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.

Stable endocytic structures navigate the complex pellicle of apicomplexan parasites.

Apicomplexan parasites have immense impacts on humanity, but their basic cellular processes are often poorly understood. Where endocytosis occurs in these cells, how conserved this process is with other eukaryotes, and what the functions of endocytosis are across this phylum are major unanswered questions. Using the apicomplexan model Toxoplasma, we identified the molecular composition and behavior of unusual, fixed endocytic structures. Here, stable complexes of endocytic proteins differ markedly from the dynamic assembly/disassembly of these machineries in other eukaryotes. We identify that these endocytic structures correspond to the 'micropore' that has been observed throughout the Apicomplexa. Moreover, conserved molecular adaptation of this structure is seen in apicomplexans including the kelch-domain protein K13 that is central to malarial drug-resistance. We determine that a dominant function of endocytosis in Toxoplasma is plasma membrane homeostasis, rather than parasite nutrition, and that these specialized endocytic structures originated early in infrakingdom Alveolata likely in response to the complex cell pellicle that defines this medically and ecologically important ancient eukaryotic lineage.

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.

Quality of life in older adults with chronic kidney disease and transient changes in renal function: Findings from the Oxford Renal cohort.

BACKGROUND: Quality of life (QoL) is an important measure of disease burden and general health perception. The relationship between early chronic kidney disease (CKD) and QoL remains poorly understood. The Oxford Renal Study (OxRen) cohort comprises 1063 adults aged ≥60 years from UK primary care practices screened for early CKD, grouped according to existing or screen-detected CKD diagnoses, or biochemistry results indicative of reduced renal function (referred to as transient estimated glomerular filtration rate (eGFR) reduction). OBJECTIVES: This study aimed to compare QoL in participants known to have CKD at recruitment to those identified as having CKD through a screening programme. METHODS: Health profile data and multi-attribute utility scores were reported for two generic questionnaires: 5-level EuroQol-5 Dimension (EQ-5D-5L) and ICEpop CAPability measure for Adults (ICECAP-A). QoL was compared between patients with existing and screen-detected CKD; those with transient eGFR reduction served as the reference group in univariable and multivariable linear regression. RESULTS: Mean and standard deviation utility scores were not significantly different between the subgroups for EQ-5D-5L (screen-detected:0.785±0.156, n = 480, transient:0.779±0.157, n = 261, existing CKD:0.763±0.171, n = 322, p = 0.216) or ICECAP-A (screen-detected:0.909±0.094, transient:0.904±0.110, existing CKD:0.894±0.115, p = 0.200). Age, smoking status, and number of comorbidities were identified as independent predictors of QoL in this cohort. CONCLUSION: QoL of participants with existing CKD diagnoses was not significantly different from those with screen-detected CKD or transient eGFR reduction and was similar to UK mean scores for the same age, suggesting that patient burden of early CKD is minor. Moreover, CKD-related comorbidities contribute more significantly to disease burden in earlier stages of CKD than renal function per se. Larger prospective studies are required to define the relationship between QoL and CKD progression more precisely. These data also confirm the essentially asymptomatic nature of CKD, implying that routine screening or case finding are required to diagnose it.

Comparative efficacy and safety of the artemisinin derivatives compared to quinine for treating severe malaria in children and adults: A systematic update of literature and network meta-analysis.

