Uptake, effectiveness and safety of COVID-19 vaccines in individuals at clinical risk due to immunosuppressive drug therapy or transplantation procedures: a population-based cohort study in England.

BACKGROUND: Immunocompromised individuals are at increased risk of severe COVID-19 outcomes, underscoring the importance of COVID-19 vaccination in this population. The lack of comprehensive real-world data on vaccine uptake, effectiveness and safety in these individuals presents a critical knowledge gap, highlighting the urgency to better understand and address the unique challenges faced by immunocompromised individuals in the context of COVID-19 vaccination. METHODS: We analysed data from 12,274,946 people in the UK aged > 12 years from 01/12/2020 to 11/04/2022. Of these, 583,541 (4.8%) were immunocompromised due to immunosuppressive drugs, organ transplants, dialysis or chemotherapy. We undertook a cohort analysis to determine COVID-19 vaccine uptake, nested case-control analyses adjusted for comorbidities and sociodemographic characteristics to determine effectiveness of vaccination against COVID-19 hospitalisation, ICU admission and death, and a self-controlled case series assessing vaccine safety for pre-specified adverse events of interest. RESULTS: Overall, 93.7% of immunocompromised individuals received at least one COVID-19 vaccine dose, with 80.4% having received three or more doses. Uptake reduced with increasing deprivation (hazard ratio [HR] 0.78 [95%CI 0.77-0.79] in the most deprived quintile compared to the least deprived quintile for the first dose). Estimated vaccine effectiveness against COVID-19 hospitalisation 2-6 weeks after the second and third doses compared to unvaccinated was 78% (95%CI 72-83) and 91% (95%CI 88-93) in the immunocompromised population, versus 85% (95%CI 83-86) and 86% (95%CI 85-89), respectively, for the general population. Results showed COVID-19 vaccines were protective against intensive care unit (ICU) admission and death in both populations, with effectiveness of over 92% against COVID-19-related death and up to 95% in reducing ICU admissions for both populations following the third dose. COVID-19 vaccines were generally safe for immunocompromised individuals, though specific doses of ChAdOx1, mRNA-1273 and BNT162b2 raised risks of specific cardiovascular/neurological conditions. CONCLUSIONS: COVID-19 vaccine uptake is high in immunocompromised individuals on immunosuppressive drug therapy or who have undergone transplantation procedures, with documented disparities by deprivation. Findings suggest that COVID-19 vaccines are protective against severe COVID-19 outcomes in this vulnerable population, and show a similar safety profile in immunocompromised individuals and the general population, despite some increased risk of adverse events. These results underscore the importance of ongoing vaccination prioritisation for this clinically at-risk population to maximise protection against severe COVID-19 outcomes.

Adaptor protein complex 4 deficiency: a paradigm of childhood-onset hereditary spastic paraplegia caused by defective protein trafficking.

Deficiency of the adaptor protein complex 4 (AP-4) leads to childhood-onset hereditary spastic paraplegia (AP-4-HSP): SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). This study aims to evaluate the impact of loss-of-function variants in AP-4 subunits on intracellular protein trafficking using patient-derived cells. We investigated 15 patient-derived fibroblast lines and generated six lines of induced pluripotent stem cell (iPSC)-derived neurons covering a wide range of AP-4 variants. All patient-derived fibroblasts showed reduced levels of the AP4E1 subunit, a surrogate for levels of the AP-4 complex. The autophagy protein ATG9A accumulated in the trans-Golgi network and was depleted from peripheral compartments. Western blot analysis demonstrated a 3-5-fold increase in ATG9A expression in patient lines. ATG9A was redistributed upon re-expression of AP4B1 arguing that mistrafficking of ATG9A is AP-4-dependent. Examining the downstream effects of ATG9A mislocalization, we found that autophagic flux was intact in patient-derived fibroblasts both under nutrient-rich conditions and when autophagy is stimulated. Mitochondrial metabolism and intracellular iron content remained unchanged. In iPSC-derived cortical neurons from patients with AP4B1-associated SPG47, AP-4 subunit levels were reduced while ATG9A accumulated in the trans-Golgi network. Levels of the autophagy marker LC3-II were reduced, suggesting a neuron-specific alteration in autophagosome turnover. Neurite outgrowth and branching were reduced in AP-4-HSP neurons pointing to a role of AP-4-mediated protein trafficking in neuronal development. Collectively, our results establish ATG9A mislocalization as a key marker of AP-4 deficiency in patient-derived cells, including the first human neuron model of AP-4-HSP, which will aid diagnostic and therapeutic studies.

