflammation. STUDY DESIGN: We prospectively recruited 79 women with preterm or term deliveries and collected placentas for RNA sequencing, histologic analyses, and to assess levels of inflammatory mediators. Blood samples were also collected to determine the circulating immune profiles by flow cytometry and to evaluate the circulating levels of inflammatory mediators. RESULTS: Placental transcriptomic analyses revealed 102 differentially expressed genes upregulated in preterm birth, including known and novel targets, which were highly enriched for inflammatory biological processes according to gene ontology analyses. Analysis of maternal immune cells revealed distinct profiles in preterm births vs term births, including an increased percentage of CD3- cells and monocyte subsets and decreased CD3+ cells along with Th17 subsets of CD4+ lymphocytes. Supporting our bioinformatic findings, we found increases in proinflammatory mediators in the plasma, placenta, and fetal membranes (primarily the amnion) of women with preterm birth, such as interleukin-6 and tumor necrosis factor-α. These findings were not distinct between spontaneous and iatrogenic preterm births except at a molecular level where spontaneous preterm birth presented with an elevated inflammatory profile compared with iatrogenic preterm birth. Analysis of placental histology revealed increased structural and inflammatory lesions in preterm vs term births. We found that genes upregulated in placentas with inflammatory lesions have enrichment of proinflammatory pathways. CONCLUSION: This work sheds light on changes within the immune system in preterm birth on multiple levels and compartments to help identify pregnancies at high risk of preterm birth and to discover novel therapeutic targets for preterm birth.

Leveraging monitoring, evaluation, and learning to scale the Enabling Inclusion® program for children with disabilities in India and globally.

Introduction: Children with disabilities in low- and middle-income countries face many challenges and lack adequate services, including access to rehabilitation professionals. To address this lack of access, Amar Seva Sangam Ayikudy (ASSA), a non-governmental organization (NGO) in India, designed a technology-leveraged rehabilitation program called Enabling Inclusion® (EI®), and implemented it in one state (Tamil Nadu, India) before scaling it. The model is supported by the EI® app, which enables organizations to screen, assess and monitor progress of children with disabilities via rehabilitation specialists and community rehabilitation workers, and to provide family-centered, goal-based interventions. An extensive monitoring, evaluation, and learning (MEL) framework is embedded into the program. This paper explores how this MEL system supported the scaling of the EI® model, reaching additional beneficiaries nationally and globally. Methods: This paper describes ASSA's MEL framework and demonstrates its use for decision-making in the process of scaling. It also explores how collaborations with various government departments, NGOs, and private partners contributed to the scaling of the EI® model and technology. Results: Scaling of the EI® program was achieved by (1) expansion of the program in rural Tamil Nadu (vertical scale-up) in partnership with the Tamil Nadu government and private partners, and (2) by licensing the EI® app and model to other NGOs in various states in India and globally (horizontal scale-up). Systematic examination of key program and performance indicators, as well as stakeholder feedback, informed decisions to modify the EI® app over time. This included further customizing to the needs of children and service providers, covering a greater range of age groups and contexts, and modifying service delivery models. Child functional independence, participation, and inclusion was further strengthened by mobilizing parent empowerment groups, community awareness programs, school advocacy, and entitlements from the government. Flexibility in the implementation model of the EI® app allowed for adaptation to local contexts and organizations, and facilitated its scale-up. Conclusion: A dynamic, inclusive, and locally grounded MEL system, a flexible and collaborative approach, and an adaptive implementation model increased the accessibility of an early intervention and childhood rehabilitation program for children with disabilities and their families throughout the state of Tamil Nadu, across India, and internationally.

Impact of a family-centred early intervention programme in South India on caregivers of children with developmental delays.

