A polymeric protein-loaded microsphere delivery system for use in bone tissue engineering

The bone graft procedure is the gold standard therapy for large bone defects and usually involves implanting autologous bone into the defect site. The need to find more patient-friendly alternatives to the bone graft procedure is a driving force behind recent advances in bone tissue engineering. Different synthetic and natural biomaterials are being investigated for their use in the repair of large bone defects. However, there is still a need for scaffold materials that are able to sinter in situ with the capability of delivering growth factors that promote the bone repair process with minimal invasion. In this study, our main aim was to develop a porous, protein-loaded microsphere delivery system with the capability of sintering in situ and with injectable potential. Poly (lactic-co-glycolic acid) (PLGA) was used for this formulation due to its biodegradability, biocompatibility, controllable mechanical properties and good processing capabilities. An optimised procedure for formulating porous and non-porous (protein-loaded) microspheres was established and the microspheres were extensively characterised. There was an inverse relationship between the molecular weight of the PLGA and both the protein release and compressive strength. An intermediate molecular weight (53 kDa) variety of PLGA was chosen for further work based on balancing the need for retaining sufficient compressive strength and a slower protein release profile. The burst release of protein was addressed by investigating various coatings. The combination of chitosan and PLGA to form composite PLGA/chitosan microspheres resulted in the desired reduction in the burst release. The protein-loaded and porous microspheres were combined as a paste and found to sinter at body temperature (37°C) into scaffolds. Whilst previous investigations have focused primarily on a single type of PLGA microsphere (with or without an additional biomaterial), in this study we combined both porous and protein-loaded microspheres into a single delivery system. Furthermore, successful sintering was confirmed when a suspension of the microspheres was injected through a 19 G needle. The biocompatibility and osteogenic potential of the scaffolds were investigated. The composite PLGA/chitosan scaffolds supported the growth of MG-63 osteosarcoma cells and a primary human stem cell line. Furthermore, the scaffolds also supported the osteogenesis of the stem cells, as demonstrated by the presence of the late protein marker of osteogenesis, osteocalcin, and positive von Kossa staining, which is indicative of mineralization. The composite PLGA/chitosan and porous microspheres combine both porosity and the ability to load and sustain the release of protein into one system. Moreover, their ability to sinter at body temperature when injected or applied as a paste demonstrates the dual functionality of the system. This represents a novel approach to delivering protein for tissue regeneration as presently, there has been no report of the combination of PLGA/chitosan microspheres with porous PLGA microspheres as a system that is able to sinter, both post-injection and when packed as a paste, at 37°C. Therefore, the formulation presented in this thesis shows potential for further in vitro and in vivo testing to determine its suitability for bone tissue engineering applications

Linking migration and hospital data in England: linkage process and evaluation of bias

Introduction: Difficulties ascertaining migrant status in national data sources such as hospital records have limited large-scale evaluation of migrant healthcare needs in many countries, including England. Linkage of immigration data for migrants and refugees, with National Health Service (NHS) hospital care data enables research into the relationship between migration and health for a large cohort of international migrants. / Objectives: We aimed to describe the linkage process and compare linkage rates between migrant sub-groups to evaluate for potential bias for data on non-EU migrants and resettled refugees linked to Hospital Episode Statistics (HES) in England. / Methods: We used stepwise deterministic linkage to match records from migrants and refugees to a unique healthcare identifier indicating interaction with the NHS (linkage stage 1 to NHS Personal Demographic Services, PDS), and then to hospital records (linkage stage 2 to HES). We calculated linkage rates and compared linked and unlinked migrant characteristics for each linkage stage. / Results: Of the 1,799,307 unique migrant records, 1,134,007 (63%) linked to PDS and 451,689 (25%) linked to at least one hospital record between 01/01/2005 and 23/03/2020. Individuals on work, student, or working holiday visas were less likely to link to a hospital record than those on settlement and dependent visas and refugees. Migrants from the Middle East and North Africa and South Asia were four times more likely to link to at least one hospital record, compared to those from East Asia and the Pacific. Differences in age, sex, visa type, and region of origin between linked and unlinked samples were small to moderate. / Conclusion: This linked dataset represents a unique opportunity to explore healthcare use in migrants. However, lower linkage rates disproportionately affected individuals on shorter-term visas so future studies of these groups may be more biased as a result. Increasing the quality and completeness of identifiers recorded in administrative data could improve data linkage quality

A dual-application poly (DL-lactic-co-glycolic) acid (PLGA)-chitosan composite scaffold for potential use in bone tissue engineering

