The long-term impact of vaginal surgical mesh devices on pain clinic and psychological service referrals, anti-inflammatory testing and pelvic scans in UK primary care: A cohort study with the Clinical Practice Research Datalink.

OBJECTIVE: To examine long-term complications in women with stress urinary incontinence (SUI) and pelvic organ prolapse (POP), with and without surgical mesh implants. DESIGN: Longitudinal open cohort study from 1 April 2006 (or 1 April 2012) to 30 November 2018. SETTING: The Clinical Practice Research Datalink (CPRD) Gold database, which is linked to Hospital Episodes Statistics (HES) inpatient data, the HES Diagnostic Imaging Dataset (DID), Office for National Statistics mortality data and Index of Multiple Deprivation socio-economic status data. SAMPLE: Women aged ≥18 years with a diagnostic SUI/POP Read code. METHODS: Rates are estimated using negative binomial regression. MAIN OUTCOME MEASURES: Rates of referrals for: psychological and pain services; urinalysis, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) testing; and pelvic ultrasound, computed tomography (CT) and magnetic resonance imaging (MRI) scans. RESULTS: A cohort of 220 544 women were eligible for inclusion; 74% (n = 162 687) had SUI, 37% (n = 82 123) had POP and 11% (n = 24 266) had both. Rates of psychological referrals and CT scans were lower in women with SUI mesh surgery, but this was offset by higher rates of CRP testing in women with SUI or POP mesh, MRI scans in women with SUI mesh, and urinalysis testing and referrals to pain clinics for women with POP mesh. CONCLUSIONS: Our results suggest a higher burden of morbidity in women with SUI/POP mesh surgery, and that these women may require ongoing follow-up in the primary care setting.

The impact of vaginal surgical mesh devices on consultation rates by type and health care provider in UK primary care: A cohort study in the Clinical Practice Research Datalink.

OBJECTIVES: To examine consultation rates by type of consultation and health care provider in women with stress urinary incontinence (SUI) and/or pelvic organ prolapse (POP), with and without surgical mesh implants. STUDY DESIGN: Longitudinal open cohort study from April 2006 to November 2018 in the Clinical Practice Research Datalink (CPRD). MAIN OUTCOME MEASURES: Rates of consultations with general practitioners (GPs), nurses, other clinicians and administrators by consultation type (face-to-face, telephone or administrative), and types of administrative consultations, estimated using negative binomial regression. RESULTS: Of 220,544 women eligible for inclusion, 74 % (n = 162,687) had SUI, 37 % (n = 82,123) had POP, and 11 % (n = 24,266) had both. Face-to-face consultation rates were stable over time, at about 9 per year. Administrative consultations with GPs and administrators increased between 2006 and 2018, but averaged 31 per year. After adjustment, for both SUI and POP mesh surgery, there were lower rates of face-to-face consultations with GPs, higher rates of face-to-face consultations with other clinicians, higher rates of telephone consultations with GPs and other clinicians, and higher rates of administrative consultations with GPs, nurses and administrators. The higher rate of consultations with GPs coded as administrative consisted of results recording and administrative codes, and the higher rates of consultations with administrators were coded as repeat issue, other, administration and third-party consultations. CONCLUSIONS: Caring for women with mesh places a higher administrative burden on GPs and administrators. There may be potential to reduce this workload through a more streamlined care pathway.

Association between disability status and health care utilisation for common childhood illnesses in 10 countries in sub-Saharan Africa: a cross-sectional study in the Multiple Indicator Cluster Survey.