BACKGROUND: This study evaluated the impact on caregiver strain and family empowerment among caregivers of children with disabilities who received training and education as part of a family-centred community-based early intervention programme in South India. METHODS: This prospective open cohort longitudinal study compared change from baseline to two years post-intervention among caregivers of the first cohort of children who were enrolled in the programme. Paired t-tests determined effect on the Modified Caregiver Strain Index (MCSI) and Family Empowerment Scale (FES), and p-values were adjusted for multiple comparisons using the False Discovery Rate approach. RESULTS: Of the 308 caregivers (91% women), 44% provided care to children with cerebral palsy and 56% to children with other developmental delays. The mean age of the children at baseline was 3.3 (±1.5 years). The overall mean change from baseline in the FES was 4.1 (95% CI: 3.3, 4.9; p < 0.001) representing improved empowerment. The mean change for the MCSI score was -3.7 (95% CI: -4.5, -2.9; p < 0.001) representing reduced caregiver strain. CONCLUSIONS: A family-centred early intervention programme that provides training and education to caregivers of children with developmental delays demonstrated positive change in caregiver strain and family empowerment.Implications for RehabilitationThe well-being of a child is influenced by the well-being of their caregiver.Improving caregiver well-being can help improve care and support for children with developmental delays.A family-centred early intervention therapy programme that includes training and education to caregivers can reduce strain and improve family empowerment.

Pain coping skills training un-locks patient-centered pain care during the COVID- 19 lockdown.

BACKGROUND: In 2020, the COVID-19 virus sparked a crisis constituting a nationwide public health emergency that rapidly altered the provision of healthcare services for all Americans. Infectious disease mitigation led to widespread lockdowns of perceived nonessential services, programs, and non-emergent healthcare interventions. This lockdown exacerbated the public health dyad of uncontrolled pain and the opioid epidemic, which was already in a crisis state. Current literature supports the management of uncontrolled pain with a biopsychosocial approach, empowering patients to explore self-care to enhance activities of daily living. Pain Coping Skills Training (PCST) delivers real-life strategies that improve quality of life and strengthen self-efficacy. Self-efficacy has been identified as a patient outcome measure that demonstrates improved patient-perceived function and quality of life despite pain intensity. Studies have shown that nurse practitioners (APRN) are well-positioned to provide PCST to chronic pain sufferers. METHODS: A pretest-posttest design was utilized for this project to enhance pain self- efficacy through an APRN-led community-based intervention. INTERVENTION: Community-dwelling adults treated in a specialty pain management practice were self-selected to participate in a 6-week telehealth delivered PCST Program. This APRN delivered program presented basic pain education and a broad range of evidence-based nonpharmacologic pain management self-care tools. The primary outcome was improved Pain Self-efficacy measured with the pain self-efficacy questionnaire (PSEQ), with secondary outcomes of improved perceived pain intensity and function measured with the pain, enjoyment, and general activity (PEG) scale tracked weekly. RESULTS: Baseline PSEQ and weekly PEG scores were obtained and compared to scores after the program. Collateral data points included confidence in using complementary and alternative nonpharmacologic interventions, satisfaction with the program, and a qualitative patient statement regarding pre-and post-intervention participation. CONCLUSIONS: This project concluded that a Nurse Practitioner delivered PCST program via telehealth technology could provide community-dwelling adults with an intervention that improves pain self-efficacy, enhances self-reported PEG measures, and meets the social distancing requirements that continue to impact patients during the COVID-19 pandemic.

Perceptions of family-centred care among caregivers of children with cerebral palsy in South India: An exploratory study.

