Oral Chinese herbal medicine combined with donepezil for mild cognitive impairment: A systematic review and meta-analysis.

BACKGROUND: This study aims to evaluate the add-on effects of oral Chinese herbal medicine (CHM) for mild cognitive impairment (MCI), when used in addition to donepezil compared to donepezil alone. METHODS: Randomized controlled trials comparing these treatments across all types of MCI were identified from nine databases and three registers until August 2023. Outcome measures were Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and adverse events (AEs). Methodological quality was assessed using Cochrane risk-of-bias tool, and evidence certainty was evaluated using the GRADE method. RESULTS: Involving 1611 participants across 20 studies, meta-analysis results indicate that oral CHM combined with donepezil significantly improved cognitive function in MCI patients compared to donepezil alone, as evidenced by MMSE (1.88 [1.52, 2.24], I2 = 41%, 12 studies, 993 participants) and MoCA (MD: 2.01 [1.57, 2.44], I2 = 52%, 11 studies, 854 participants). Eleven studies reported details of AEs, identifying gastrointestinal symptoms and insomnia as the most common symptoms. No significant difference in AEs frequency was found between the groups (RR: 0.91 [0.59, 1.39], I2 = 4%, 11 studies, 808 participants). All 20 studies were evaluated as having "some concerns" regarding the overall risk of bias. The certainty of evidence for MMSE was "moderate" and "low" for MoCA. From frequently utilized herbs, two classical CHM formulae were identified: Kai xin san and Si wu decoction. The observed treatment effects of commonly used herbs may be exerted through multiple pharmacological mechanisms, including anti-inflammatory, anti-oxidative stress, anti-apoptotic actions, promotion of neuronal survival and modulation of the cholinergic system. CONCLUSIONS: The concurrent use of oral CHM and donepezil appears to be more effective than donepezil alone in improving the cognitive function of MCI, without leading to an increase in AEs. While recognizing concerns of overall methodological quality, this combined therapy should be considered as an alternative option for clinical practice.

The effectiveness and safety of acupoint herbal patching for allergic rhinitis: protocol for a systematic review and meta-analysis.

BACKGROUND: Allergic rhinitis (AR) is a common inflammatory disease of the nasal mucosa that is characterized by symptoms such as sneezing, nasal congestion, nasal itching, and rhinorrhoea. In recent years, acupoint herbal patching (AHP) therapy has gained a growing interest as a potential management option for AR. This systematic review and meta-analysis will evaluate the clinical research evidence on the effectiveness and safety of AHP as a treatment option for AR outside of the Sanfu or Sanjiu days (summer or winter solstice). The results of this review will provide up-to-date evidence-based guidance for healthcare providers and individuals seeking alternative treatments for AR. METHODS: A comprehensive search of electronic databases (PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, China National Knowledge Infrastructure (CNKI), CQVIP, Sino-Med, and Wanfang Databases) will be conducted from their inception to June 2023. The inclusion criteria will be limited to randomized controlled trials that evaluate the effectiveness or efficacy of non-Sanfu or non-Sanjiu AHP for AR. The primary outcome measure will be the total nasal symptom score. The methodological quality of included studies will be assessed using the Revised Cochrane risk-of-bias tool for randomized trials (RoB 2), and meta-analyses will be performed using RevMan (V.5.3) statistical software. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach will be used to determine the certainty of evidence. DISCUSSION: This systematic review and meta-analysis will provide valuable insights into the effectiveness and safety of non-Sanfu or non-Sanjiu AHP as a treatment option for AR. The study aims to produce a high-quality review by adhering to PRISMA-P guidelines and using clinical guideline recommended outcome measures. The results of this review may offer additional treatment options for AR patients who seek complementary and alternative therapies, and hold significant implications for future research in this field. Overall, this study has the potential to inform clinical practice and improve patient outcomes. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022181322.

Real-world Chinese herbal medicine for Parkinson's disease: a hospital-based retrospective analysis of electronic medical records.

