Patients with chronic kidney disease (CKD) are at substantially higher risk for developing cognitive impairment compared with the general population, and both lower glomerular filtration rate and the ...presence of albuminuria are associated with the development of cognitive impairment and poorer cognitive function. Given the excess of vascular disease seen in individuals with CKD, cerebrovascular disease is likely the predominant pathology underlying these associations, though impaired clearance of uremic metabolites, depression, sleep disturbance, anemia, and polypharmacy may also contribute. Modification of vascular disease risk factors may be helpful in limiting decline, though definite data are lacking. Specific to CKD, targeting a low blood pressure and reduction in albuminuria with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers may slow cognitive decline, albeit modestly. Initiation of dialysis can improve severe impairment associated with uremia but does not appear to affect more subtle chronic cognitive impairment. In contrast, kidney transplantation appears to lead to improved cognitive function in many transplant recipients, suggesting that dialysis methods do not provide the same cognitive benefits as having a functioning kidney. Management of patients with both CKD and cognitive impairment should include a comprehensive plan including more frequent follow-up visits; involvement of family in shared decision making; measures to improve compliance, such as written instruction and pill counts; and a focus on advance directives in conjunction with an emphasis on understanding an individual patient’s life goals. Further research is needed on novel therapies, including innovative dialysis methods, that aim to limit the development of cognitive impairment, slow decline in those with prevalent impairment, and improve cognitive function.
Aspirin (acetylsalicylic acid) has become one of the most commonly used drugs, given its role as an analgesic, antipyretic and agent for cardiovascular prophylaxis. Several decades of research have ...provided considerable evidence demonstrating its potential for the prevention of cancer, particularly colorectal cancer. Broader clinical recommendations for aspirin-based chemoprevention strategies have recently been established; however, given the known hazards of long-term aspirin use, larger-scale adoption of an aspirin chemoprevention strategy is likely to require improved identification of individuals for whom the protective benefits outweigh the harms. Such a precision medicine approach may emerge through further clarification of aspirin's mechanism of action.
High-quality evidence indicates that regular use of aspirin is effective in reducing the risk for precancerous colorectal neoplasia and colorectal cancer (CRC). This has led to US and international ...guidelines recommending aspirin for the primary prevention of CRC in specific populations. In this review, we summarize key questions that require addressing prior to broader adoption of aspirin-based chemoprevention, review recent evidence related to the benefits and harms of aspirin use among specific populations, and offer a rationale for precision prevention approaches. We specifically consider the mechanistic implications of evidence showing differences in aspirin's effects according to age, the potential role of modifiable mechanistic biomarkers for personalizing prevention, and emerging evidence that the gut microbiota may offer novel aspirin-associated preventive targets to reduce high-risk neoplasia.
The Pfizer-BioNTech (BNT162b2) and the Oxford-AstraZeneca (ChAdOx1 nCoV-19) COVID-19 vaccines have shown excellent safety and efficacy in phase 3 trials. We aimed to investigate the safety and ...effectiveness of these vaccines in a UK community setting.
In this prospective observational study, we examined the proportion and probability of self-reported systemic and local side-effects within 8 days of vaccination in individuals using the COVID Symptom Study app who received one or two doses of the BNT162b2 vaccine or one dose of the ChAdOx1 nCoV-19 vaccine. We also compared infection rates in a subset of vaccinated individuals subsequently tested for SARS-CoV-2 with PCR or lateral flow tests with infection rates in unvaccinated controls. All analyses were adjusted by age (≤55 years vs >55 years), sex, health-care worker status (binary variable), obesity (BMI <30 kg/m2vs ≥30 kg/m2), and comorbidities (binary variable, with or without comorbidities).