The development of patient-friendly alternatives to bone-graft procedures is the driving force for new frontiers in bone tissue engineering. Poly (DL-lactic-co-glycolic acid), (PLGA) and chitosan are well-studied and easy-to-process polymers from which scaffolds can be fabricated. In this study, a novel dual-application scaffold system was formulated from porous PLGA and protein-loaded PLGA/chitosan microspheres. Physicochemical and in vitro protein release attributes were established. The therapeutic relevance, cytocompatibility with primary human mesenchymal stem cells (hMSCs) and osteogenic properties were tested. There was a significant reduction in burst release from the composite PLGA/chitosan microspheres compared with PLGA alone. Scaffolds sintered from porous microspheres at 37°C were significantly stronger than the PLGA control, with compressive strengths of 0.846 ± 0.272 MPa and 0.406 ± 0.265 MPa, respectively (p < 0.05). The formulation also sintered at 37°C following injection through a needle, demonstrating its injectable potential. The scaffolds demonstrated cytocompatibility, with increased cell numbers observed over an 8-day study period. Von Kossa and immunostaining of the hMSC-scaffolds confirmed their osteogenic potential with the ability to sinter at 37°C in situ

Gaza, armed conflict and child health

Pneumococcal Conjugate Vaccines (PCVs) have substantially reduced the burden of disease caused by Streptococcus pneumoniae (the pneumococcus). However, protection is limited to vaccine serotypes, and when administered to children who are colonized with pneumococci at the time of vaccination, immune responses to the vaccine are blunted. Here, we investigate the potential of a killed whole cell pneumococcal vaccine (WCV) to reduce existing pneumococcal carriage and mucosal disease when given therapeutically to infant mice colonized with pneumococci. We show that a single dose of WCV reduced pneumococcal carriage density in an antibody-dependent manner. Therapeutic vaccination induced robust immune responses to pneumococcal surface antigens CbpA, PspA (family 1) and PiaA. In a co-infection model of otitis media, a single dose of WCV reduced pneumococcal middle ear infection. Lastly, in a two-dose model, therapeutic administration of WCV reduced nasal shedding of pneumococci. Taken together, our data demonstrate that WCV administered in colonized mice reduced pneumococcal density in the nasopharynx and the middle ear, and decreased shedding. WCVs would be beneficial in low and middle-income settings where pneumococcal carriage in children is high

Deprivation, essential and non-essential activities and SARS-CoV-2 infection following the lifting of national public health restrictions in England and Wales [version 1; peer review: awaiting peer review]

BACKGROUND: Individuals living in deprived areas in England and Wales undertook essential activities more frequently and experienced higher rates of SARS-CoV-2 infection than less deprived communities during periods of restrictions aimed at controlling the Alpha (B.1.1.7) variant. We aimed to understand whether these deprivation-related differences changed once restrictions were lifted. METHODS: Among 11,231 adult Virus Watch Community Cohort Study participants multivariable logistic regressions were used to estimate the relationships between deprivation and self-reported activities and deprivation and infection (self-reported lateral flow or PCR tests and linkage to National Testing data and Second Generation Surveillance System (SGSS)) between August – December 2021, following the lifting of national public health restrictions. RESULTS: Among 11,231 adult Virus Watch Community Cohort Study participants multivariable logistic regressions were used to estimate the relationships between deprivation and self-reported activities and deprivation and infection (self-reported lateral flow or PCR tests and linkage to National Testing data and Second Generation Surveillance System (SGSS)) between August – December 2021, following the lifting of national public health restrictions. CONCLUSIONS: The lack of association between deprivation and infection is likely due to the increased engagement in non-essential activities among the least deprived balancing the increased work-related exposure among the most deprived. The differences in activities highlight stark disparities in an individuals’ ability to choose how to limit infection exposure

Sexual and reproductive health and rights of migrant women attending primary care in England: A population-based cohort study of 1.2 million individuals of reproductive age (2009–2018)

Background: Evidence on the sexual and reproductive health and rights (SRHR) of migrants is lacking globally. We describe SRHR healthcare resource use and long-acting reversible contraceptives (LARCs) prescriptions for migrant versus non-migrant women attending primary care in England (2009–2018). // Methods: This population-based observational cohort study, using Clinical Practice Research Datalink (CPRD) GOLD, included females living in England aged 15 to 49. Migration was defined using a validated codelist. Rates per 100 person years at risk (pyar) and adjusted rate ratios (RRs) were measured in migrants versus non-migrants for consultations related to all-causes, six exemplar SRHR outcomes, and LARC prescriptions. Proportions of migrants and non-migrants ever prescribed LARC were calculated. // Findings: There were 25,112,116 consultations across 1,246,353 eligible individuals. 98,214 (7.9 %) individuals were migrants. All-cause consultation rates were lower in migrants versus non-migrants (509 vs 583/100pyar;RR 0.9;95 %CI 0.9–0.9), as were consultations rates for emergency contraception (RR 0.7;95 %CI 0.7–0.7) and cervical screening (RR 0.96;95 %CI 0.95–0.97). Higher rates of consultations were found in migrants for abortion (RR 1.2;95 %CI 1.1–1.2) and management of fertility problems (RR 1.39;95 %CI 1.08–1.79). No significant difference was observed for chlamydia testing and domestic violence. Of 1,205,258 individuals eligible for contraception, the proportion of non-migrants ever prescribed LARC (12.2 %;135,047/1,107,894) was almost double that of migrants (6.91 %;6,728/97,364). Higher copper intrauterine devices prescription rates were found in migrants (RR 1.53;95 %CI 1.45–1.61), whilst hormonal LARC rates were lower for migrants: levonorgestrel intrauterine device (RR 0.63;95 %CI 0.60–0.66), subdermal implant (RR 0.72;95 %CI 0.69–0.75), and progesterone-only injection (RR 0.35;95 %CI 0.34–0.36). // Interpretation: Healthcare resource use differs between migrant and non-migrant women of reproductive age. Opportunities identified for tailored interventions include access to primary care, LARCs, emergency contraception and cervical screening. An inclusive approach to examining health needs is essential to actualise sexual and reproductive health as a human right