Background: Parkinson's disease (PD) is a progressive neurodegenerative condition. Chinese medicine therapies have demonstrated effectiveness for PD in controlled settings. However, the utilization of Chinese medicine therapies for PD in real-world clinical practice and the characteristics of patients seeking these therapies have not been thoroughly summarized. Method: The study retrospectively analyzed initial patient encounters (PEs) with a first-listed diagnosis of PD, based on electronic medical records from Guangdong Provincial Hospital of Chinese Medicine between July 2018 and July 2023. Results: A total of 3,206 PEs, each corresponding to an individual patient, were eligible for analyses. Approximately 60% of patients made initial visits to the Chinese medicine hospital after receiving a PD diagnosis, around 4.59 years after the onset of motor symptoms. Over 75% of the patients visited the Internal Medicine Outpatient Clinic at their initial visits, while a mere 13.85% visited PD Chronic Care Clinic. Rest tremor (61.98%) and bradykinesia (52.34%) are the most commonly reported motor symptoms, followed by rigidity (40.70%). The most commonly recorded non-motor symptoms included constipation (31.88%) and sleep disturbance (25.27%). Integration of Chinese medicine and conventional medicine therapies was the most common treatment method (39.15%), followed by single use of Chinese herbal medicine (27.14%). The most frequently prescribed herbs for PD included Glycyrrhiza uralensis Fisch. (gan cao), Astragalus mongholicus Bunge (huang qi), Atractylodes macrocephala Koidz. (bai zhu), Angelica sinensis (Oliv.) Diels (dang gui), Rehmannia glutinosa (Gaertn.) DC. (di huang), Paeonia lactiflora Pall. (bai shao), Bupleurum chinense DC. (chai hu), Citrus aurantium L. (zhi qiao/zhi shi/chen pi), Panax ginseng C. A. Mey. (ren shen), and Poria cocos (Schw.) Wolf (fu ling). These herbs contribute to formulation of Bu zhong yi qi tang (BZYQT). Conclusion: Patients typically initiated Chinese medical care after the establishment of PD diagnosis, ~4.59 years post-onset of motor symptoms. The prevalent utilization of CHM decoctions and patented Chinese herbal medicine products, underscores its potential in addressing both motor and non-motor symptoms. Despite available evidence, rigorous clinical trials are needed to validate and optimize the integration of CHM, particularly BZYQT, into therapeutic strategies for PD.

Seed distribution stability in permanent breast seed implant brachytherapy.

PURPOSES: In this study we aim to quantitatively evaluate the stability of implanted seeds in permanent breast seed implant (PBSI) brachytherapy and assess any impact on treatment quality. METHODS AND MATERIALS: Sixty-seven consecutive patients who received PBSI treatment at BC Cancer Kelowna from 2013 to 2021 with post-implant CT images available were included in this study. For each patient, two sets of post-implant CT scans were retrospectively analyzed: Day0, obtained immediately after implant, and Day30, obtained approximately one month following implant. Seed distributions were quantified using the 90% isodose contour, outlier seed maximum spread, and number of seeds located in the seroma as well as seroma quadrants. These were then compared between Day0 and Day30. Post-implant dosimetry of target volumes as well as critical structures were compared. RESULTS: The 90% isodose volume was found to decrease over time. All seeds remained in the breast region however the maximum spread of seeds increased in all directions from Day0 to Day30. All recorded target volume dosimetric parameters were, on average, lower on Day30 compared to Day0 but mean dosimetry levels still met clinical goals. Dose in critical structures was overall similar. CONCLUSIONS: In this study, we quantitatively described the changes in seed distributions as well as dosimetry from Day0 to Day30 post PBSI procedure. We addressed concerns related to seed stability in breast tissue and provided clinical evidence on dosimetric efficacy of the PBSI technique.

Ethnic inequities in 6-8 week baby check coverage in England 2006- 2021: a cohort study using the Clinical Practice Research Datalink.