The diagnostic accuracy of HbA1c , compared to the oral glucose tolerance test, for screening for type 2 diabetes mellitus in Africa-A systematic review and meta-analysis.

OBJECTIVE: To assess the diagnostic accuracy of glycated haemoglobin A1c (HbA1c ), compared to fasting plasma glucose (FPG) and the oral glucose tolerance test (OGTT), in screening for type 2 diabetes (T2D) in Africa. METHODS: We systematically searched databases for studies that compared the HbA1c to either the OGTT, or the FPG for T2D diagnosis were included. The QUADAS 2 tool was used for assessing the quality of included studies. We used the split component synthesis (SCS) method for the meta-analysis of diagnostic accuracy studies to pool the studies for meta-analysis of sensitivity and specificity, primarily at the HbA1c ≥48 mmol/mol (6.5%) cut-off and at other cut-offs. We assessed heterogeneity using the I2  statistic and publication bias using Doi plots. RESULTS: Eleven studies, from seven African countries, with 12,925 participants, were included. Against the OGTT, HbA1c ≥48 mmol/mol (6.5%) had a pooled sensitivity of 57.7% (95% confidence interval [CI] 43.4-70.9) and specificity of 92.3% (95% CI 83.9-96.5). Against the FPG, HbA1c ≥48 mmol/mol (6.5%) had a pooled sensitivity of 64.5% (95% CI 50.5-76.4) and specificity of 94.3% (95% CI 87.9-97.5). The highest sensitivity for HbA1c , against the OGTT, was at the 42 mmol/mol (6.0%) cut-off. CONCLUSION: In Africa, the HbA1c ≥48 mmol/mol (6.5%) cut-off may miss almost half of the individuals with T2D based on blood glucose measures.

Adaptor protein complexes and disease at a glance.

Adaptor protein (AP) complexes are heterotetramers that select cargo for inclusion into transport vesicles. Five AP complexes (AP-1 to AP-5) have been described, each with a distinct localisation and function. Furthermore, patients with a range of disorders, particularly involving the nervous system, have now been identified with mutations in each of the AP complexes. In many cases this has been correlated with aberrantly localised membrane proteins. In this Cell Science at a Glance article and the accompanying poster, we summarize what is known about the five AP complexes and discuss how this helps to explain the clinical features of the different genetic disorders.

Role of the AP-5 adaptor protein complex in late endosome-to-Golgi retrieval.

The AP-5 adaptor protein complex is presumed to function in membrane traffic, but so far nothing is known about its pathway or its cargo. We have used CRISPR-Cas9 to knock out the AP-5 ζ subunit gene, AP5Z1, in HeLa cells, and then analysed the phenotype by subcellular fractionation profiling and quantitative mass spectrometry. The retromer complex had an altered steady-state distribution in the knockout cells, and several Golgi proteins, including GOLIM4 and GOLM1, were depleted from vesicle-enriched fractions. Immunolocalisation showed that loss of AP-5 led to impaired retrieval of the cation-independent mannose 6-phosphate receptor (CIMPR), GOLIM4, and GOLM1 from endosomes back to the Golgi region. Knocking down the retromer complex exacerbated this phenotype. Both the CIMPR and sortilin interacted with the AP-5-associated protein SPG15 in pull-down assays, and we propose that sortilin may act as a link between Golgi proteins and the AP-5/SPG11/SPG15 complex. Together, our findings suggest that AP-5 functions in a novel sorting step out of late endosomes, acting as a backup pathway for retromer. This provides a mechanistic explanation for why mutations in AP-5/SPG11/SPG15 cause cells to accumulate aberrant endolysosomes, and highlights the role of endosome/lysosome dysfunction in the pathology of hereditary spastic paraplegia and other neurodegenerative disorders.

Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia.

