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.

Ethnic inequities in routine childhood vaccinations in England 2006-2021: an observational cohort study using electronic health records.

Background: Population groups that are underserved by England's childhood vaccination programme must be identified to address the country's declining vaccination coverage. We examined routine childhood vaccination coverage in England by maternal ethnicity between 2006 and 2021. Methods: We created first, second and fifth birthday cohorts using mother-child linked electronic health records from the Clinical Practice Research Datalink (CPRD) Aurum. After validation against the UK Health Security Agency (UKHSA) and National Health Service England (NHSE) annual statistical reports, we described vaccination coverage for each vaccine by ethnicity and year. We used modified Poisson regression to analyse the effect of ethnicity on receiving the primary and full course of each vaccine. Findings: Up to 1,170,804 children born after 1 April 2006 were included in the first birthday cohort, reducing to 645,492 by the fifth birthday. Children were followed up until 31 March 2021 at the latest. Children born to mothers in 9 minority ethnic groups and those of unknown ethnicity had lower vaccination coverage (61.3-97.5%) than the White British group (79.9-97.8%) for all vaccines. Indian, Pakistani, Bangladeshi, Chinese, Any other Asian background, and White and Asian ethnic groups had similar vaccination coverage to the White British group (above 90% for most vaccines in most years). Inequities particularly affected the Caribbean group (e.g. 61% coverage for the 6/5/4-in-1 full course in 2020-21 by children's fifth birthday; RR 0.66, 95% CI 0.6-0.74 compared with the White British group) and Any other Black, African and Caribbean background (e.g. coverage 68% for the MMR primary course in 2020-21; RR 0.71, 95% CI 0.64-0.78). These inequities widened over the study period. For example, the absolute difference in coverage between the Caribbean and White British groups for the full course of MMR increased from 12% in 2011-12 to 22% in 2019-20. These inequities remained even after accounting for sociodemographic, maternal and birth related factors, and also widened from primary course to full course. Interpretation: Our findings suggest that urgent policy action is needed to address the ethnic inequities throughout England's routine childhood vaccination programme, which have been worsening over time. Funding: University of Oxford Clarendon Fund, St Cross College and Nuffield Department of Population Health.

Small numbers, big impact: making a utilitarian case for the contribution of inclusion health to population health in England.

Inclusion health groups make up a small proportion of the general population, so despite the extreme social exclusion and poor health outcomes that these groups experience, they are often overlooked in public health investment and policy development. In this paper, we demonstrate that a utilitarian argument can be made for investment in better support for inclusion health groups despite their small size. That is, by preventing social exclusion, there is the potential for large aggregate health benefits to the whole population. We illustrate this by reframing existing published mortality estimates into population attributable fractions to show that 12% of all-cause premature deaths (95% CI 10.03% to 14.29%) are attributable to the circumstances of people who experience homelessness, use drugs and/or have been in prison. We also show that a large proportion of cause-specific premature deaths in the general population can be attributed to specific inclusion health groups, such as 43% of deaths due to viral hepatitis (95% CI 30.35% to 56.61%) and nearly 4000 deaths due to cancer (3844, 95% CI 3438 to 4285) between 2013 and 2021 attributed to individuals who use illicit opioids. Considering the complexity of the inclusion health policy context and the sparseness of evidence, we discuss how a shift in policy framing from 'inclusion health vs the rest of the population' to 'the impact of social exclusion on broader population health' makes a better case for increased policy attention and investment in inclusion health. We discuss the strengths and limitations of this approach and how it can be applied to public health policy, resource prioritisation and future research.

Ethnic differences and inequities in paediatric healthcare utilisation in the UK: a scoping review.