Between Dec 8, and March 10, 2021, 627 383 individuals reported being vaccinated with 655 590 doses: 282 103 received one dose of BNT162b2, of whom 28 207 received a second dose, and 345 280 received one dose of ChAdOx1 nCoV-19. Systemic side-effects were reported by 13·5% (38 155 of 282 103) of individuals after the first dose of BNT162b2, by 22·0% (6216 of 28 207) after the second dose of BNT162b2, and by 33·7% (116 473 of 345 280) after the first dose of ChAdOx1 nCoV-19. Local side-effects were reported by 71·9% (150 023 of 208 767) of individuals after the first dose of BNT162b2, by 68·5% (9025 of 13 179) after the second dose of BNT162b2, and by 58·7% (104 282 of 177 655) after the first dose of ChAdOx1 nCoV-19. Systemic side-effects were more common (1·6 times after the first dose of ChAdOx1 nCoV-19 and 2·9 times after the first dose of BNT162b2) among individuals with previous SARS-CoV-2 infection than among those without known past infection. Local effects were similarly higher in individuals previously infected than in those without known past infection (1·4 times after the first dose of ChAdOx1 nCoV-19 and 1·2 times after the first dose of BNT162b2). 3106 of 103 622 vaccinated individuals and 50 340 of 464 356 unvaccinated controls tested positive for SARS-CoV-2 infection. Significant reductions in infection risk were seen starting at 12 days after the first dose, reaching 60% (95% CI 49–68) for ChAdOx1 nCoV-19 and 69% (66–72) for BNT162b2 at 21–44 days and 72% (63–79) for BNT162b2 after 45–59 days.
Systemic and local side-effects after BNT162b2 and ChAdOx1 nCoV-19 vaccination occur at frequencies lower than reported in phase 3 trials. Both vaccines decrease the risk of SARS-CoV-2 infection after 12 days.
ZOE Global, National Institute for Health Research, Chronic Disease Research Foundation, National Institutes of Health, UK Medical Research Council, Wellcome Trust, UK Research and Innovation, American Gastroenterological Association.
Endoscopic screening reduces incidence and mortality of colorectal cancer (CRC) because precursor lesions, such as conventional adenomas or serrated polyps, are removed. Individuals with ...polypectomies are advised to undergo colonoscopy surveillance to prevent CRC. However, guidelines for surveillance intervals after diagnosis of a precursor lesion, particularly for individuals with serrated polyps, vary widely, and lack sufficient supporting evidence. Consequently, some high-risk patients do not receive enough surveillance and lower-risk subjects receive excessive surveillance.
We examined the association between findings from first endoscopy and CRC risk among 122,899 participants who underwent flexible sigmoidoscopy or colonoscopy in the Nurses’ Health Study 1 (1990–2012), Nurses’ Health Study 2 (1989–2013), or the Health Professionals Follow-up Study (1990–2012). Endoscopic findings were categorized as no polyp, conventional adenoma, or serrated polyp (hyperplastic polyp, traditional serrated adenoma, or sessile serrated adenoma, with or without cytological dysplasia). Conventional adenomas were classified as advanced (≥10 mm, high-grade dysplasia, or tubulovillous or villous histology) or nonadvanced, and serrated polyps were assigned to categories of large (≥10 mm) or small (<10 mm). We used a Cox proportional hazards regression model to calculate the hazard ratios (HRs) of CRC incidence, after adjusting for various potential risk factors.
After a median follow-up period of 10 years, we documented 491 incident cases of CRC: 51 occurred in 6161 participants with conventional adenomas, 24 in 5918 participants with serrated polyps, and 427 in 112,107 participants with no polyp. Compared with participants with no polyp detected during initial endoscopy, the multivariable HR for incident CRC in individuals with an advanced adenoma was 4.07 (95% confidence interval CI 2.89–5.72) and the HR for CRC in individuals with a large serrated polyp was 3.35 (95% CI 1.37–8.15). In contrast, there was no significant increase in risk of CRC in patients with nonadvanced adenomas (HR 1.21; 95% CI 0.68–2.16, P = .52) or small serrated polyps (HR 1.25; 95% CI 0.76–2.08; P = .38).
These findings provide support for guidelines that recommend repeat lower endoscopy within 3 years of a diagnosis of advanced adenoma and large serrated polyps. In contrast, patients with nonadvanced adenoma or small serrated polyps may not require more intensive surveillance than patients without polyps.