Bi-allelic loss-of-function variants in genes that encode subunits of the adaptor protein complex 4 (AP-4) lead to prototypical yet poorly understood forms of childhood-onset and complex hereditary spastic paraplegia: SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). Here, we report a detailed cross-sectional analysis of clinical, imaging and molecular data of 156 patients from 101 families. Enrolled patients were of diverse ethnic backgrounds and covered a wide age range (1.0-49.3 years). While the mean age at symptom onset was 0.8 ± 0.6 years [standard deviation (SD), range 0.2-5.0], the mean age at diagnosis was 10.2 ± 8.5 years (SD, range 0.1-46.3). We define a set of core features: early-onset developmental delay with delayed motor milestones and significant speech delay (50% non-verbal); intellectual disability in the moderate to severe range; mild hypotonia in infancy followed by spastic diplegia (mean age: 8.4 ± 5.1 years, SD) and later tetraplegia (mean age: 16.1 ± 9.8 years, SD); postnatal microcephaly (83%); foot deformities (69%); and epilepsy (66%) that is intractable in a subset. At last follow-up, 36% ambulated with assistance (mean age: 8.9 ± 6.4 years, SD) and 54% were wheelchair-dependent (mean age: 13.4 ± 9.8 years, SD). Episodes of stereotypic laughing, possibly consistent with a pseudobulbar affect, were found in 56% of patients. Key features on neuroimaging include a thin corpus callosum (90%), ventriculomegaly (65%) often with colpocephaly, and periventricular white-matter signal abnormalities (68%). Iron deposition and polymicrogyria were found in a subset of patients. AP4B1-associated SPG47 and AP4M1-associated SPG50 accounted for the majority of cases. About two-thirds of patients were born to consanguineous parents, and 82% carried homozygous variants. Over 70 unique variants were present, the majority of which are frameshift or nonsense mutations. To track disease progression across the age spectrum, we defined the relationship between disease severity as measured by several rating scales and disease duration. We found that the presence of epilepsy, which manifested before the age of 3 years in the majority of patients, was associated with worse motor outcomes. Exploring genotype-phenotype correlations, we found that disease severity and major phenotypes were equally distributed among the four subtypes, establishing that SPG47, SPG50, SPG51 and SPG52 share a common phenotype, an 'AP-4 deficiency syndrome'. By delineating the core clinical, imaging, and molecular features of AP-4-associated hereditary spastic paraplegia across the age spectrum our results will facilitate early diagnosis, enable counselling and anticipatory guidance of affected families and help define endpoints for future interventional trials.

Systematic Review and Metaanalysis Comparing the Bias and Accuracy of the Modification of Diet in Renal Disease and Chronic Kidney Disease Epidemiology Collaboration Equations in Community-Based Populations.

BACKGROUND: The majority of patients with chronic kidney disease are diagnosed and monitored in primary care. Glomerular filtration rate (GFR) is a key marker of renal function, but direct measurement is invasive; in routine practice, equations are used for estimated GFR (eGFR) from serum creatinine. We systematically assessed bias and accuracy of commonly used eGFR equations in populations relevant to primary care. CONTENT: MEDLINE, EMBASE, and the Cochrane Library were searched for studies comparing measured GFR (mGFR) with eGFR in adult populations comparable to primary care and reporting both the Modification of Diet in Renal Disease (MDRD) and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations based on standardized creatinine measurements. We pooled data on mean bias (difference between eGFR and mGFR) and on mean accuracy (proportion of eGFR within 30% of mGFR) using a random-effects inverse-variance weighted metaanalysis. We included 48 studies of 26875 patients that reported data on bias and/or accuracy. Metaanalysis of within-study comparisons in which both formulae were tested on the same patient cohorts using isotope dilution-mass spectrometry-traceable creatinine showed a lower mean bias in eGFR using CKD-EPI of 2.2 mL/min/1.73 m2 (95% CI, 1.1-3.2; 30 studies; I2 = 74.4%) and a higher mean accuracy of CKD-EPI of 2.7% (1.6-3.8; 47 studies; I2 = 55.5%). Metaregression showed that in both equations bias and accuracy favored the CKD-EPI equation at higher mGFR values. SUMMARY: Both equations underestimated mGFR, but CKD-EPI gave more accurate estimates of GFR.

Clinical and genetic characterization of AP4B1-associated SPG47.