COVID-19 vaccination coverage for half a million non-EU migrants and refugees in England

Despite evidence suggesting that some migrants are at risk of under-immunization and have experienced severe health inequities during the pandemic, data are limited on migrants’ COVID-19 vaccine coverage globally. Here we linked data from non-European Union migrants and resettled refugees to the national COVID-19 vaccination dataset in England. We estimated patterns in second and third dose delays and overdue doses between 12 December 2020 and 20 April 2022 by age, visa type and ethnicity. Of the 465,470 linked records, 91.8% (427,073/465,470) of migrants received a second dose and 51.3% (238,721/465,470) received a third. Refugees had the highest risk of delayed second (adjusted odds ratio 1.66; 95% confidence interval 1.55–1.79) and third dose (1.55; 1.43–1.69). Black migrants were twice as likely to have a second dose delayed (2.37; 2.23–2.54) than white migrants, but this trend reversed for the third dose. Older migrants (>65 years) were four times less likely to have received their second or third dose compared with the general population in England aged >65 or older. Policymakers, researchers and practitioners should work to understand and address personal and structural barriers to vaccination for diverse migrant populations

Development and Validation of a Primary Care Electronic Health Record Phenotype to Study Migration and Health in the UK.

International migrants comprised 14% of the UK's population in 2020; however, their health is rarely studied at a population level using primary care electronic health records due to difficulties in their identification. We developed a migration phenotype using country of birth, visa status, non-English main/first language and non-UK-origin codes and applied it to the Clinical Practice Research Datalink (CPRD) GOLD database of 16,071,111 primary care patients between 1997 and 2018. We compared the completeness and representativeness of the identified migrant population to Office for National Statistics (ONS) country-of-birth and 2011 census data by year, age, sex, geographic region of birth and ethnicity. Between 1997 to 2018, 403,768 migrants (2.51% of the CPRD GOLD population) were identified: 178,749 (1.11%) had foreign-country-of-birth or visa -status codes, 216,731 (1.35%) non-English-main/first-language codes, and 8288 (0.05%) non-UK-origin codes. The cohort was similarly distributed versus ONS data by sex and region of birth. Migration recording improved over time and younger migrants were better represented than those aged ≥50. The validated phenotype identified a large migrant cohort for use in migration health research in CPRD GOLD to inform healthcare policy and practice. The under-recording of migration status in earlier years and older ages necessitates cautious interpretation of future studies in these groups

SARS-CoV-2 infections in migrants and the role of household overcrowding: a causal mediation analysis of Virus Watch data

BACKGROUND: Migrants are over-represented in SARS-CoV-2 infections globally; however, evidence is limited for migrants in England and Wales. Household overcrowding is a risk factor for SARS-CoV-2 infection, with migrants more likely to live in overcrowded households than UK-born individuals. We aimed to estimate the total effect of migration status on SARS-CoV-2 infection and to what extent household overcrowding mediated this effect. METHODS: We included a subcohort of individuals from the Virus Watch prospective cohort study during the second SARS-CoV-2 wave (1 September 2020-30 April 2021) who were aged ≥18 years, self-reported the number of rooms in their household and had no evidence of SARS-CoV-2 infection pre-September 2020. We estimated total, indirect and direct effects using Buis' logistic decomposition regression controlling for age, sex, ethnicity, clinical vulnerability, occupation, income and whether they lived with children. RESULTS: In total, 23 478 individuals were included. 9.07% (187/2062) of migrants had evidence of infection during the study period vs 6.27% (1342/21 416) of UK-born individuals. Migrants had 22% higher odds of infection during the second wave (total effect; OR 1.22, 95% CI 1.01 to 1.47). Household overcrowding accounted for approximately 36% (95% CI -4% to 77%) of these increased odds (indirect effect, OR 1.07, 95% CI 1.03 to 1.12; proportion accounted for: indirect effect on log odds scale/total effect on log odds scale=0.36). CONCLUSION: Migrants had higher odds of SARS-CoV-2 infection during the second wave compared with UK-born individuals and household overcrowding explained 36% of these increased odds. Policy interventions to reduce household overcrowding for migrants are needed as part of efforts to tackle health inequalities during the pandemic and beyond