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A total of 2,618,862 participants reported their potential symptoms of COVID-19 on a smartphone-based app. Among the 18,401 who had undergone a SARS-CoV-2 test, the proportion of participants who ...reported loss of smell and taste was higher in those with a positive test result (4,668 of 7,178 individuals; 65.03%) than in those with a negative test result (2,436 of 11,223 participants; 21.71%) (odds ratio = 6.74; 95% confidence interval = 6.31-7.21). A model combining symptoms to predict probable infection was applied to the data from all app users who reported symptoms (805,753) and predicted that 140,312 (17.42%) participants are likely to have COVID-19.
COVID-19 vaccines show excellent efficacy in clinical trials and effectiveness in real-world data, but some people still become infected with SARS-CoV-2 after vaccination. This study aimed to ...identify risk factors for post-vaccination SARS-CoV-2 infection and describe the characteristics of post-vaccination illness.
This prospective, community-based, nested, case-control study used self-reported data (eg, on demographics, geographical location, health risk factors, and COVID-19 test results, symptoms, and vaccinations) from UK-based, adult (≥18 years) users of the COVID Symptom Study mobile phone app. For the risk factor analysis, cases had received a first or second dose of a COVID-19 vaccine between Dec 8, 2020, and July 4, 2021; had either a positive COVID-19 test at least 14 days after their first vaccination (but before their second; cases 1) or a positive test at least 7 days after their second vaccination (cases 2); and had no positive test before vaccination. Two control groups were selected (who also had not tested positive for SARS-CoV-2 before vaccination): users reporting a negative test at least 14 days after their first vaccination but before their second (controls 1) and users reporting a negative test at least 7 days after their second vaccination (controls 2). Controls 1 and controls 2 were matched (1:1) with cases 1 and cases 2, respectively, by the date of the post-vaccination test, health-care worker status, and sex. In the disease profile analysis, we sub-selected participants from cases 1 and cases 2 who had used the app for at least 14 consecutive days after testing positive for SARS-CoV-2 (cases 3 and cases 4, respectively). Controls 3 and controls 4 were unvaccinated participants reporting a positive SARS-CoV-2 test who had used the app for at least 14 consecutive days after the test, and were matched (1:1) with cases 3 and 4, respectively, by the date of the positive test, health-care worker status, sex, body-mass index (BMI), and age. We used univariate logistic regression models (adjusted for age, BMI, and sex) to analyse the associations between risk factors and post-vaccination infection, and the associations of individual symptoms, overall disease duration, and disease severity with vaccination status.
Between Dec 8, 2020, and July 4, 2021, 1 240 009 COVID Symptom Study app users reported a first vaccine dose, of whom 6030 (0·5%) subsequently tested positive for SARS-CoV-2 (cases 1), and 971 504 reported a second dose, of whom 2370 (0·2%) subsequently tested positive for SARS-CoV-2 (cases 2). In the risk factor analysis, frailty was associated with post-vaccination infection in older adults (≥60 years) after their first vaccine dose (odds ratio OR 1·93, 95% CI 1·50–2·48; p<0·0001), and individuals living in highly deprived areas had increased odds of post-vaccination infection following their first vaccine dose (OR 1·11, 95% CI 1·01–1·23; p=0·039). Individuals without obesity (BMI <30 kg/m2) had lower odds of infection following their first vaccine dose (OR 0·84, 95% CI 0·75–0·94; p=0·0030). For the disease profile analysis, 3825 users from cases 1 were included in cases 3 and 906 users from cases 2 were included in cases 4. Vaccination (compared with no vaccination) was associated with reduced odds of hospitalisation or having more than five symptoms in the first week of illness following the first or second dose, and long-duration (≥28 days) symptoms following the second dose. Almost all symptoms were reported less frequently in infected vaccinated individuals than in infected unvaccinated individuals, and vaccinated participants were more likely to be completely asymptomatic, especially if they were 60 years or older.
To minimise SARS-CoV-2 infection, at-risk populations must be targeted in efforts to boost vaccine effectiveness and infection control measures. Our findings might support caution around relaxing physical distancing and other personal protective measures in the post-vaccination era, particularly around frail older adults and individuals living in more deprived areas, even if these individuals are vaccinated, and might have implications for strategies such as booster vaccinations.