BACKGROUND: Inequities in the coverage of 6-8-week maternal checks, health visitor reviews, and infant vaccinations have been reported in England. Ethnic inequities in 6-8-week baby checks have not been studied nationally. AIM: To examine the effect of maternal ethnicity on 6-8 week baby check coverage in England 2006-2021. DESIGN AND SETTING: This cohort study used electronic health records from primary care in England. METHOD: Baby check coverage was calculated in 16 ethnic groups, by year and region. Risk ratios were estimated using modified Poisson regression. Coverage and timing of baby checks in relation to maternal checks and infant vaccinations by ethnic group were calculated. RESULTS: Ethnic inequities in 6-8 week baby check coverage in England varied by year and region. Coverage increased 2006-2007 to 2015-2016, then stabilised to 80-90% for most groups. Coverage was lowest for Bangladeshi and Pakistani groups 2006-2007 to 2011-2012. In the West Midlands, coverage was lowest at approximately 60% for four groups: Bangladeshi, Caribbean, African, and Any other Black, African or Caribbean background. In the North West, coverage was lowest for Bangladeshi (65.3%) and Pakistani (69.2%) groups. These patterns remained after adjusting for other factors and persisted over time. Coverage was highest in those whose mothers received a maternal check and those who received at least one dose of 8-week infant vaccinations. CONCLUSION: Coordinated action at the level of integrated commissioning boards, primary care networks, and GP practices is required to better understand the reasons behind these inequities and redress the persistent disparities in 6-8 week baby check coverage.

Chinese herbal medicine bath therapy for psoriasis vulgaris using topical calcipotriol as the comparator: A systematic review with meta-analysis and association rule analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Psoriasis is a chronic inflammatory skin disease. Vitamin D analogues are the first-line topical agents for the long-term management of psoriasis. Chinese herbal medicine (CHM) bath therapy is commonly employed for psoriasis. However, the effects and safety of CHM bath therapy for psoriasis vulgaris, using topical calcipotriol as the comparator, remain inconclusive. Furthermore, the combination of herbs, a distinctive feature of CHM, is essential for its therapeutic effects due to the individual and synergistic properties of the herbs involved. AIM OF THE STUDY: The review was conducted to evaluate the effectiveness and safety of CHM bath therapy for psoriasis vulgaris, using calcipotriol as the comparator. Potential herbs and herb combinations of CHM bath therapy were also explored for further drug discovery. MATERIALS AND METHODS: Nine databases were searched from inception until March 05, 2024. Randomised controlled trials (RCTs) investigating CHM bath therapy, using calcipotriol as the comparator, were included. Statistical analyses were performed using RevMan 5.4, Stata 12.0 and SPSS Clementine 12.0 software. The evidence certainty for outcomes was assessed using the approach proposed by the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group. Moreover, association rule analysis on herbs identified in the systematic review was conducted to explore the potential herbs and herb combinations. RESULTS: A total of 17 RCTs involving 1,379 participants were included in this systematic review. The findings of this review revealed that: 1) CHM bath therapy produced comparable effects to calcipotriol in reducing Psoriasis Area and Severity Index (PASI), Psoriasis Scalp Severity Index (PSSI), and itch visual analogue scale (VAS) at the end of the treatment phase; as well as exhibited a superior long-term effect than calcipotriol through decreasing relapse rates at the end of the follow-up phase; 2) CHM bath therapy showed an additional benefit when combined with calcipotriol in managing psoriasis vulgaris at the end of the treatment phase, in terms of PASI, PSSI, itch VAS, IL-17, IL-23, CD3+ and CD4+ T cells. The certainty of the evidence was rated as 'very low', 'low' or 'moderate' based on the GRADE assessment, considering some concerns or high risk of bias of included studies, substantial heterogeneity, and existing publication bias of some outcomes. Additionally, the proportions of participants reporting adverse events were similar in both groups. Association rule analysis of all included herbs identified 23 herb combinations including Prunus persica (L.) Batsch and Carthamus tinctorius L., as well as 11 frequently used herbs, such as Kochia scoparia (L.) Schrad., Dictamnus dasycarpus Turcz. And Sophora flavescens Ait. CONCLUSIONS: The effects of CHM bath therapy were comparable with those of topical calcipotriol but demonstrated a longer-lasting effect. Combining CHM bath therapy with calcipotriol also provided an additional benefit for adult psoriasis vulgaris. However, the certainty of the evidence was downgraded due to the methodological limitations of included studies. To confirm the findings of this review, future investigations should involve double-blinded, placebo-controlled RCTs. Importantly, it appears worthwhile to consider further research for drug development utilising the identified herbs or herb combinations.

Add-on effects of Chinese herbal medicine external application (FZHFZY) to topical urea for mild-to-moderate psoriasis vulgaris: Protocol for a double-blinded randomized controlled pilot trial embedded with a qualitative study.