BACKGROUND: The artemisinin derivatives are the preferred antimalaria drugs for treating severe Plasmodium falciparum malaria. However, their clinical effectiveness compared to each other is unknown. Our objective, therefore, was to evaluate the efficacy and safety of the artemisinin derivatives and quinine for treating severe P. falciparum malaria in children and adults using a network meta-analysis. METHODS AND FINDINGS: Review protocol was registered with PROSPERO, CRD42020218190. We updated the search strategies of three Cochrane systematic reviews which included published and unpublished randomised control trials (RCTs) that have compared specific artemisinin derivatives to quinine in treating severe malaria. Search included CENTRAL, MEDLINE, Embase, LILACS, ISI Web of Science and trial registries up to February 2021. We screened studies, extracted data, assessed risk of bias, and quality of evidence in duplicate. Separate network meta-analyses in the frequentist framework, using a random effects model, with quinine as reference, were conducted for adults and children, and rankings were produced using p-scores to assess mortality, parasite clearance, coma recovery, fever clearance, neurological sequela and adverse events. Searches identified 818 citations, 33 RCTs were eligible. We pooled 7795 children and 3182 adults. The networks involved artesunate, artemether, rectal artemisinin, arteether and quinine. Compared to quinine, artesunate reduced mortality in children (risk ratio (RR), 0.76; 95%CI [0.65 to 0.89], moderate quality), adults (RR, 0.55; 95%CI [0.40 to 0.75], moderate quality) and in cerebral malaria (RR, 0.72; 95%CI [0.55 to 0.94], moderate quality). Compared to rectal artemisinin and intramuscular arteether, the efficacy and safety of parenteral artesunate, and intramuscular artemether in treating severe malaria are not clear. Rankings showed that none of the artemisinin drugs were consistently superior in all the outcomes assessed. Indirect evidence produced were of very low ratings due to suspected publication bias and imprecision. CONCLUSIONS: Artesunate reduces mortality compared to quinine for both adults and children in Asia and Africa including cerebral malaria. The artemisinin derivatives remain the best treatment for severe malaria but their comparative clinical effectiveness is yet to be fully explored.

Change in glomerular filtration rate over time in the Oxford Renal Cohort Study: observational study.

BACKGROUND: Decline in kidney function can result in adverse health outcomes. The Oxford Renal Cohort Study has detailed baseline assessments from 884 participants ≥60 years of age. AIM: To determine the proportion of participants with a decline in estimated glomerular filtration rate (eGFR), identify determinants of decline, and determine proportions with chronic kidney disease (CKD) remission. DESIGN AND SETTING: Observational cohort study in UK primary care. METHOD: Data were used from baseline and annual follow-up assessments to monitor change in kidney function. Rapid eGFR decline was defined as eGFR decrease >5 ml/min/1.73 m2/year, improvement as eGFR increase >5 ml/min/1.73 m2/year, and remission in those with CKD at baseline and eGFR >60 ml/min/1.73 m2 during follow-up. Cox proportional hazard models were used to identify factors associated with eGFR decline. RESULTS: There was a net decline in eGFR in the 884 participants over 5 years of follow-up. In 686 participants with >2 eGFR tests with a median follow-up of 2.1 years, 164 (24%) evidenced rapid GFR decline, 185 (27%) experienced eGFR improvement, and 82 of 394 (21%) meeting CKD stage 1-4 at baseline experienced remission. In the multivariable analysis, smoking status, higher systolic blood pressure, and being known to have CKD at cohort entry were associated with rapid GFR decline. Those with CKD stage 3 at baseline were less likely to exhibit GFR decline compared with normal kidney function. CONCLUSION: This study established that 24% of people evidenced rapid GFR decline whereas 21% evidenced remission of CKD. People at risk of rapid GFR decline may benefit from closer monitoring and appropriate treatment to minimise risks of adverse outcomes, although only a small proportion meet the National Institute for Health and Care Excellence criteria for referral to secondary care.

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.

Feasibility and Acceptability of Community Coronavirus Disease 2019 Testing Strategies (FACTS) in a University Setting.

BACKGROUND: During the coronavirus disease 2019 (COVID-19) pandemic in 2020, the UK government began a mass severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing program. This study aimed to determine the feasibility and acceptability of organized regular self-testing for SARS-CoV-2. METHODS: This was a mixed-methods observational cohort study in asymptomatic students and staff at University of Oxford, who performed SARS-CoV-2 antigen lateral flow self-testing. Data on uptake and adherence, acceptability, and test interpretation were collected via a smartphone app, an online survey, and qualitative interviews. RESULTS: Across 3 main sites, 551 participants (25% of those invited) performed 2728 tests during a follow-up of 5.6 weeks; 447 participants (81%) completed at least 2 tests, and 340 (62%) completed at least 4. The survey, completed by 214 participants (39%), found that 98% of people were confident to self-test and believed self-testing to be beneficial. Acceptability of self-testing was high, with 91% of ratings being acceptable or very acceptable. A total of 2711 (99.4%) test results were negative, 9 were positive, and 8 were inconclusive. Results from 18 qualitative interviews with students and staff revealed that participants valued regular testing, but there were concerns about test accuracy that impacted uptake and adherence. CONCLUSIONS: This is the first study to assess feasibility and acceptability of regular SARS-CoV-2 self-testing. It provides evidence to inform recruitment for, adherence to, and acceptability of regular SARS-CoV-2 self-testing programs for asymptomatic individuals using lateral flow tests. We found that self-testing is acceptable and people were able to interpret results accurately.