Background: Approximately 70 million children in sub-Saharan Africa (SSA) are disabled, yet little is known about the prevalence of and care-seeking patterns for common childhood illnesses, such as acute respiratory infection (ARI), diarrhoea, and fever. Methods: Data were from 10 SSA countries with data available from 2017 to 2020 in the UNICEF-supported Multiple Indicator Cluster Survey (MICS) online repository. Children aged 2-4 years who completed the child functioning module were included. Using logistic regression, we examined the association between disability and ARI, diarrhoea and fever in the past two weeks and care-seeking behaviour for these illnesses. Using multinomial logistic regression, we examined the association between disability and the type of health care providers from which caregivers sought care. Findings: There were 51,901 children included. Overall, there were small absolute differences in illnesses between disabled and non-disabled children. However, there was evidence disabled children had a greater odds of ARI (aOR = 1.33, 95% C.I 1.16-1.52), diarrhoea (aOR = 1.27, 95% C.I. 1.12-1.44), and fever (aOR = 1.19 95% CI 1.06-1.35) compared to non-disabled children. There was no evidence that caregivers of disabled children had a greater odds of seeking care for ARI (aOR = 0.90, 95% C.I 0.69-1.19), diarrhoea (aOR = 1.06, 95% C.I. 0.84-1.34), and fever (aOR = 1.07, 95% C.I 0.88-1.30) compared to caregivers of non-disabled children. Caregivers of disabled children had a higher odds of seeking care from a trained health worker for ARI (aOR = 1.76, 95% C.I. 1.25-2.47) and fever (aOR = 1.49, 95% C.I. 1.03-2.14) or non-health professional (aOR = 1.89, 95% C.I. 1.19-2.98) for ARI than from an unspecified health facility worker compared to caregivers of non-disabled children, but no associations were not seen for diarrhoea. Interpretation: While the data showed relatively small absolute differences, disability was associated with ARI, diarrhoea and fever and caregivers of disabled children sought care from trained health workers for ARI and fever more than non-disabled children. The overall small absolute differences show closing gaps in illness and access to care may be possible, but highlights that more research on illness severity, care quality, and outcomes should be conducted to further assess health inequities for disabled children. Funding: SR receives funding from the Rhodes Trust.

U8 variants on the brain: a small nucleolar RNA and human disease.

Small nucleolar RNAs (snoRNAs) are non-coding RNAs vital for ribosomal RNA (rRNA) maturation. The U8 snoRNA, encoded by the SNORD118 gene in humans, is an atypical C/D box snoRNA as it promotes rRNA cleavage rather than 2'-O-methylation and is unique to vertebrates. The U8 snoRNA is critical for cleavage events that produce the mature 5.8S and 28S rRNAs of the large ribosomal subunit. Unexpectedly, single nucleotide polymorphisms (SNPs) in the SNORD118 gene were recently found causal to the neurodegenerative disease leukoencephalopathy, brain calcifications, and cysts (LCC; aka Labrune syndrome), but its molecular pathogenesis is unclear. Here, we will review current knowledge on the function of the U8 snoRNA in ribosome biogenesis, and connect it to the preservation of brain function in humans as well as to its dysregulation in inherited white matter disease.

Blood eosinophils to guide inhaled maintenance therapy in a primary care COPD population.

Blood eosinophils are a potentially useful biomarker for guiding inhaled corticosteroid (ICS) treatment decisions in COPD. We investigated whether existing blood eosinophil counts predict benefit from initiation of ICS compared to bronchodilator therapy. We used routinely collected data from UK primary care in the Clinical Practice Research Datalink. Participants were aged ≥40 years with COPD, were ICS-naïve and starting a new inhaled maintenance medication (intervention group: ICS; comparator group: long-acting bronchodilator, non-ICS). Primary outcome was time to first exacerbation, compared between ICS and non-ICS groups, stratified by blood eosinophils ("high" ≥150 cells·µL-1 and "low" <150 cells·µL-1). Out of 9475 eligible patients, 53.9% initiated ICS and 46.1% non-ICS treatment with no difference in eosinophils between treatment groups (p=0.71). Exacerbation risk was higher in patients prescribed ICS than those prescribed non-ICS treatment, but with a lower risk in those with high eosinophils (hazard ratio (HR) 1.04, 95% CI 0.98-1.10) than low eosinophils (HR 1.19, 95% CI 1.09-1.31) (p-value for interaction 0.01). Risk of pneumonia hospitalisation with ICS was greatest in those with low eosinophils (HR 1.26, 95% CI 1.05-1.50; p-value for interaction 0.04). Results were similar whether the most recent blood eosinophil count or the mean of blood eosinophil counts was used. In a primary care population, the most recent blood eosinophil count could be used to guide initiation of ICS in COPD patients. We suggest that ICS should be considered in those with higher eosinophils and avoided in those with lower eosinophils (<150 cells·µL-1).

Disability training for health workers: A global evidence synthesis.