Psoriasis vulgaris is a chronic dermatological disease with a high global prevalence. It significantly reduces patients' quality of life and is associated with a substantial economic burden. Conventional therapies for mild-to-moderate psoriasis are often associated with insufficient long-term symptomatic relief and side effects. Chinese herbal medicine (CHM) is commonly used for psoriasis management. A CHM formula, namely Fu zheng he fu zhi yang (FZHFZY), has shown promising treatment effects in clinical practice when used as a bath therapy. However, its efficacy and safety has not been evaluated by a rigorous randomized controlled trial (RCT). Therefore, we designed a double-blinded pilot RCT embedded with a qualitative study on CHM formula FZHFZY plus topical urea for mild-to-moderate psoriasis vulgaris to advance the evidence development and practice of CHM external application for psoriasis. This will be a mixed-method design consisting of a pilot RCT and a qualitative study. The pilot RCT is a two-arm, parallel, placebo-controlled, double-blinded trial. Sixty eligible participants will be randomized at a 1:1 ratio to receive eight weeks' treatment of either FZHFZY plus 10% urea cream, or placebo plus 10% urea cream, with 12-week follow-up visits after the treatment phase. The CHM or placebo will be administered externally as a bath therapy. Outcome measures include trial feasibility, efficacy and safety. The primary efficacy outcome will be Psoriasis Area Severity Index (PASI). Secondary efficacy outcomes include Physician Global Assessment, PASI-75, PASI-50, Body Surface Area, Dermatology Life Quality Index, Skindex-16, itch visual analogue scale and relapse. The qualitative study will be conducted to collect participants' feedback on CHM external application and their experience with the pilot RCT. This study will advance the evidence-based clinical practice of using CHM for psoriasis vulgaris and then to support translation of findings into clinical practice in the future. Trial registration number: ChiCTR2200064092.

The efficacy and safety of Chinese herbal medicine for mild cognitive impairment: a systematic review and meta-analysis of randomized placebo-controlled trials.

Objective: Effective and safe treatments for mild cognitive impairment (MCI) are limited. Chinese herbal medicine (CHM) is commonly used in China to manage MCI. However, its efficacy and safety remain uncertain. This review aims to evaluate the efficacy and safety of CHM for MCI. Methods: Nine databases were searched from their inceptions to January 2023. Randomized, placebo-controlled trials of oral CHM for MCI were included. Study quality was assessed using the Cochrane risk-of-bias tool 2.0, and the certainty of evidence was evaluated via the GRADE approach. Results: Thirteen studies, involving 1,043 participants, were analyzed. Most of the studies (10 out of 13) were associated with "some concerns" regarding the overall risk of bias. Meta-analyses results indicated that CHM significantly improved cognitive function compared to placebo in terms of Mini-Mental State Examination (MMSE) (MD: 1.90 [1.22, 2.58], I2 = 87%, 11 studies, 823 participants) and Montreal Cognitive Assessment (MoCA) (MD: 2.88 [1.69, 4.06], I2 = 81%, 3 studies, 241 participants). The certainty of evidence for MMSE was assessed as "moderate", while it was "low" for MoCA. One study did not report adverse events (AEs), one study reported no statistical difference between the groups in terms of AEs, and 11 studies provided detailed numbers of AE cases where gastrointestinal symptoms were the most commonly reported AEs. Two studies reported no SAEs among participants and one study found no significant difference in SAEs proportions between groups. The meta-analysis revealed no significant difference in AEs between the two groups (RR: 1.31 [0.92, 1.87), I2 = 0%, 11 studies, 839 participants). The cognitive-enhancing function of commonly used herbs (Panax ginseng C.A.Mey., Acorus calamus var. angustatus Besser, and Polygala tenuifolia Willd.) may be attributed to mechanisms including antioxidant, anti-apoptotic, anti-neurotoxic, anti-cytotoxic, and anti-inflammatory actions. Conclusion: Chinese herbal medicine holds potential as an effective intervention to improve cognitive function in MCI patients, supported by meta-analyses evidence of low to moderate certainty. Although current data suggests CHM is generally safe, caution is advised due to the lack of AE reporting or detailed information in some instances. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=400292, identifier [CRD42023400292].

Adding Chinese herbal medicine bath therapy to conventional therapies for psoriasis vulgaris: A systematic review with meta-analysis of randomised controlled trials.