BACKGROUND: Parental views and expectations about family-centred care (FCC) need to be understood for its successful implementation. Knowledge of caregiver's perceptions and needs, within their social and cultural context, forms the basis for effective health care partnerships with families. The purpose of this study was to explore perceptions about FCC among caregivers of children with cerebral palsy (CP) in South India. METHOD: Fourteen caregivers of children with CP (aged 4-12 years) living in rural areas of the coastal region of Karnataka, India, participated in this qualitative study. Face-to-face semi-structured interviews were recorded and transcribed for analysis using the framework and hybrid approaches. Thematic mapping of the categories and themes was done to explore relationships about perceptions of FCC. RESULTS: Caregiver's life emerged inductively as a new theme highlighting caregiver's own physical and mental health, family roles and well-being, integrating the onus of care with household responsibilities, limited participation in personal activities and social isolation. The qualitative findings revealed the ubiquity of respectful and trusting relationships with health professionals while expressing paucity of coordinated comprehensive care, sporadic partnerships and opportunities for shared decision-making; desire for receiving specific information related to child's progress and prognosis; and general information on community resources and the need of empowerment and support groups. CONCLUSION: Our study has practical implications for the implementation of FCC within the South Indian context, by recognizing unique caregiver needs and expectations in sync with cultural perspectives towards childhood disability such as societal stigma, values and traditional beliefs; attitudes towards medical professionals; and life stressors and gender responsibilities.

Prenatal administration of IL-1Ra attenuate the neurodevelopmental impacts following non-pathogenic inflammation during pregnancy.

Prenatal inflammation negatively affects placental function, subsequently altering fetal development. Pathogen-associated molecular patterns (PAMPs) are used to mimics infections in preclinical models but rarely detected during pregnancy. Our group previously developed an animal model of prenatal exposure to uric acid (endogenous mediator), leading to growth restriction alongside IL-1-driven placental inflammation (Brien et al. in J Immunol 198(1):443-451, 2017). Unlike PAMPs, the postnatal impact of prenatal non-pathogenic inflammation is still poorly understood. Therefore, we investigated the effects of prenatal uric acid exposure on postnatal neurodevelopment and the therapeutic potential of the IL-1 receptor antagonist; IL-1Ra. Uric acid induced growth restriction and placental inflammation, which IL-1Ra protected against. Postnatal evaluation of both structural and functional aspects of the brain revealed developmental changes. Both astrogliosis and microgliosis were observed in the hippocampus and white matter at postnatal day (PND)7 with IL-1Ra being protective. Decreased myelin density was observed at PND21, and reduced amount of neuronal precursor cells was observed in the Dentate Gyrus at PND35. Functionally, motor impairments were observed as evaluated with the increased time to fully turn upward (180 degrees) on the inclined plane and the pups were weaker on the grip strength test. Prenatal exposure to sterile inflammation, mimicking most clinical situation, induced growth restriction with negative impact on neurodevelopment. Targeted anti-inflammatory intervention prenatally could offer a strategy to protect brain development during pregnancy.

Pandemic stress and SARS-CoV-2 infection are associated with pathological changes at the maternal-fetal interface.

INTRODUCTION: The reported effects of SARS-CoV-2 on pregnancy outcomes are conflicting; studies frequently overlook the placenta, which is critical for the health of the mother and infant(s). This study aimed to determine the effect of pandemic stress ± SARS CoV-2 infection on placental histopathology. METHODS: Women were recruited in Canada (n = 69); France (n = 21) or in the UK (n = 25), between March and October 2020. Historic controls (N = 20) were also included. Placenta and fetal membrane samples were collected rapidly after delivery and were fixed and stained for histopathological analysis. Maternal demographical data and obstetric outcomes were recorded. RESULTS: Over 80% of the placentas from SARS-CoV-2+ pregnancies had histopathological abnormalities: predominantly structural (71-86%) or inflammatory (9-22%), depending on geographical location. Excessive fibrin was seen in all sites, whereas deciduitis (Canada), calcifications (UK), agglutinations and chorangiosis (France) predominated in different locations. The frequency of abnormalities was significantly higher than in SARS-CoV-2 negative women (50%, p < 0.05). Demographic and obstetric data were similar in the SARS-CoV-2+ women across all sites - characterised by predominantly Black/Middle Eastern women, and women with elevated body mass index. DISCUSSION: Overall, the frequency of placental abnormalities is increased in SARS-CoV-2+ women, but the incidence of placental abnormalities is also higher in SARS-CoV-2- women that gave birth during the pandemic, which highlights the importance of appropriate control groups to ascertain the roles of pandemic stress and SARS-CoV-2 infection on the placenta and pregnancy outcomes.