High-throughput imaging of ATG9A distribution as a diagnostic functional assay for adaptor protein complex 4-associated hereditary spastic paraplegia.

Adaptor protein complex 4-associated hereditary spastic paraplegia is caused by biallelic loss-of-function variants in AP4B1, AP4M1, AP4E1 or AP4S1, which constitute the four subunits of this obligate complex. While the diagnosis of adaptor protein complex 4-associated hereditary spastic paraplegia relies on molecular testing, the interpretation of novel missense variants remains challenging. Here, we address this diagnostic gap by using patient-derived fibroblasts to establish a functional assay that measures the subcellular localization of ATG9A, a transmembrane protein that is sorted by adaptor protein complex 4. Using automated high-throughput microscopy, we determine the ratio of the ATG9A fluorescence in the trans-Golgi-network versus cytoplasm and ascertain that this metric meets standards for screening assays (Z'-factor robust >0.3, strictly standardized mean difference >3). The 'ATG9A ratio' is increased in fibroblasts of 18 well-characterized adaptor protein complex 4-associated hereditary spastic paraplegia patients [mean: 1.54 ± 0.13 versus 1.21 ± 0.05 (standard deviation) in controls] and receiver-operating characteristic analysis demonstrates robust diagnostic power (area under the curve: 0.85, 95% confidence interval: 0.849-0.852). Using fibroblasts from two individuals with atypical clinical features and novel biallelic missense variants of unknown significance in AP4B1, we show that our assay can reliably detect adaptor protein complex 4 function. Our findings establish the 'ATG9A ratio' as a diagnostic marker of adaptor protein complex 4-associated hereditary spastic paraplegia.

Perceptions on undertaking regular asymptomatic self-testing for COVID-19 using lateral flow tests: a qualitative study of university students and staff.

OBJECTIVES: Successful implementation of asymptomatic testing programmes using lateral flow tests (LFTs) depends on several factors, including feasibility, acceptability and how people act on test results. We aimed to examine experiences of university students and staff of regular asymptomatic self-testing using LFTs, and their subsequent behaviours. DESIGN AND SETTING: A qualitative study using semistructured remote interviews and qualitative survey responses, which were analysed thematically. PARTICIPANTS: People who were participating in weekly testing feasibility study, between October 2020 and January 2021, at the University of Oxford. RESULTS: We interviewed 18 and surveyed 214 participants. Participants were motivated to regularly self-test as they wanted to know whether or not they were infected with SARS-CoV-2. Most reported that a negative test result did not change their behaviour, but it did provide them with reassurance to engage with permitted activities. In contrast, some participants reported making decisions about visiting other people because they felt reassured by a negative test result. Participants valued the training but some still doubted their ability to carry out the test. Participants were concerned about safety of attending test sites with lots of people and reported home testing was most convenient. CONCLUSIONS: Clear messages highlighting the benefits of regular testing for family, friends and society in identifying asymptomatic cases are needed. This should be coupled with transparent communication about the accuracy of LFTs and how to act on either a positive or negative result. Concerns about safety, convenience of testing and ability to do tests need to be addressed to ensure successful scaling up of asymptomatic testing.

Point-of-care HbA1c testing in an urban primary care diabetes clinic in South Africa: a mixed methods feasibility study.