BACKGROUND: Chinese herbal medicine (CHM) bath is commonly used in China as an adjuvant therapy for managing psoriasis vulgaris. Previous systematic reviews showed that CHM bath therapy was effective and safe for psoriasis vulgaris, however, without exploration of the specifics of CHM bath therapy such as the optimal temperature, duration of each session, and the total treatment duration. PURPOSE: To evaluate the add-on effects of CHM bath therapy to conventional therapies for adult psoriasis vulgaris. METHODS: We conducted a comprehensive search in nine medical databases from inception to September 2022 to identify relevant randomised controlled trials (RCTs) published in Chinese or English. The included studies compared the combination of CHM bath therapy and conventional therapies to conventional therapies alone for adult psoriasis vulgaris. Methodological quality assessment of the included RCTs was performed using the Cochrane risk-of-bias tool 2 (RoB 2). Statistical analysis was carried out using RevMan 5.4, R 4.2.3 and Stata 12.0 software. The certainty of evidence of outcome measures was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation Working Group (GRADE) system. RESULTS: A total of 23 RCTs involving 2,183 participants were included in this systematic review. Findings suggested that the combination of CHM bath therapy and conventional therapies was more effective in reducing Psoriasis Area and Severity Index (PASI), Dermatology Life Quality Index (DLQI) and itch visual analogue scale, compared to using conventional therapies alone. These enhanced effects were notably observed when the CHM bath was set above 38 °C and had a duration of 20 and 30 min, as assessed by DLQI. Moreover, an eight-week treatment duration resulted in better effects for PASI compared to shorter durations. Additionally, the top ten frequently used herbs in the included studies were identified. Despite the findings, the certainty of evidence was rated as 'low' or 'moderate' based on the GRADE assessment, and significant heterogeneity was detected in subgroup and sensitivity analyses. CONCLUSION: The CHM bath therapy combined with conventional therapies is more effective and safer than conventional therapies alone for adult psoriasis vulgaris. The results suggest a potential correlation between treatment effects and factors such as extended treatment duration, increased bath temperature, and longer bath sessions. However, the certainty of evidence was downgraded due to methodological limitations of the included studies. To confirm the findings of this systematic review, a double-blinded, placebo-controlled RCT is needed in the future.

Real-world observations and impacts of Chinese herbal medicine for migraine: results of a registry-based cohort study.

Background: Migraine is a prevalent, recurrent condition with substantial disease burden. Chinese herbal medicine (CHM) has been used frequently for migraine in controlled clinical settings. This study is to summarise the characteristics of patients who seek clinical care in a tertiary Chinese medicine hospital in China; to gather their preferences and values of using CHM; to explore the effect of CHM for migraine and its comorbidities in a real-world setting, and to collect first-hand expertise of clinicians' practice pattern in prescribing CHM for migraine. Methods: This registry-based cohort study was prospectively conducted at Guangdong Provincial Hospital of Chinese Medicine from December 2020 to May 2022. Adult migraine patients seeking their initial anti-migraine clinical care at the hospital were consecutively recruited and followed up for 12 weeks. Practitioners specialised in headache management prescribed individualised treatments without research interference. Standardised case report forms were employed to gather information on patients' preferences and perspective of seeking clinical care, as well as to assess participants' migraine severity, comorbidities, and quality of life, at 4-weeks intervals. Various analytical methods were utilised based on the computed data. Results: In this study, we observed 248 participants. Of these, 73 received CHM treatment for 28 days or longer. Notably, these participants exhibited a greater disease severity, compared to those treated with CHM for less than 28 days. Of the 248 participants, 83.47% of them expected CHM would effectively reduce the severity of their migraine, around 50% expected effects for migraine-associated comorbidities, while 51.61% expressing concerns about potential side effects. CHM appeared to be effective in reducing monthly migraine days and pain intensity, improving patients' quality of life, and potentially reducing comorbid anxiety, with a minimum of 28 days CHM treatment. Herbs such as gan cao, gui zhi, chuan xiong, fu ling, bai zhu, yan hu suo, etc. were frequently prescribed for migraine, based on patients' specific symptoms. Conclusion: CHM appeared to be beneficial for migraine and comorbid anxiety in real-world clinical practice when used continuously for 28 days or more. Clinical Trial Registration: clinicaltrials.gov, identifier ChiCTR2000041003.

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.

A postimplant dosimetry simulation framework for robustness evaluation in permanent breast seed implant brachytherapy.