Neutrally charged self-assembling peptide hydrogel recapitulates in vitro mechanisms of breast cancer progression.

Self-assembling peptide hydrogels (SAPH) are a popular biomaterial due to their biocompatibility with a wide range of cell types, synthetic design, structural properties that provide a more accurate 3D microenvironment, and potential for cell- and/or drug-delivery system. Mimicking solid tumors in vitro using hydrogels is one method of testing anti-cancer drug efficacy and observing cancerous cell-ECM interactions within a 3D system. In this study, a SAPH, PeptiGel®Alpha1, was used to model in vitro the 3D breast tumor microenvironment. PeptiGel®Alpha1 is composed of entangled nanofibers with consistent diameter and mechanical properties similar to breast cancer that more accurately mimic the stiffness of breast tumor tissue than Matrigel® or collagen type I. PeptiGel®Alpha1 supported the viability and growth of the breast cancer cell lines MCF-7 and MDA-MB-231 and recapitulated key features of solid tumors such as hypoxia and invasion. MCF-7 cells in the hydrogels formed large spheroids resembling acini, while MDA-MB-231 remained dispersed. When treated with tamoxifen, PeptiGel®Alpha1 acted as a barrier, providing drug penetration geometry similar to that in vivo, providing better prediction of the drug effect. Finally, it was observed that MCF-7 cells engulfed the peptide matrix after 14 days, highlighting a potential use in drug delivery. PeptiGel®Alpha1 is a suitable platform for in vitro modeling of breast cancer.

Expanding access to nurse-managed medication for opioid use disorder.

BACKGROUND: Advanced practice registered nurses (APRNs) are increasingly caring for individuals with opioid use disorder. Advances have been made to increase APRN education, outreach, and prescribing privileges, but as demand for medication for opioid use disorder (MOUD) grows, evidence suggests that policy and care barriers inhibit the ability of APRNs to support MOUD. PURPOSE: This paper highlights the significant challenges of expanding access to buprenorphine prescribing by APRNs. FINDINGS: Barriers and recommendations were derived from the culmination of literature review, expert consensus discussions among a diverse stakeholder panel including patient representatives, and feedback from community webinars with care providers. DISCUSSION: We provide an overview of existing care barriers, promising practices, and proposed recommendations to enhance the care of individuals and communities with opioid use disorder.

TGF-ß3-loaded graphene oxide - self-assembling peptide hybrid hydrogels as functional 3D scaffolds for the regeneration of the nucleus pulposus.

Intervertebral disc (IVD) degeneration is a process that starts in the central nucleus pulposus (NP) and leads to inflammation, extracellular matrix (ECM) degradation, and progressive loss of disc height. Early treatment of IVD degeneration is critical to the reduction of low back pain and related disability. As such, minimally invasive therapeutic approaches that can halt and reverse NP degeneration at the early stages of the disease are needed. Recently, we developed an injectable graphene oxide (GO) - self-assembling peptide FEFKFEFK (F: phenylalanine; K: lysine; E: glutamic acid) hybrid hydrogels as potential delivery platform for cells and/or drugs in the NP. In this current study, we explored the possibility of using the GO present in these hybrid hydrogels as a vehicle for the sequestration and controlled delivery of transforming growth factor beta-3 (TGF-ß3), an anabolic growth factor (GF) known to direct NP cell fate and function. For this purpose, we first investigated the potential of GO to bind and sequestrate TGF-ß3. We then cultured bovine NP cells in the new functional scaffolds and investigated their response to the presence of GO and TGF-ß3. Our results clearly showed that GO flakes can sequestrate TGF-ß3 through strong binding interactions resulting in a slow and prolonged release, with the GF remaining active even when bound to the GO flakes. The adsorption of the GF on the GO flakes to create TGF-ß3-loaded GO flakes and their subsequent incorporation in the hydrogels through mixing, [(GO/TGF-ß3Ads)-F8] hydrogel, led to the upregulation of NP-specific genes, accompanied by the production and deposition of an NP-like ECM, rich in aggrecan and collagen II. NP cells actively interacted with TGF-ß3-loaded GO flakes and remodeled the scaffolds through endocytosis. This work highlights the potential of using GO as a nanocarrier for the design of functional hybrid peptide-based hydrogels. STATEMENT OF SIGNIFICANCE: Intervertebral disc (IVD) degeneration is a process that starts in the central nucleus pulposus (NP) and leads to inflammation, extracellular matrix (ECM) degradation, and progressive loss of disc height. As such, minimally invasive therapeutic approaches that can halt and reverse NP degeneration at the early stages of the disease are needed. In this current study, we explored the possibility of using peptide - GO hybrid hydrogels as a vehicle for the sequestration and controlled delivery of transforming growth factor beta-3 (TGF-ß3), an anabolic growth factor (GF) known to direct NP cell fate and function.