The hereditary spastic paraplegias (HSPs) are a heterogeneous group of disorders characterized by degeneration of the corticospinal and spinocerebellar tracts leading to progressive spasticity. One subtype, spastic paraplegia type 47 (SPG47 or HSP-AP4B1), is due to bi-allelic loss-of-function mutations in the AP4B1 gene. AP4B1 is a subunit of the adapter protein complex 4 (AP-4), a heterotetrameric protein complex that regulates the transport of membrane proteins. Since 2011, 11 individuals from six families with AP4B1 mutations have been reported, nine of whom had homozygous mutations and were from consanguineous families. Here we report eight patients with AP4B1-associated SPG47, the majority born to non-consanguineous parents and carrying compound heterozygous mutations. Core clinical features in this cohort and previously published patients include neonatal hypotonia that progresses to spasticity, early onset developmental delay with prominent motor delay and severely impaired or absent speech development, episodes of stereotypic laughter, seizures including frequent febrile seizures, thinning of the corpus callosum, and delayed myelination/white matter loss. Given that some of the features of AP-4 deficiency overlap with those of cerebral palsy, and the discovery of the disorder in non-consanguineous populations, we believe that AP-4 deficiency may be more common than previously appreciated.

Recessive loss-of-function mutations in AP4S1 cause mild fever-sensitive seizures, developmental delay and spastic paraplegia through loss of AP-4 complex assembly.

We report two siblings with infantile onset seizures, severe developmental delay and spastic paraplegia, in whom whole-genome sequencing revealed compound heterozygous mutations in the AP4S1 gene, encoding the σ subunit of the adaptor protein complex 4 (AP-4). The effect of the predicted loss-of-function variants (p.Gln46Profs*9 and p.Arg97*) was further investigated in a patient's fibroblast cell line. We show that the premature stop mutations in AP4S1 result in a reduction of all AP-4 subunits and loss of AP-4 complex assembly. Recruitment of the AP-4 accessory protein tepsin, to the membrane was also abolished. In retrospect, the clinical phenotype in the family is consistent with previous reports of the AP-4 deficiency syndrome. Our study reports the second family with mutations in AP4S1 and describes the first two patients with loss of AP4S1 and seizures. We further discuss seizure phenotypes in reported patients, highlighting that seizures are part of the clinical manifestation of the AP-4 deficiency syndrome. We also hypothesize that endosomal trafficking is a common theme between heritable spastic paraplegia and some inherited epilepsies.

Loss of AP-5 results in accumulation of aberrant endolysosomes: defining a new type of lysosomal storage disease.

Adaptor proteins (AP 1-5) are heterotetrameric complexes that facilitate specialized cargo sorting in vesicular-mediated trafficking. Mutations in AP5Z1, encoding a subunit of the AP-5 complex, have been reported to cause hereditary spastic paraplegia (HSP), although their impact at the cellular level has not been assessed. Here we characterize three independent fibroblast lines derived from skin biopsies of patients harbouring nonsense mutations in AP5Z1 and presenting with spastic paraplegia accompanied by neuropathy, parkinsonism and/or cognitive impairment. In all three patient-derived lines, we show that there is complete loss of AP-5 ζ protein and a reduction in the associated AP-5 µ5 protein. Using ultrastructural analysis, we show that these patient-derived lines consistently exhibit abundant multilamellar structures that are positive for markers of endolysosomes and are filled with aberrant storage material organized as exaggerated multilamellar whorls, striated belts and 'fingerprint bodies'. This phenotype can be replicated in a HeLa cell culture model by siRNA knockdown of AP-5 ζ. The cellular phenotype bears striking resemblance to features described in a number of lysosomal storage diseases (LSDs). Collectively, these findings reveal an emerging picture of the role of AP-5 in endosomal and lysosomal homeostasis, illuminates a potential pathomechanism that is relevant to the role of AP-5 in neurons and expands the understanding of recessive HSPs. Moreover, the resulting accumulation of storage material in endolysosomes leads us to propose that AP-5 deficiency represents a new type of LSDs.

Performance of point-of-care HbA1c test devices: implications for use in clinical practice - a systematic review and meta-analysis.