BACKGROUND: Permanent breast seed implant (PBSI) brachytherapy is a promising treatment that has the potential to be widely utilized with increased standardization, optimization, and robustness. Excellent early efficacy and very high patient acceptance were reported, however, to further evaluate and improve planning strategies, a framework to quantify plan robustness to implant uncertainties is necessary. PURPOSE: In this study, we aim to quantify clinical seed displacement using an automated algorithm and develop and validate a PBSI post-implant dosimetry simulation framework to evaluate PBSI plan robustness to implant uncertainties. METHODS AND MATERIALS: Clinical PBSI seed displacements were quantified for 63 consecutive patients. A PBSI simulator was developed in Matlab (2020) by resampling clinical seed displacements and computing a range of possible post-implant dosimetry outcomes under various seed displacement scenarios. Simulations were performed retrospectively on 63 previous clinical plans to evaluate plan robustness to seed displacement. RESULTS: Mean seed displacement for the whole cohort was 10 ± 6 mm. A clinical seed displacement database was established and a user interface was developed for the simulation framework. For all clinical plans, the median (range) value of simulated median ETV V90 in various seed displacement scenarios was 97.8% (87.5-100%). CONCLUSIONS: A PBSI postimplant dosimetry simulation framework was developed and validated. Simulation results showed that the current PTV planning margin is sufficient to provide adequate postimplant dose coverage of ETV. This simulator can be used to evaluate plan robustness to seed displacement and will facilitate future research in improving PBSI planning methods.

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.

Synaptotagmin-11 regulates immune functions of microglia in vivo.

Membrane trafficking pathways mediate key microglial activities such as cell migration, cytokine secretion, and phagocytosis. However, the underlying molecular mechanism remains poorly understood. Previously, we found that synaptotagmin-11 (Syt11), a non-Ca2+ -binding Syt associated with Parkinson's disease (PD) and schizophrenia, inhibits cytokine release and phagocytosis in primary microglia. Here we reported the in vivo function of Syt11 in microglial immune responses using an inducible microglia-specific Syt11-conditional-knockout (cKO) mouse strain. Syt11-cKO resulted in activation of microglia and elevated mRNA levels of IL-6, TNF-α, IL-1ß, and iNOS in various brain regions under both resting state and LPS-induced acute inflammation state in adult mice. In a PD mouse model generated by microinjection of preformed α-synuclein fibrils into the striatum, a reduced number of microglia migrated toward the injection sites and an enhanced phagocytosis of α-synuclein fibrils by microglia were found in Syt11-cKO mice. To understand the molecular mechanism of Syt11 function, we identified its direct binding proteins vps10p-tail-interactor-1a (vti1a) and vti1b. The linker domain of Syt11 interacted with both proteins and a peptide derived from it competitively inhibited the interaction of Syt11 with vti1a/vti1b in vitro and in cells. Importantly, application of this peptide induced more cytokine secretion in wild-type microglia upon LPS treatment, phenocopying defects in Syt11 knockdown cells. Altogether, we propose that Syt11 inhibits microglial activation in vivo and regulates cytokine secretion through interactions with vti1a and vti1b.

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.

Synaptotagmin-11 Inhibits Synaptic Vesicle Endocytosis via Endophilin A1.

Synaptic vesicle (SV) endocytosis is a critical and well-regulated process for the maintenance of neurotransmission. We previously reported that synaptotagmin-11 (Syt11), an essential non-Ca2+-binding Syt associated with brain diseases, inhibits neuronal endocytosis (Wang et al., 2016). Here, we found that Syt11 deficiency caused accelerated SV endocytosis and vesicle recycling under sustained stimulation and led to the abnormal membrane partition of synaptic proteins in mouse hippocampal boutons of either sex. Furthermore, our study revealed that Syt11 has direct but Ca2+-independent binding with endophilin A1 (EndoA1), a membrane curvature sensor and endocytic protein recruiter, with high affinity. EndoA1-knockdown significantly reversed Syt11-KO phenotype, identifying EndoA1 as a main inhibitory target of Syt11 during SV endocytosis. The N-terminus of EndoA1 and the C2B domain of Syt11 were responsible for this interaction. A peptide (amino acids 314-336) derived from the Syt11 C2B efficiently blocked Syt11-EndoA1 binding both in vitro and in vivo Application of this peptide inhibited SV endocytosis in WT hippocampal neurons but not in EndoA1-knockdown neurons. Moreover, intracellular application of this peptide in mouse calyx of Held terminals of either sex effectively hampered both fast and slow SV endocytosis at physiological temperature. We thus propose that Syt11 ensures the precision of protein retrieval during SV endocytosis by inhibiting EndoA1 function at neuronal terminals.SIGNIFICANCE STATEMENT Endocytosis is a key stage of synaptic vesicle (SV) recycling. SV endocytosis retrieves vesicular membrane and protein components precisely to support sustained neurotransmission. However, the molecular mechanisms underlying the regulation of SV endocytosis remain elusive. Here, we reported that Syt11-KO accelerated SV endocytosis and impaired membrane partition of synaptic proteins. EndoA1 was identified as a main inhibitory target of Syt11 during SV endocytosis. Our study reveals a novel inhibitory mechanism of SV endocytosis in preventing hyperactivation of endocytosis, potentially safeguarding the recycling of synaptic proteins during sustained neurotransmission.