INTRODUCTION: Monitoring and treatment of type 2 diabetes in South Africa usually takes place in primary care using random blood glucose testing to guide treatment decisions. This study explored the feasibility of using point-of-care haemoglobin A1c (HbA1c) testing in addition to glucose testing in a busy primary care clinic in Cape Town, South Africa. SUBJECTS: 185 adults aged 19-88 years with type 2 diabetes. MATERIALS AND METHODS: Participants recruited to this mixed methods cohort study received a point-of-care HbA1c test. Doctors were asked to use the point-of-care HbA1c result for clinical decision-making. Qualitative interviews were held with clinical staff. RESULTS: Point-of-care HbA1c test results were obtained for 165 participants of whom 109 (65%) had poor glycaemic control (>8% HbA1c, 64 mmol/mol). Medical officers reported using a combination of HbA1c and blood glucose 77% of the time for clinical decision-making. Nurses found the analyser easy to use and doctors valued having the HbA1c result to help with decision-making. DISCUSSION: Our results suggest that 30% of patients may have received inappropriate medication or not received necessary additional medication if random blood glucose alone had been used in routine appointments. Clinicians valued having access to the HbA1c test result to help them make treatment decisions.

Prevalence and factors associated with multimorbidity among primary care patients with decreased renal function.

OBJECTIVES: To establish the prevalence of multimorbidity in people with chronic kidney disease (CKD) stages 1-5 and transiently impaired renal function and identify factors associated with multimorbidity. DESIGN AND SETTING: Prospective cohort study in UK primary care. PARTICIPANTS: 861 participants aged 60 and older with decreased renal function of whom, 584 (65.8%) had CKD and 277 (32.2%) did not have CKD. INTERVENTIONS: Participants underwent medical history and clinical assessment, and blood and urine sampling. PRIMARY AND SECONDARY OUTCOME MEASURES: Multimorbidity was defined as presence of ≥2 chronic conditions including CKD. Prevalence of each condition, co-existing conditions and multimorbidity were described and logistic regression was used to identify predictors of multimorbidity. RESULTS: The mean (±SD) age of participants was 74±7 years, 54% were women and 98% were white. After CKD, the next most prevalent condition was hypertension (n = 511, 59.3%), followed by obesity (n = 265, 30.8%) ischemic heart disease (n = 145, 16.8%) and diabetes (n = 133, 15.4%). Having two co-existing conditions was most common (27%), the most common combination of which was hypertension and obesity (29%). One or three conditions was the next most prevalent combination (20% and 21% respectively). The prevalence of multimorbidity was 73.9% (95%CI 70.9-76.8) in all participants and 86.6% (95%CI 83.9-89.3) in those with any-stage CKD. Logistic regression found a significant association between increasing age (OR 1.07, 95%CI 1.04-0.10), increasing BMI (OR 1.15, 95%CI 1.10-1.20) and decreasing eGFR (OR 0.99, 95%CI 0.98-1.00) with multimorbidity. CONCLUSIONS: This analysis is the first to provide an accurate estimate of the prevalence of multimorbidity in a screened older primary care population living with or at risk of CKD across all stages. Hypertension and obesity were the most common combination of conditions other than CKD that people were living with, suggesting that there may be multiple reasons for closely monitoring health status in individuals with CKD.

Rag GTPases and phosphatidylinositol 3-phosphate mediate recruitment of the AP-5/SPG11/SPG15 complex.

Adaptor protein complex 5 (AP-5) and its partners, SPG11 and SPG15, are recruited onto late endosomes and lysosomes. Here we show that recruitment of AP-5/SPG11/SPG15 is enhanced in starved cells and occurs by coincidence detection, requiring both phosphatidylinositol 3-phosphate (PI3P) and Rag GTPases. PI3P binding is via the SPG15 FYVE domain, which, on its own, localizes to early endosomes. GDP-locked RagC promotes recruitment of AP-5/SPG11/SPG15, while GTP-locked RagA prevents its recruitment. Our results uncover an interplay between AP-5/SPG11/SPG15 and the mTORC1 pathway and help to explain the phenotype of AP-5/SPG11/SPG15 deficiency in patients, including the defect in autophagic lysosome reformation.

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.

Loss of ap4s1 in zebrafish leads to neurodevelopmental defects resembling spastic paraplegia 52.