ZOE, the UK Government Department of Health and Social Care, the Wellcome Trust, the UK Engineering and Physical Sciences Research Council, UK Research and Innovation London Medical Imaging and Artificial Intelligence Centre for Value Based Healthcare, the UK National Institute for Health Research, the UK Medical Research Council, the British Heart Foundation, and the Alzheimer's Society.
The mammalian heart undergoes maturation during postnatal life to meet the increased functional requirements of an adult. However, the key drivers of this process remain poorly defined. We are ...currently unable to recapitulate postnatal maturation in human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs), limiting their potential as a model system to discover regenerative therapeutics. Here, we provide a summary of our studies, where we developed a 96-well device for functional screening in human pluripotent stem cell-derived cardiac organoids (hCOs). Through interrogation of >10,000 organoids, we systematically optimize parameters, including extracellular matrix (ECM), metabolic substrate, and growth factor conditions, that enhance cardiac tissue viability, function, and maturation. Under optimized maturation conditions, functional and molecular characterization revealed that a switch to fatty acid metabolism was a central driver of cardiac maturation. Under these conditions, hPSC-CMs were refractory to mitogenic stimuli, and we found that key proliferation pathways including β-catenin and Yes-associated protein 1 (YAP1) were repressed. This proliferative barrier imposed by fatty acid metabolism in hCOs could be rescued by simultaneous activation of both β-catenin and YAP1 using genetic approaches or a small molecule activating both pathways. These studies highlight that human organoids coupled with higher-throughput screening platforms have the potential to rapidly expand our knowledge of human biology and potentially unlock therapeutic strategies.
Context is known to affect how a stimulus is perceived. A variety of illusions have been attributed to contextual processing-from orientation tilt effects to chromatic induction phenomena, but their ...neural underpinnings remain poorly understood. Here, we present a recurrent network model of classical and extraclassical receptive fields that is constrained by the anatomy and physiology of the visual cortex. A key feature of the model is the postulated existence of near- versus far- extraclassical regions with complementary facilitatory and suppressive contributions to the classical receptive field. The model accounts for a variety of contextual illusions, reveals commonalities between seemingly disparate phenomena, and helps organize them into a novel taxonomy. It explains how center-surround interactions may shift from attraction to repulsion in tilt effects, and from contrast to assimilation in induction phenomena. The model further explains enhanced perceptual shifts generated by a class of patterned background stimuli that activate the two opponent extraclassical regions cooperatively. Overall, the ability of the model to account for the variety and complexity of contextual illusions provides computational evidence for a novel canonical circuit that is shared across visual modalities.
Goal: Current methods for estimating respiratory rate (RR) from the photoplethysmogram (PPG) typically fail to distinguish between periods of high- and low-quality input data, and fail to perform ...well on independent "validation" datasets. The lack of robustness of existing methods directly results in a lack of penetration of such systems into clinical practice. The present work proposes an alternative method to improve the robustness of the estimation of RR from the PPG. Methods: The proposed algorithm is based on the use of multiple autoregressive models of different orders for determining the dominant respiratory frequency in the three respiratory-induced variations (frequency, amplitude, and intensity) derived from the PPG. The algorithm was tested on two different datasets comprising 95 eight-minute PPG recordings (in total) acquired from both children and adults in different clinical settings, and its performance using two window sizes (32 and 64 seconds) was compared with that of existing methods in the literature. Results: The proposed method achieved comparable accuracy to existing methods in the literature, with mean absolute errors (median, 25th-75th percentiles for a window size of 32 seconds) of 1.5 (0.3-3.3) and 4.0 (1.8-5.5) breaths per minute (for each dataset respectively), whilst providing RR estimates for a greater proportion of windows (over 90% of the input data are kept). Conclusion: Increased robustness of RR estimation by the proposed method was demonstrated. Significance: This work demonstrates that the use of large publicly available datasets is essential for improving the robustness of wearable-monitoring algorithms for use in clinical practice.
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