BACKGROUND: Point-of-care (POC) devices could be used to measure hemoglobin A1c (HbA1c) in the doctors' office, allowing immediate feedback of results to patients. Reports have raised concerns about the analytical performance of some of these devices. We carried out a systematic review and meta-analysis using a novel approach to compare the accuracy and precision of POC HbA1c devices. METHODS: Medline, Embase and Web of Science databases were searched in June 2015 for published reports comparing POC HbA1c devices with laboratory methods. Two reviewers screened articles and extracted data on bias, precision and diagnostic accuracy. Mean bias and variability between the POC and laboratory test were combined in a meta-analysis. Study quality was assessed using the QUADAS2 tool. RESULTS: Two researchers independently reviewed 1739 records for eligibility. Sixty-one studies were included in the meta-analysis of mean bias. Devices evaluated were A1cgear, A1cNow, Afinion, B-analyst, Clover, Cobas b101, DCA 2000/Vantage, HemoCue, Innovastar, Nycocard, Quo-Lab, Quo-Test and SDA1cCare. Nine devices had a negative mean bias which was significant for three devices. There was substantial variability in bias within devices. There was no difference in bias between clinical or laboratory operators in two devices. CONCLUSIONS: This is the first meta-analysis to directly compare performance of POC HbA1c devices. Use of a device with a mean negative bias compared to a laboratory method may lead to higher levels of glycemia and a lower risk of hypoglycaemia. The implications of this on clinical decision-making and patient outcomes now need to be tested in a randomized trial.

Adaptor protein complexes AP-4 and AP-5: new players in endosomal trafficking and progressive spastic paraplegia.

The adaptor proteins (APs) are a family of five heterotetrameric complexes with important functions in vesicle trafficking. While the roles of APs 1-3 are broadly established, comparatively little is known about AP-4 and AP-5. Current evidence suggests that AP-4 mediates TGN to endosome transport of specific cargo proteins, such as the amyloid precursor protein APP, and that it is involved in basolateral sorting in polarized cells. Furthermore, several independent studies have reported human patients with mutations in AP-4 genes. AP-4 deficiency causes severe intellectual disability and progressive spastic para- or tetraplegia, supporting an important role for AP-4 in brain function and development. The newly discovered AP-5 complex appears to be involved in endosomal dynamics; its precise localization and function are still unclear. Intriguingly, AP-5 deficiency is also associated with progressive spastic paraplegia, suggesting that AP-5, like AP-4, plays a fundamental role in neuronal development and homeostasis. The unexpected phenotypic parallels between AP-4 and AP-5 patients may in turn suggest a functional relationship of the two APs in vesicle trafficking.

Quantifying the effects of diuretics and ß-adrenoceptor blockers on glycaemic control in diabetes mellitus - a systematic review and meta-analysis.

AIMS: Although there are reports that ß-adrenoceptor antagonists (beta-blockers) and diuretics can affect glycaemic control in people with diabetes mellitus, there is no clear information on how blood glucose concentrations may change and by how much. We report results from a systematic review to quantify the effects of these antihypertensive drugs on glycaemic control in adults with established diabetes. METHODS: We systematically reviewed the literature to identify randomized controlled trials in which glycaemic control was studied in adults with diabetes taking either beta-blockers or diuretics. We combined data on HbA1c and fasting blood glucose using fixed effects meta-analysis. RESULTS: From 3864 papers retrieved, we found 10 studies of beta-blockers and 12 studies of diuretics to include in the meta-analysis. One study included both comparisons, totalling 21 included reports. Beta-blockers increased fasting blood glucose concentrations by 0.64 mmol l(-1) (95% CI 0.24, 1.03) and diuretics by 0.77 mmol l(-1) (95% CI 0.14, 1.39) compared with placebo. Effect sizes were largest in trials of non-selective beta-blockers (1.33, 95% CI 0.72, 1.95) and thiazide diuretics (1.69, 95% CI 0.60, 2.69). Beta-blockers increased HbA1c concentrations by 0.75% (95% CI 0.30, 1.20) and diuretics by 0.24% (95% CI -0.17, 0.65) compared with placebo. There was no significant difference in the number of hypoglycaemic events between beta-blockers and placebo in three trials. CONCLUSIONS: Randomized trials suggest that thiazide diuretics and non-selective beta-blockers increase fasting blood glucose and HbA1c concentrations in patients with diabetes by moderate amounts. These data will inform prescribing and monitoring of beta-blockers and diuretics in patients with diabetes.

Diagnostic accuracy of point-of-care tests for detecting albuminuria: a systematic review and meta-analysis.