BACKGROUND: Despite the increased policy attention on ethnic health inequities since the COVID-19 pandemic, research on ethnicity and healthcare utilisation in children has largely been overlooked. OBJECTIVES: This scoping review aimed to describe and appraise the quantitative evidence on ethnic differences (unequal) and inequities (unequal, unfair and disproportionate to healthcare needs) in paediatric healthcare utilisation in the UK 2001-2021. METHODS: We searched Embase, Medline and grey literature sources and mapped the number of studies that found differences and inequities by ethnic group and healthcare utilisation outcome. We summarised the distribution of studies across various methodological parameters. RESULTS: The majority of the 61 included studies (n=54, 89%) identified ethnic differences or inequities in paediatric healthcare utilisation, though inequities were examined in fewer than half of studies (n=27, 44%). These studies mostly focused on primary and preventive care, and depending on whether ethnicity data were aggregated or disaggregated, findings were sometimes conflicting. Emergency and outpatient care were understudied, as were health conditions besides mental health and infectious disease. Studies used a range of ethnicity classification systems and lacked the use of theoretical frameworks. Children's ethnicity was often the explanatory factor of interest while parent/caregiver ethnicity was largely overlooked. DISCUSSION: While the current evidence base can assist policy makers to identify inequities in paediatric healthcare utilisation among certain ethnic groups, we outline recommendations to improve the validity, generalisability and comparability of research to better understand and thereby act on ethnic inequities in paediatric healthcare.

Migrants' primary care utilisation before and during the COVID-19 pandemic in England: An interrupted time series analysis.

Background: How international migrants access and use primary care in England is poorly understood. We aimed to compare primary care consultation rates between international migrants and non-migrants in England before and during the COVID-19 pandemic (2015-2020). Methods: Using data from the Clinical Practice Research Datalink (CPRD) GOLD, we identified migrants using country-of-birth, visa-status or other codes indicating international migration. We linked CPRD to Office for National Statistics deprivation data and ran a controlled interrupted time series (ITS) using negative binomial regression to compare rates before and during the pandemic. Findings: In 262,644 individuals, pre-pandemic consultation rates per person-year were 4.35 (4.34-4.36) for migrants and 4.60 (4.59-4.60) for non-migrants (RR:0.94 [0.92-0.96]). Between 29 March and 26 December 2020, rates reduced to 3.54 (3.52-3.57) for migrants and 4.2 (4.17-4.23) for non-migrants (RR:0.84 [0.8-0.88]). The first year of the pandemic was associated with a widening of the gap in consultation rates between migrants and non-migrants to 0.89 (95% CI 0.84-0.94) times the ratio before the pandemic. This widening in ratios was greater for children, individuals whose first language was not English, and individuals of White British, White non-British and Black/African/Caribbean/Black British ethnicities. It was also greater in the case of telephone consultations, particularly in London. Interpretation: Migrants were less likely to use primary care than non-migrants before the pandemic and the first year of the pandemic exacerbated this difference. As GP practices retain remote and hybrid models of service delivery, they must improve services and ensure primary care is accessible and responsive to migrants' healthcare needs. Funding: This study was funded by the Medical Research Council (MC_PC 19070 and MR/V028375/1) and a Wellcome Clinical Research Career Development Fellowship (206602).

What can the UK learn from the impact of migrant populations on national life expectancy?

Improvements in life expectancy at birth in the UK had stalled prior to 2020 and have fallen during the COVID-19 pandemic. The stagnation took place at a time of relatively high net migration, yet we know that migrants to Australia, the USA and some Nordic countries have positively impacted national life expectancy trends, outperforming native-born populations in terms of life expectancy. It is important to ascertain whether migrants have contributed positively to life expectancy in the UK, concealing worsening trends in the UK-born population, or whether relying on national life expectancy calculations alone may have masked excess mortality in migrant populations. We need a better understanding of the role and contribution of migrant populations to national life expectancy trends in the UK.

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.

Social prescribing for migrants in the United Kingdom: A systematic review and call for evidence.