A Systematic Review of the Safety of Blocking the IL-1 System in Human Pregnancy.

Blockade of the interleukin-1 (IL-1) pathway has been used therapeutically in several inflammatory diseases including arthritis and cryopyrin-associated periodic syndrome (CAPS). These conditions frequently affect women of childbearing age and continued usage of IL-1 specific treatments throughout pregnancy has been reported. IL-1 is involved in pregnancy complications and its blockade could have therapeutic potential. We systematically reviewed all reported cases of IL-1 blockade in human pregnancy to assess safety and perinatal outcomes. We searched several databases to find reports of specific blockade of the IL-1 pathway at any stage of pregnancy, excluding broad spectrum or non-specific anti-inflammatory intervention. Our literature search generated 2439 references of which 22 studies included, following extensive review. From these, 88 different pregnancies were assessed. Most (64.8%) resulted in healthy term deliveries without any obstetrical/neonatal complications. Including pregnancy exposed to Anakinra or Canakinumab, 12 (15.0%) resulted in preterm birth and one stillbirth occurred. Regarding neonatal complications, 2 cases of renal agenesis (2.5%) were observed, and 6 infants were diagnosed with CAPS (7.5%). In conclusion, this systematic review describes that IL-1 blockade during pregnancy is not associated with increased adverse perinatal outcomes, considering that treated women all presented an inflammatory disease associated with elevated risk of pregnancy complications.

Engineering a cell-hydrogel-fibre composite to mimic the structure and function of the tendon synovial sheath.

The repair of tendon injuries is often compromised by post-operative peritendinous adhesions. Placing a physical barrier at the interface between the tendon and the surrounding tissue could potentially solve this problem by reducing adhesion formation. At present, no such system is available for routine use in clinical practice. Here, we propose the development of a bilayer membrane combining a nanofibrous poly(ε-caprolactone) (PCL) electrospun mesh with a layer of self-assembling peptide hydrogel (SAPH) laden with type-B synoviocytes. This bilayer membrane would act as an anti-adhesion system capable of restoring tendon lubrication, while assisting with synovial sheath regeneration. The PCL mesh showed adequate mechanical properties (Young's modulus=19±4 MPa, ultimate tensile stress=9.6±1.7 MPa, failure load=0.5±0.1 N), indicating that the membrane is easy to handle and capable to withstand the frictional forces generated on the tendon's surface during movement (~0.3 N). Morphological analysis confirmed the generation of a mesh with nanosized PCL fibres and small pores (< 3 µm), which prevented fibroblast infiltration to impede extrinsic healing but still allowing diffusion of nutrients and waste. Rheological tests showed that incorporation of SAPH layer allows good lubrication properties when the membrane is articulated against porcine tendon or hypodermis, suggesting that restoration of tendon gliding is possible upon implantation. Moreover, viability and metabolic activity tests indicated that the SAPH was conducive to rabbit synoviocyte growth and proliferation over 28 days of 3D culture, sustaining cell production of specific matrix components, particularly hyaluronic acid. Synoviocyte-laden peptide hydrogel promoted a sustained endogenous production of hyaluronic acid, providing an anti-friction layer that potentially restores the tendon gliding environment.