BACKGROUND: Experts recommend screening for albuminuria in patients at risk for kidney disease. PURPOSE: To systematically review evidence about the diagnostic accuracy of point-of-care (POC) tests for detecting albuminuria in individuals for whom guidelines recommend such detection. DATA SOURCES: Cochrane Library, EMBASE, Medion database, MEDLINE, and Science Citation Index from 1963 through 5 December 2013; hand searches of other relevant journals; and reference lists. STUDY SELECTION: Cross-sectional studies, published in any language, that compared the accuracy of machine-read POC tests of urinary albumin-creatinine ratio with that of laboratory measurement. DATA EXTRACTION: Two independent reviewers extracted study data and assessed study quality using the QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies 2) tool. DATA SYNTHESIS: Sixteen studies (n = 3356 patients) that evaluated semiquantitative or quantitative POC tests and used random urine samples collected in primary or secondary ambulatory care settings met inclusion criteria. Pooling results from a bivariate random-effects model gave sensitivity and specificity estimates of 76% (95% CI, 63% to 86%) and 93% (CI, 84% to 97%), respectively, for the semiquantitative test. Sensitivity and specificity estimates for the quantitative test were 96% (CI, 78% to 99%) and 98% (CI, 93% to 99%), respectively. The negative likelihood ratios for the semiquantitative and quantitative tests were 0.26 (CI, 0.16 to 0.40) and 0.04 (CI, 0.01 to 0.25), respectively. LIMITATION: Accuracy estimates were based on data from single-sample urine measurement, but guidelines require that diagnosis of albuminuria be based on at least 2 of 3 samples collected in a 6-month period. CONCLUSION: A negative semiquantitative POC test result does not rule out albuminuria, whereas quantitative POC testing meets required performance standards and can be used to rule out albuminuria. PRIMARY FUNDING SOURCE: None.

The fifth adaptor protein complex.

Adaptor protein (AP) complexes sort cargo into vesicles for transport from one membrane compartment of the cell to another. Four distinct AP complexes have been identified, which are present in most eukaryotes. We report the existence of a fifth AP complex, AP-5. Tagged AP-5 localises to a late endosomal compartment in HeLa cells. AP-5 does not associate with clathrin and is insensitive to brefeldin A. Knocking down AP-5 subunits interferes with the trafficking of the cation-independent mannose 6-phosphate receptor and causes the cell to form swollen endosomal structures with emanating tubules. AP-5 subunits can be found in all five eukaryotic supergroups, but they have been co-ordinately lost in many organisms. Concatenated phylogenetic analysis provides robust resolution, for the first time, into the evolutionary order of emergence of the adaptor subunit families, showing AP-3 as the basal complex, followed by AP-5, AP-4, and AP-1 and AP-2. Thus, AP-5 is an evolutionarily ancient complex, which is involved in endosomal sorting, and which has links with hereditary spastic paraplegia.

Incidence of menstrual symptoms suggestive of possible endometriosis in adolescents: and variance in these by ethnicity and socio-economic status.

BACKGROUND: Dysmenorrhoea affects up to 94% of adolescents who menstruate; approximately one third miss school and activities. Dysmenorrhoea can occur without identified pelvic pathology (primary dysmenorrhoea) or in association with other conditions (secondary dysmenorrhoea). In adolescence, the commonest cause of secondary dysmenorrhoea is endometriosis. The incidence of symptoms in adolescence suggesting possible endometriosis has not been previously documented in GP records. AIM: To document incidence of adolescent endometriosis and symptoms associated with endometriosis in English GP records. METHOD: Data from the QResearch primary care database were used for adolescent females aged 10- 19 years between 1 January 2011 and 30 June 2021, reported using descriptive statistics. RESULTS: The population cohort included 2 843 347 female adolescents; 98 887 participants had coded dysmenorrhoea (3.48%) and 1994 (0.07%) had documented endometriosis. The cumulative incidence for the cohort who turned 10 years old in 2011 was 7.2% for dysmenorrhoea and 0.12% for endometriosis. The period prevalence of coded symptoms during adolescence potentially associated with dysmenorrhoea and endometriosis includes: heavy menstrual bleeding (3.73%), irregular menstrual bleeding (2.21%), pelvic pain (0.63%), dyspareunia (0.40%), premenstrual syndrome (PMS)/premenstrual dysphoric disorder (PMDD) (0.22%), cystitis (8.45%), and irritable bowel syndrome (IBS) (1.00%). Disparities in coding were observed for these variables by ethnicity and socioeconomic status. Incidence of prescribed hormonal medication, with and without coded dysmenorrhoea, varied by ethnicity. This was less apparent for non-steroidal anti-inflammatory medications. CONCLUSION: Prevalence of coded dysmenorrhoea in GP records is significantly lower than community surveys suggest; however, adolescent menstrual symptoms are commonly encountered in primary care, and deserve specific guidance and resources. There are demographic patterns, likely structural, that warrant further exploration.