BACKGROUND: The health needs of international migrants living in the United Kingdom (UK) extend beyond mainstream healthcare to services that address the wider determinants of health and wellbeing. Social prescribing, which links individuals to these wider services, is a key component of the UK National Health Service (NHS) strategy, yet little is known about social prescribing approaches and outcomes for international migrants. This review describes the evidence base on social prescribing for migrants in the UK. METHODS: A systematic review was undertaken, which identified studies through a systematic search of 4 databases and 8 grey literature sources (January 2000 to June 2020) and a call for evidence on the UK government website (July to October 2020). Published and unpublished studies of evaluated social prescribing programmes in the UK were included where at least 1 participant was identified as a migrant. Screening, data extraction and quality appraisal were performed by one reviewer, with a second reviewer checking 20% of studies. A narrative synthesis was conducted. FINDINGS: Of the 4544 records identified, 32 were included in this review. The overall body of evidence was low in quality. Social prescribing approaches for migrants in the UK varied widely between programmes. Link workers who delivered services to migrants often took on additional support roles and/or actively delivered parts of the prescribed activities themselves, which is outside of the scope of the typical link worker role. Evidence for improvements to health and wellbeing and changes in healthcare utilisation were largely anecdotal and lacked measures of effect. Improved self-esteem, confidence, empowerment and social connectivity were frequently described. Facilitators of successful implementation included provider responsiveness to migrants' preferences in relation to language, culture, gender and service delivery format. Barriers included limited funding and provider capability. CONCLUSIONS: Social prescribing programmes should be tailored to the individual needs of migrants. Link workers also require appropriate training on how to support migrants to address the wider determinants of health. Robust evaluation built into future social prescribing programmes for migrants should include better data collection on participant demographics and measurement of outcomes using validated and culturally and linguistically appropriate tools. Future research is needed to explore reasons for link workers taking on additional responsibilities when providing services to migrants, and whether migrants' needs are better addressed through a single-function link worker role or transdisciplinary support roles.

Migration health research in the United Kingdom: A scoping review.

BACKGROUND: One in seven people living in the United Kingdom (UK) is an international migrant, rendering migrants an important population group with diverse and dynamic health and healthcare needs. However, there has been no attempt to map contemporary trends within migration health research conducted in the UK. The aim of this scoping review was to describe trends within migration health research and identify gaps for future research agendas. METHODS: PubMed and Embase were systematically searched for empirical research with a primary focus on the concepts "health" and "migrants" published between 2001 and 2019. Findings were analysed using the UCL-Lancet Commission on Migration and Health Conceptual Framework for Migration and Health. RESULTS: In total, 399 studies were included, with almost half (41.1%; 164/399) published in the last five years of the study period between 2015 and 2019 and a third (34.1%; 136/399) conducted in London. Studies included asylum seekers (14.8%; 59/399), refugees (12.3%; 49/399), and undocumented migrants or migrants with insecure status (3.5%; 14/399), but most articles (74.9%; 299/399) did not specify a migrant sub-group. The most studied health topics were specific disease outcomes such as infectious diseases (24.1% of studies) and mental health (19.1%) compared to examining systems or structures that impact health (27.8%), access to healthcare (26.3%), or specific exposures or behaviours (35.3%). CONCLUSIONS: There has been a growing interest in migration health. Ensuring a diverse geographic distribution of research conducted in the UK and disaggregation by migrant sub-group is required for a nuanced and region-specific understanding of specific health needs, interventions and appropriate service delivery for different migrant populations. More research is needed to understand how migration policy and legislation intersect with both the social determinants of health and access to healthcare to shape the health of migrants in the UK.

Could α-Klotho Unlock the Key Between Depression and Dementia in the Elderly: from Animal to Human Studies.

α-Klotho is known for its aging-related functions and is associated with neurodegenerative diseases, accelerated aging, premature morbidity, and mortality. Recent literature suggests that α-Klotho is also involved in the regulation of mental functions, such as cognition and psychosis. While most of studies of α-Klotho are focusing on its anti-aging functions and protective role in dementia, increasing evidence showed many shared symptoms between depression and dementia, while depression has been proposed as the preclinical stage of dementia such as Alzheimer's disease (AD). To see whether and how α-Klotho can be a key biological link between depression and dementia, in this review, we first gathered the evidence on biological distribution and function of α-Klotho in psychiatric functions from animal studies to human clinical investigations with a focus on the regulation of cognition and mood. Then, we discussed and highlighted the potential common underlying mechanisms of α-Klotho between psychiatric diseases and cognitive impairment. Finally, we hypothesized that α-Klotho might serve as a neurobiological link between depression and dementia through the regulation of oxidative stress and inflammation.

Action potential bursts enhance transmitter release at a giant central synapse.