Autosomal recessive spastic paraplegia 52 is caused by biallelic mutations in AP4S1 which encodes a subunit of the adaptor protein complex 4 (AP-4). Using next-generation sequencing, we identified three novel unrelated SPG52 patients from a cohort of patients with cerebral palsy. The discovered variants in AP4S1 lead to reduced AP-4 complex formation in patient-derived fibroblasts. To further understand the role of AP4S1 in neuronal development and homeostasis, we engineered the first zebrafish model of AP-4 deficiency using morpholino-mediated knockdown of ap4s1. In this model, we discovered several phenotypes mimicking SPG52, including altered CNS development, locomotor deficits, and abnormal neuronal excitability.

Prevalence of chronic kidney disease in the community using data from OxRen: a UK population-based cohort study.

BACKGROUND: Chronic kidney disease (CKD) is a largely asymptomatic condition of diminished renal function, which may not be detected until advanced stages without screening. AIM: To establish undiagnosed and overall CKD prevalence using a cross-sectional analysis. DESIGN AND SETTING: Longitudinal cohort study in UK primary care. METHOD: Participants aged ≥60 years were invited to attend CKD screening visits to determine whether they had reduced renal function (estimated glomerular filtration rate [eGFR] <60 ml/min/1.73 m2 or albumin:creatinine ratio ≥3 mg/mmol). Those with existing CKD, low eGFR, evidence of albuminuria, or two positive screening tests attended a baseline assessment (CKD cohort). RESULTS: A total of 3207 participants were recruited and 861 attended the baseline assessment. The CKD cohort consisted of 327 people with existing CKD, 257 people with CKD diagnosed through screening (CKD prevalence of 18.2%, 95% confidence interval [CI] = 16.9 to 19.6), and 277 with borderline/transient decreased renal function. In the CKD cohort, 54.4% were female, mean standard deviation (SD) age was 74.0 (SD 6.9) years, and mean eGFR was 58.0 (SD 18.4) ml/min/1.73 m2. Of the 584 with confirmed CKD, 44.0% were diagnosed through screening. Over half of the CKD cohort (51.9%, 447/861) fell into CKD stages 3-5 at their baseline assessment, giving an overall prevalence of CKD stages 3-5 of 13.9% (95% CI = 12.8 to 15.1). More people had reduced eGFR using the Modification of Diet in Renal Disease (MDRD) equation than with CKD Epidemiology Collaboration (CKD-EPI) equation in the 60-75-year age group and more had reduced eGFR using CKD-EPI in the ≥80-year age group. CONCLUSION: This study found that around 44.0% of people living with CKD are undiagnosed without screening, and prevalence of CKD stages 1-5 was 18.2% in participants aged >60 years. Follow-up will provide data on annual incidence, rate of CKD progression, determinants of rapid progression, and predictors of cardiovascular events.

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.

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.

Efficacy of population-wide diabetes and obesity prevention programs: An overview of systematic reviews on proximal, intermediate, and distal outcomes and a meta-analysis of impact on BMI.

We conducted an overview of systematic reviews and a meta-analysis of the impact on body mass index (BMI) of primary studies of population-wide obesity and diabetes prevention programs, in order to evaluate their efficacy. We searched eight databases for reviews of population-level programs reporting effect on diet, physical activity, BMI, or prevalence of obesity/overweight or type 2 diabetes mellitus (T2DM). Meta-analysis of primary studies within reviews reporting effect on BMI. Interventions were categorized using ANGELO framework and quality assessment using AMSTAR. Fifty-three systematic reviews were included. Primary studies were largely natural experiments or cross-sectional studies of national data. Increased price of sugar-sweetened beverages (SSBs) and fast food, decreased price of fruit and vegetables, food labelling, and grocery store interventions were associated with positive effects on diet. Park and playground renovations and point-of-choice prompts to increase stair use were associated with positive effects on physical activity. Increased price of SSBs, menu labelling, grocery store interventions, and multicomponent interventions were associated with small reductions in BMI. There was insufficient evidence of impact of any interventions on the prevalence of overweight, obesity, or T2DM. We have identified a promising suite of population-wide actions to improve diet, increase physical activity, and reduce BMI. Impact on subsequent incidence of T2DM remains speculative.