Effectiveness and safety of COVID-19 vaccination in people with blood cancer.

BACKGROUND: People with blood cancer have increased risk of severe COVID-19 outcomes and poor response to vaccination. We assessed the safety and effectiveness of COVID-19 vaccines in this vulnerable group compared to the general population. METHODS: Individuals aged ≥12 years as of 1st December 2020 in the QResearch primary care database were included. We assessed adjusted COVID-19 vaccine effectiveness (aVE) against COVID-19-related hospitalisation and death in people with blood cancer using a nested matched case-control study. Using the self-controlled case series methodology, we compared the risk of 56 pre-specified adverse events within 1-28 days of a first, second or third COVID-19 vaccine dose in people with and without blood cancer. FINDINGS: The cohort comprised 12,274,948 individuals, of whom 81,793 had blood cancer. COVID-19 vaccines were protective against COVID-19-related hospitalisation and death in people with blood cancer, although they were less effective, particularly against COVID-19-related hospitalisation, compared to the general population. In the blood cancer population, aVE against COVID-19-related hospitalisation was 64% (95% confidence interval [CI] 48%-75%) 14-41 days after a third dose, compared to 80% (95% CI 78%-81%) in the general population. Against COVID-19-related mortality, aVE was >80% in people with blood cancer 14-41 days after a second or third dose. We found no significant difference in risk of adverse events 1-28 days after any vaccine dose between people with and without blood cancer. INTERPRETATION: Our study provides robust evidence which supports the use of COVID-19 vaccinations for people with blood cancer.

Safety outcomes following COVID-19 vaccination and infection in 5.1 million children in England.

The risk-benefit profile of COVID-19 vaccination in children remains uncertain. A self-controlled case-series study was conducted using linked data of 5.1 million children in England to compare risks of hospitalisation from vaccine safety outcomes after COVID-19 vaccination and infection. In 5-11-year-olds, we found no increased risks of adverse events 1-42 days following vaccination with BNT162b2, mRNA-1273 or ChAdOX1. In 12-17-year-olds, we estimated 3 (95%CI 0-5) and 5 (95%CI 3-6) additional cases of myocarditis per million following a first and second dose with BNT162b2, respectively. An additional 12 (95%CI 0-23) hospitalisations with epilepsy and 4 (95%CI 0-6) with demyelinating disease (in females only, mainly optic neuritis) were estimated per million following a second dose with BNT162b2. SARS-CoV-2 infection was associated with increased risks of hospitalisation from seven outcomes including multisystem inflammatory syndrome and myocarditis, but these risks were largely absent in those vaccinated prior to infection. We report a favourable safety profile of COVID-19 vaccination in under-18s.

Uptake of COVID-19 vaccination in people with blood cancer: Population-level cohort study of 12 million patients in England.

BACKGROUND: People with blood cancers have increased risk of severe outcomes from COVID-19 and were prioritised for vaccination. METHODS: Individuals in the QResearch database aged 12 years and above on 1st December 2020 were included in the analysis. Kaplan-Meier analysis described time to COVID-19 vaccine uptake in people with blood cancer and other high-risk disorders. Cox regression was used to identify factors associated with vaccine uptake in people with blood cancer. RESULTS: The analysis included 12,274,948 individuals, of whom 97,707 had a blood cancer diagnosis. 92% of people with blood cancer received at least one dose of vaccine, compared to 80% of the general population, but there was lower uptake of each subsequent vaccine dose (31% for fourth dose). Vaccine uptake decreased with social deprivation (HR 0.72, 95% CI 0.70, 0.74 for most deprived versus most affluent quintile for first vaccine). Compared with White groups, uptake of all vaccine doses was significantly lower in people of Pakistani and Black ethnicity, and more people in these groups remain unvaccinated. CONCLUSIONS: COVID-19 vaccine uptake declines following second dose and there are ethnic and social disparities in uptake in blood cancer populations. Enhanced communication of benefits of vaccination to these groups is needed.