BACKGROUND: Health worker training on disability is a recognized component of achieving high standards of health for people with disabilities, given that health worker's lack of knowledge, stigma, and negative attitudes towards people with disabilities act as barriers to high quality health care. OBJECTIVE: To understand the published literature on training health workers about disability. METHODS: We searched five databases for relevant peer-reviewed articles published between January 2012 and January 2021. Studies that focused on training health care workers to improve knowledge, confidence, self-efficacy, and competence to support people with physical, sensory, or intellectual impairments were included. Data about the details of the intervention (setting, participants, format, impact assessments, etc.) and its effects were extracted. RESULTS: There is an array of highly local tools to train health workers across stages of their training and careers (preservice, in-service, and continuing professional development). Studies involving people with disabilities in the training, community placements, simulations, or interactive sessions were found to be most effective in improving knowledge, confidence, competency, and self-efficacy. CONCLUSIONS: As part of initiatives to build inclusive health systems and improve health outcomes for people with disabilities, health workers around the world need to receive appropriate and evidence-based training that combines multiple methods and involves people with disabilities. To monitor progress on the impact of training, there should also be a standardized measure of impact on core outcomes.

A novel non-viral delivery method that enables efficient engineering of primary human T cells for ex vivo cell therapy applications.

BACKGROUND AIMS: Next-generation immune cell therapy products will require complex modifications using engineering technologies that can maintain high levels of cell functionality. Non-viral engineering methods have the potential to address limitations associated with viral vectors. However, while electroporation is the most widely used non-viral modality, concerns about its effects on cell functionality have led to the exploration of alternative approaches. Here the authors have examined the suitability of the Solupore non-viral delivery system for engineering primary human T cells for cell therapy applications. METHODS: The Solupore system was used to deliver messenger RNA (mRNA) and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) guide RNA ribonucleoprotein (RNP) cargos to T cells, and efficiency was measured by flow cytometry. Cell perturbation was assessed by immune gene expression profiling, including an electroporation comparator. In vitro and in vivo cytotoxicity of chimeric antigen receptor (CAR) T cells generated using the Solupore system was evaluated using a real-time cellular impedance assay and a Raji-luciferase mouse tumor model, respectively. RESULTS: Efficient transfection was demonstrated through delivery of mRNA and CRISPR CAS9 RNP cargos individually, simultaneously and sequentially using the Solupore system while consistently maintaining high levels of cell viability. Gene expression profiling revealed minimal alteration in immune gene expression, demonstrating the low level of perturbation experienced by the cells during this transfection process. By contrast, electroporation resulted in substantial changes in immune gene expression in T cells. CAR T cells generated using the Solupore system exhibited efficient cytotoxicity against target cancer cells in vitro and in vivo. CONCLUSIONS: The Solupore system is a non-viral means of simply, rapidly and efficiently delivering cargos to primary human immune cells with retention of high cell viability and functionality.

The Long-Term Impact of Vaginal Surgical Mesh Devices in UK Primary Care: A Cohort Study in the Clinical Practice Research Datalink.

PURPOSE: Stress urinary incontinence (SUI) and pelvic organ prolapse (POP) may be treated with surgical mesh devices; evidence of their long-term complications is lacking. PATIENTS AND METHODS: Rates of diagnoses of depression, anxiety or self-harm (composite measure) and sexual dysfunction, and rates of prescriptions for antibiotics and opioids were estimated in women with and without mesh surgery, with a diagnostic SUI/POP code, registered in the Clinical Practice Research Datalink (CPRD) gold database. RESULTS: There were 220,544 women eligible for inclusion; 74% (n = 162,687) had SUI, 37% (n = 82,123) had POP, and 11% (n = 24,266) had both. Women undergoing mesh surgery for SUI or POP had about 1.1 times higher rates of antibiotic use. Women with no previous history of the outcome, who underwent mesh surgery had 2.43 (95% CI 2.19-2.70) and 1.47 (95% CI 1.19-1.81) times higher rates of depression, anxiety, or self-harm, 1.88 (95% CI 1.50-2.36) and 1.64 (95% CI 1.02-2.63) times higher rates of sexual dysfunction and 1.40 (95% CI 1.26-1.56) and 1.23 (95% CI 1.01-1.49) times higher opioid use for SUI and POP, respectively. Women with a history of depression, anxiety and self-harm had 0.3 times lower rates of these outcomes with SUI or POP mesh surgery (HR for SUI 0.70 (95% CI 0.67-0.73), HR for POP 0.72 (95% CI 0.65-0.79)). Women with a history of opioid use who had POP mesh surgery had about 0.09 times lower rates (HR 0.91 (95% CI 0.86-0.96)) of prescriptions. Negative control outcome analyses showed no evidence of an association between asthma consultations and mesh surgery in women with POP, but the rate was 0.09 times lower (HR 0.91 (95% CI 0.87-0.94)) in women with SUI mesh surgery, suggesting that study results are subject to some residual confounding. CONCLUSION: Mesh surgery was associated with poor mental and sexual health outcomes, alongside increased opioid and antibiotic use, in women with no history of these outcomes and improved mental health, and lower opioid use, in women with a previous history of these outcomes. Although our results suggest an influence of residual confounding, careful consideration of the benefits and risk of mesh surgery for women with SUI or POP on an individual basis is required.