Rapid-Cycle Evaluation in an Early Intervention Program for Children With Developmental Disabilities in South India: Optimizing Service Providers' Quality of Work-Life, Family Program Engagement, and School Enrollment.

Background: This paper explores how implementation and refinement of an early intervention (EI) program for children with delayed development was informed by an iterative, intentional and structured process of measurement. Providing access to early intervention therapy for children in rural areas of India is challenging due to a lack of rehabilitation therapists and programs. Following a biopsychosocial framework and principles of community-based rehabilitation, a non-governmental organization, Amar Seva Sangam (ASSA), overcame those barriers by designing a digital technology supported EI program in rural Tamil Nadu, India. Program objectives included providing service access; supporting program engagement, child development and school enrollment; and positioning the intervention for scale-up. This paper contributes to a growing body of literature on how program design and implementation can be informed through a cyclical process of data collection, analysis, reflection, and adaptation. Methods: Through several strands of data collection, the design and implementation of the EI program was adapted and improved. This included qualitative data from focus groups and interviews with caregivers and service providers, and a mobile application that collected and monitored longitudinal quantitative data, including program engagement rates, developmental progression, caregiver outcomes, and school enrollment status. Results: Measurements throughout the program informed decision-making by identifying facilitators and barriers to service providers' quality of work-life, family program engagement, and school enrollment. Consultation with key stakeholders, including caregivers and service providers, and data driven decision making led to continual program changes that improved service provider quality of work-life, program engagement and school enrollment. These changes included addressing gender-related work challenges for service providers; forming caregiver support networks; introducing psychological counseling for caregivers; providing medical consultations and assistive devices; creating community awareness programs; improving access to therapy services; focusing on caregiver education, motivation and support; and advocacy for accessibility in schools. Conclusion: The process of using evidence-informed and stakeholder driven adaptations to the early intervention program, led to improved service provider quality of work-life, greater program engagement, improved school enrollment and positioned the intervention for scale-up, providing lessons that may be beneficial in other contexts.

Specific inflammatory profile in each pregnancy complication: A comparative study.

PROBLEM: Pre-eclampsia (PE), preterm birth (PTB) and intra-uterine growth restriction (IUGR) affect 5%-12% of pregnancies. They have been associated with placental inflammation, although the detection of inflammatory mediators in the maternal circulation is still controversial. Our goal was to determine the inflammatory changes occurring in the second part of pregnancy to identify profiles distinguishing pathological pregnancies from each other. METHOD OF STUDY: We performed a nested case-control study of 200 women randomly selected from a cohort recruited at the CHU de Quebec-Universite Laval, Quebec, Canada. Women with uncomplicated term pregnancy (CTRL); PE (severe or not); PTB or IUGR (N = 50/each) were included. Plasma samples, obtained from the late second trimester and at delivery, were analysed for over 30 selected mediators (including cytokines/alarmins), by multiplex, ELISA or specific assays. Demographic and obstetrical information were obtained for classification. RESULTS: In CTRL, we observed significant differences between 2nd trimester and delivery, with increased levels of inflammatory mediators (ex. MCP-1, IL-6), supporting an inflammatory profile towards term. Increased levels of IL-6, CXCL10 and CRP were observed in PE as compared to CTRL. In PTB, we observed increased CXCL9 in 2nd trimester and decreased progesterone at delivery. In IUGR, increased HMGB1 and IL-1α were observed only in the 2nd trimester. CONCLUSIONS: Our work showed significant inflammatory changes in uncomplicated pregnancies towards delivery, supporting that normal delivery is pro-inflammatory, although not to the same extent as in pathological pregnancies. Inflammatory profiles are specific to each pregnancy complication which may help to understand the contribution of inflammation to the clinical presentation of these conditions.