Patterns of action potentials (APs), often in the form of bursts, are critical for coding and processing information in the brain. However, how AP bursts modulate secretion at synapses remains elusive. Here, using the calyx of Held synapse as a model we compared synaptic release evoked by AP patterns with a different number of bursts while the total number of APs and frequency were fixed. The ratio of total release produced by multiple bursts to that by a single burst was defined as 'burst-effect'.We found that four bursts of 25 stimuli at 100 Hz increased the totalcharge of EPSCs to 1.47 ± 0.04 times that by a single burst of 100 stimuli at the same frequency.Blocking AMPA receptor desensitization and saturation did not alter the burst-effect, indicating that it was mainly determined by presynaptic mechanisms. Simultaneous dual recordings of presynaptic membrane capacitance (Cm) and EPSCs revealed a similar burst-effect, being 1.58±0.13by Cm and 1.49±0.05 by EPSCs. Reducing presynapticCa2+ influx by lowering extracellular Ca2+concentration or buffering residual intracellular Ca2+ with EGTA inhibited the burst-effect. We further developed a computational model largely recapitulating the burst-effect and demonstrated that this effect is highly sensitive to dynamic change in availability of the releasable pool of synaptic vesicles during various patterns of activities. Taken together, we conclude that AP bursts modulate synaptic output mainly through intricate interaction between depletion and replenishment of the large releasable pool. This burst-effect differs from the somatic burst-effect previously described from adrenal chromaffin cells, which substantially depends on activity-induced accumulation of Ca2+ to facilitate release of a limited number of vesicles in the releasable pool. Hence, AP bursts may play an important role in dynamically regulating synaptic strength and fidelity during intense neuronal activity at central synapses.

Degenerative phenotypes caused by the combined deficiency of murine HIP1 and HIP1r are rescued by human HIP1.

The members of the huntingtin-interacting protein-1 (HIP1) family, HIP1 and HIP1-related (HIP1r), are multi-domain proteins that interact with inositol lipids, clathrin and actin. HIP1 is over-expressed in a variety of cancers and both HIP1 and HIP1r prolong the half-life of multiple growth factor receptors. To better understand the physiological importance of the HIP1 family in vivo, we have analyzed a large cohort of double Hip1/Hip1r knockout (DKO) mice. All DKO mice were dwarfed, afflicted with severe vertebral defects and died in early adulthood. These phenotypes were not observed during early adulthood in the single Hip1 or Hip1r knockouts, indicating that HIP1 and HIP1r compensate for one another. Despite the ability of HIP1 and HIP1r to modulate growth factor receptor levels when over-expressed, studies herein using DKO fibroblasts indicate that the HIP1 family is not necessary for endocytosis but is necessary for the maintenance of diverse adult tissues in vivo. To test if human HIP1 can function similar to mouse HIP1, transgenic mice with 'ubiquitous' expression of the human HIP1 cDNA were generated and crossed with DKO mice. Strikingly, the compound human HIP1 transgenic DKO mice were completely free from dwarfism and spinal defects. This successful rescue demonstrates that the human HIP1 protein shares some interchangeable functions with both HIP1 and HIP1r in vivo. In addition, we conclude that the degenerative phenotypes seen in the DKO mice are due mainly to HIP1 and HIP1r protein deficiency rather than altered expression of neighboring genes or disrupted intronic elements.

A Hip1R-cortactin complex negatively regulates actin assembly associated with endocytosis.

Actin polymerization plays a critical role in clathrin-mediated endocytosis in many cell types, but how polymerization is regulated is not known. Hip1R may negatively regulate actin assembly during endocytosis because its depletion increases actin assembly at endocytic sites. Here, we show that the C-terminal proline-rich domain of Hip1R binds to the SH3 domain of cortactin, a protein that binds to dynamin, actin filaments and the Arp2/3 complex. We demonstrate that Hip1R deleted for the cortactin-binding site loses its ability to rescue fully the formation of abnormal actin structures at endocytic sites induced by Hip1R siRNA. To determine when this complex might function during endocytosis, we performed live cell imaging. The maximum in vivo recruitment of Hip1R, clathrin and cortactin to endocytic sites was coincident, and all three proteins disappeared together upon formation of a clathrin-coated vesicle. Finally, we showed that Hip1R inhibits actin assembly by forming a complex with cortactin that blocks actin filament barbed end elongation.