Do depressive symptoms and subjective well-being influence the valence or visual perspective of autobiographical memories in young adults?

The present study examines predictors of autobiographical memory valence and visual perspective. Participants (N = 144) between the ages of 18-35 years completed an online survey assessing depressive symptoms, and different aspects of subjective well-being (i.e., life satisfaction, positive affect, and negative affect). Participants retrieved six autobiographical memories cued via positive, negative, and neutral words and completed a questionnaire assessing characteristics of the memories, including memory valence and visual perspective. Using structural equation modelling, we found that the valence of neutral cued memories were significantly negatively associated with depressive symptoms and negative affect, and significantly positively associated with life satisfaction, even after controlling for current mood. Depressive symptoms were generally not significantly related to visual perspective. These results support previous findings that depressive symptoms and well-being are related to differences in memory characteristics but suggest that some of the relationships may be less robust when examined in a non-clinical sample.

Correction to: Timing of pubertal stages and breast cancer risk: the Breakthrough Generations Study.

As a consequence of responding to colleagues who asked about the publication of the original article [1], the authors have determined that the data published in Table 4 of the paper are incorrect.

Trends in kidney function testing in UK primary care since the introduction of the quality and outcomes framework: a retrospective cohort study using CPRD.

OBJECTIVES: To characterise serum creatinine and urinary protein testing in UK general practices from 2005 to 2013 and to examine how the frequency of testing varies across demographic factors, with the presence of chronic conditions and with the prescribing of drugs for which kidney function monitoring is recommended. DESIGN: Retrospective open cohort study. SETTING: Routinely collected data from 630 UK general practices contributing to the Clinical Practice Research Datalink. PARTICIPANTS: 4 573 275 patients aged over 18 years registered at up-to-standard practices between 1 April 2005 and 31 March 2013. At study entry, no patients were kidney transplant donors or recipients, pregnant or on dialysis. PRIMARY OUTCOME MEASURES: The rate of serum creatinine and urinary protein testing per year and the percentage of patients with isolated and repeated testing per year. RESULTS: The rate of serum creatinine testing increased linearly across all age groups. The rate of proteinuria testing increased sharply in the 2009-2010 financial year but only for patients aged 60 years or over. For patients with established chronic kidney disease (CKD), creatinine testing increased rapidly in 2006-2007 and 2007-2008, and proteinuria testing in 2009-2010, reflecting the introduction of Quality and Outcomes Framework indicators. In adjusted analyses, CKD Read codes were associated with up to a twofold increase in the rate of serum creatinine testing, while other chronic conditions and potentially nephrotoxic drugs were associated with up to a sixfold increase. Regional variation in serum creatinine testing reflected country boundaries. CONCLUSIONS: Over a nine-year period, there have been increases in the numbers of patients having kidney function tests annually and in the frequency of testing. Changes in the recommended management of CKD in primary care were the primary determinant, and increases persist even after controlling for demographic and patient-level factors. Future studies should address whether increased testing has led to better outcomes.

Night shift work and risk of breast cancer in women: the Generations Study cohort.

BACKGROUND: It is plausible that night shift work could affect breast cancer risk, possibly by melatonin suppression or circadian clock disruption, but epidemiological evidence is inconclusive. METHODS: Using serial questionnaires from the Generations Study cohort, we estimated hazard ratios (HR) and 95% confidence intervals (95%CI) for breast cancer in relation to being a night shift worker within the last 10 years, adjusted for potential confounders. RESULTS: Among 102,869 women recruited in 2003-2014, median follow-up 9.5 years, 2059 developed invasive breast cancer. The HR in relation to night shift work was 1.00 (95%CI: 0.86-1.15). There was a significant trend with average hours of night work per week (P = 0.035), but no significantly raised risks for hours worked per night, nights worked per week, average hours worked per week, cumulative years of employment, cumulative hours, time since cessation, type of occupation, age starting night shift work, or age starting in relation to first pregnancy. CONCLUSIONS: The lack of overall association, and no association with all but one measure of dose, duration, and intensity in our data, does not support an increased risk of breast cancer from night shift work in women.

Quality of diabetes care in breast, colorectal, and prostate cancer.