The impact of NHS charging regulations on healthcare access and utilisation among migrants in England: a systematic review.

BACKGROUND: The NHS Charges to Overseas Visitors Regulations 2015 outline when healthcare costs should be recuperated from overseas visitors in England. National and global stakeholders have expressed concerns that charging may exacerbate health inequalities and undermine public health efforts especially among vulnerable migrant groups. This review aims to systematically describe the evidence regarding the impact of NHS charging regulations on healthcare access and utilisation and health outcomes for migrants in England. METHODS: A systematic search of scientific databases and grey literature sources was performed. Quantitative and qualitative studies, case studies and grey literature published between 1 January 2014 and 1 April 2021 were included. Screening, data extraction and quality appraisal were carried out in accordance with PRISMA guidelines. RESULTS: From the 1,459 identified studies, 10 were selected for inclusion. 6 were qualitative, 3 were mixed methods and 1 was quantitative. The evidence is lacking but suggests that fears of charging and data sharing can deter some migrants from accessing healthcare. There is also evidence to suggest a lack of knowledge of the charging regulations among patients and healthcare professionals is contributing to this deterrence. CONCLUSIONS: Further independent research supported by strengthening of data collection is required to better understand the effects of charging on healthcare and health outcomes among vulnerable migrants. Our findings support improved training and communication about NHS Charging Regulations for patients and professionals.

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.

Feasibility study of defining planning target volume using surgical margins in permanent breast seed implant brachytherapy.

PURPOSE: This study investigates the feasibility and potential impacts of utilizing a Groupe Européen de Curiethérapie-European Society for Therapeutic Radiation and Oncology (GEC ESTRO) recommended surgical margin-based planning margin in permanent breast seed implant (PBSI) brachytherapy. METHODS AND MATERIALS: Seventy-nine patients were included in this retrospective study. Three margin selections were used for PTV construction: (1) 1.25 or 1.5 cm isotropic margin (PTVPBSI), (2) 2 cm minus surgical margin in each direction as recommended by GEC ESTRO (PTVaniso), and (3) 2 cm minus minimum surgical margin isotropically (PTViso). PTV volume and dose coverage using clinical PBSI plans were compared across three groups. New PBSI plans were constructed on PTVaniso for 20 patients and planning parameters were compared to original plans constructed on PTVPBSI. RESULTS: Twenty patients had surgical margins in six directions reported, with a median value of 8 mm anteriorly, and 10 mm in all other directions. PTVaniso (36.3 ± 15.0 cc) was overall smaller than PTVPBSI (55.6 ± 14.3 cc), p value < 0.05. PBSI clinical plans showed satisfactory coverage on PTVaniso, with a median (range) V100 of 97.9% (85.8%-100.0%). Comparing to original treatment plans, new plans constructed on PTVaniso reduced the number of implant seeds and skin dose. CONCLUSIONS: Clinical PBSI plans provide satisfactory coverage of GEC ESTRO recommended PTVs. In this patient cohort, GEC ESTRO planning margin resulted in smaller target volumes, and therefore, new plans constructed on PTVaniso required fewer implanted seeds and lower skin doses were achieved. However, given PBSI delivery uncertainties, further investigations are required to determine if the GEC ESTRO planning margin will be sufficiently robust.