Preparation of membrane proteins from Drosophila embryos.

INTRODUCTIONDrosophila embryos provide a unique system for the study of membrane proteins because of an extensive database in both genetics and biochemistry. Drosophila early embryos have an extraordinary peak in membrane biogenesis with a 23-fold increase in membrane area over ~45 minutes. This protocol describes purification of Drosophila membranes using equilibrium sedimentation in a sucrose density step gradient (0.5 M, 2.0 M, 2.5 M). It also includes two methods to determine the membrane association of a protein of interest: (1) alkaline wash and (2) Triton X-114 phase separation.

Multiple roles for cyclin G-associated kinase in clathrin-mediated sorting events.

Cyclin G-associated kinase (GAK), also known as auxilin 2, is a potential regulator of clathrin-mediated membrane trafficking. It possesses a kinase domain at its N-terminus that can phosphorylate the clathrin adaptors AP-1 and AP-2 in vitro. The GAK C-terminus can act as a cochaperaone in vitro for Hsc70, a heat-shock protein required for clathrin uncoating. Here we show that the specificity of GAK is very similar to that of adaptor-associated kinase 1, another mammalian adaptor kinase. We used siRNA to investigate GAK's in vivo function. We discovered that early stages of clathrin-mediated endocytosis (CME) were partially inhibited when GAK expression was knocked down. This defect was specifically caused by GAK knockdown because it could be rescued by expressing a rat GAK gene that could not be silenced by one of the siRNAs. To identify the GAK activity required during CME, we mutated the kinase domain and the J domain of the rat gene. Only GAK with a functional J domain could rescue the defect, suggesting that GAK is important for clathrin uncoating. Furthermore, we demonstrated that GAK plays a role in the clathrin-dependent trafficking from the trans Golgi network.

Actin dynamics coupled to clathrin-coated vesicle formation at the trans-Golgi network.

In diverse species, actin assembly facilitates clathrin-coated vesicle (CCV) formation during endocytosis. This role might be an adaptation specific to the unique environment at the cell cortex, or it might be fundamental, facilitating CCV formation on different membranes. Proteins of the Sla2p/Hip1R family bind to actin and clathrin at endocytic sites in yeast and mammals. We hypothesized that Hip1R might also coordinate actin assembly with clathrin budding at the trans-Golgi network (TGN). Using deconvolution and time-lapse microscopy, we showed that Hip1R is present on CCVs emerging from the TGN. These vesicles contain the mannose 6-phosphate receptor involved in targeting proteins to the lysosome, and the actin nucleating Arp2/3 complex. Silencing of Hip1R expression by RNAi resulted in disruption of Golgi organization and accumulation of F-actin structures associated with CCVs on the TGN. Hip1R silencing and actin poisons slowed cathepsin D exit from the TGN. These studies establish roles for Hip1R and actin in CCV budding from the TGN for lysosome biogenesis.

RNAi-mediated Hip1R silencing results in stable association between the endocytic machinery and the actin assembly machinery.

Actin filaments transiently associate with the endocytic machinery during clathrin-coated vesicle formation. Although several proteins that might mediate or regulate this association have been identified, in vivo demonstration of such an activity has not been achieved. Huntingtin interacting protein 1R (Hip1R) is a candidate cytoskeletal-endocytic linker or regulator because it binds to clathrin and actin. Here, Hip1R levels were lowered by RNA interference (RNAi). Surprisingly, rather than disrupting the transient association between endocytic and cytoskeletal proteins, clathrin-coated structures (CCSs) and their endocytic cargo became stably associated with dynamin, actin, the Arp2/3 complex, and its activator, cortactin. RNAi double-depletion experiments demonstrated that accumulation of the cortical actin-endocytic complexes depended on cortactin. Fluorescence recovery after photobleaching showed that dynamic actin filament assembly can occur at CCSs. Our results provide evidence that Hip1R helps to make the interaction between actin and the endocytic machinery functional and transient.