PURPOSE: Overlooking other medical conditions during cancer treatment and follow-up could result in excess morbidity and mortality, thereby undermining gains associated with early detection and improved treatment of cancer. We compared the quality of care for diabetes patients subsequently diagnosed with breast, colorectal, or prostate cancer to matched, diabetic non-cancer controls. METHODS: Longitudinal cohort study using primary care records from the Clinical Practice Research Datalink, United Kingdom. Patients with pre-existing diabetes were followed for up to 5 years after cancer diagnosis, or after an assigned index date (non-cancer controls). Quality of diabetes care was estimated based on Quality and Outcomes Framework indicators. Mixed effects logistic regression analyses were used to compare the unadjusted and adjusted odds of meeting quality measures between cancer patients and controls, overall and stratified by type of cancer. RESULTS: 3382 cancer patients and 11,135 controls contributed 44,507 person-years of follow-up. In adjusted analyses, cancer patients were less likely to meet five of 14 quality measures, including: total cholesterol ≤ 5 mmol/L (odds ratio [OR] = 0.82; 95% confidence interval [CI], 0.75-0.90); glycosylated hemoglobin ≤ 59 mmol/mol (adjusted OR = 0.77; 95% CI, 0.70-0.85); and albumin creatinine ratio testing (adjusted OR = 0.83; 95% CI, 0.75-0.91). However, cancer patients were as likely as their matched controls to meet quality measures for other diabetes services, including retinal screening, foot examination, and dietary review. CONCLUSIONS: Although in the short-term, cancer patients were less likely to achieve target thresholds for cholesterol and HbA1c, they continued to receive high-quality diabetes primary care throughout 5 years post diagnosis. IMPLICATIONS FOR CANCER SURVIVORS: These findings are important for cancer survivors with pre-existing diabetes because they indicate that high-quality diabetes care is maintained throughout the continuum of cancer diagnosis, treatment, and follow-up.

Domestic light at night and breast cancer risk: a prospective analysis of 105 000 UK women in the Generations Study.

BACKGROUND: Circadian disruption caused by exposure to light at night (LAN) has been proposed as a risk factor for breast cancer and a reason for secular increases in incidence. Studies to date have largely been ecological or case-control in design and findings have been mixed. METHODS: We investigated the relationship between LAN and breast cancer risk in the UK Generations Study. Bedroom light levels and sleeping patterns at age 20 and at study recruitment were obtained by questionnaire. Analyses were conducted on 105 866 participants with no prior history of breast cancer. During an average of 6.1 years of follow-up, 1775 cases of breast cancer were diagnosed. Cox proportional hazard models were used to calculate hazard ratios (HRs), adjusting for potential confounding factors. RESULTS: There was no association between LAN level and breast cancer risk overall (highest compared with lowest LAN level at recruitment: HR=1.01, 95% confidence interval (CI): 0.88-1.15), or for invasive (HR=0.98, 95% CI: 0.85-1.13) or in situ (HR=0.96, 95% CI: 0.83-1.11) breast cancer, or oestrogen-receptor (ER) positive (HR=0.98, 95% CI: 0.84-1.14); or negative (HR=1.16, 95% CI: 0.82-1.65) tumours separately. The findings did not differ by menopausal status. Adjusting for sleep duration, sleeping at unusual times (non-peak sleep) and history of night work did not affect the results. Night waking with exposure to light, occurring around age 20, was associated with a reduced risk of premenopausal breast cancer (HR for breast cancer overall=0.74, 95% CI: 0.55-0.99; HR for ER-positive breast cancer=0.69, 95% CI: 0.49-0.97). CONCLUSIONS: In this prospective cohort analysis of LAN, there was no evidence that LAN exposure increased the risk of subsequent breast cancer, although the suggestion of a lower breast cancer risk in pre-menopausal women with a history of night waking in their twenties may warrant further investigation.

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.

Handling missing data in propensity score estimation in comparative effectiveness evaluations: a systematic review.

AIM: Even though systematic reviews have examined how aspects of propensity score methods are used, none has reviewed how the challenge of missing data is addressed with these methods. This review therefore describes how missing data are addressed with propensity score methods in observational comparative effectiveness studies. METHODS: Published articles on observational comparative effectiveness studies were extracted from MEDLINE and EMBASE databases. RESULTS: Our search yielded 167 eligible articles. Majority of these studies (114; 68%) conducted complete case analysis with only 53 of them stating this in the methods. Only 16 articles reported use of multiple imputation. CONCLUSION: Few researchers use correct methods for handling missing data or reported missing data methodology which may lead to reporting biased findings.