The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) brought with it rapid development of both molecular and serologic assays for identification of COVID-19 infections. While ...Food and Drug Administration (FDA) emergency use authorization (EUA) is required for clinical application of SARS-CoV-2 molecular tests, submission for EUA is currently a voluntary process for manufacturers of serologic assays. The absence of FDA oversight of serologic tests is concerning given that the commercially available serologic assays are highly variable, differing in their format, the antibody class detected, the targeted antigen, and the acceptable specimen types. An added complication is the lack of a clear understanding for how such assays should be utilized and what the reported results ultimately indicate or, perhaps more importantly, what they do not indicate. Here, we provide a brief summary of the performance of a number of serologic assays reported in the literature, comment on what we do and do not know regarding our immune response to SARS-CoV-2, and provide a number of scenarios for which serologic testing will play a role during our global response to this pandemic.
Abstract
Monocytes and macrophages are essential components of the innate immune system. Herein, we report that intron retention (IR) plays an important role in the development and function of these ...cells. Using Illumina mRNA sequencing, Nanopore direct cDNA sequencing and proteomics analysis, we identify IR events that affect the expression of key genes/proteins involved in macrophage development and function. We demonstrate that decreased IR in nuclear-detained mRNA is coupled with increased expression of genes encoding regulators of macrophage transcription, phagocytosis and inflammatory signalling, including ID2, IRF7, ENG and LAT. We further show that this dynamic IR program persists during the polarisation of resting macrophages into activated macrophages. In the presence of proinflammatory stimuli, intron-retaining CXCL2 and NFKBIZ transcripts are rapidly spliced, enabling timely expression of these key inflammatory regulators by macrophages. Our study provides novel insights into the molecular factors controlling vital regulators of the innate immune response.
The contribution of language preference and ethnicity to muscle strength and physical performance is unclear. We examined the associations of reading language preferences with muscle strength and ...performance in Chinese women and compared them to other ethnicities.
The Integrated Women's Health Programme (IWHP) cohort comprised community-dwelling, midlife Singaporean women aged 45-69. Ethnic Chinese women could choose between the English or Chinese versions of the questionnaire. Malay and Indian women were presented with the English version. Sociodemographic, reproductive, anthropometric characteristics were obtained. Hand grip strength and physical performance were objectively assessed. Visceral adiposity (VAT) was determined by Dual-energy X-ray Absorptiometry. Multivariable logistic regression models were used to determine independent associations of language preference/ethnicity with muscle strength and physical performance.
The cohort comprised 1164 women (mean age: 56.3±6.2 years); 84.1% Chinese, 5.6% Malay, and 10.3% Indian. 315 Chinese participants (32.2%) had a Chinese-language reading preference (CLP). CLP women tended to be parous, of a lower socioeconomic status (lower proportions received tertiary education, lower employment rates and lower household income), and engaged in less physical activity compared to Chinese women with an English-language preference (ELP). This translated to a weaker hand grip strength (aOR: 1.56; 95%CI: 1.07-2.27), slower repeated chair stand (1.55; 1.12-2.13), poorer balance on tandem stand (2.00; 1.16-3.47), and a slower gait speed (1.62; 1.06-2.47). Compared to ELP women, Malay women had higher odds of poor hand grip strength (1.81; 1.12-2.93) while Indians had a higher odd of poor balance on one-leg stand (2.12; 1.28-3.52) and slow gait speeds on usual (1.88; 1.09-3.25) and narrow walks (1.91; 1.15-3.17).
Chinese language reading preference was associated with inferior muscle strength and physical performance. Such disparities were largest and most consistent in the CLP group, followed by Indian and Malay women compared to the ELP group. Further studies should determine if CLP-associated muscle weakness can predict adverse health outcomes.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The canonical Wnt/β-catenin signalling pathway governs diverse developmental, homeostatic and pathological processes. Palmitoylated Wnt ligands engage cell-surface frizzled (FZD) receptors and LRP5 ...and LRP6 co-receptors, enabling β-catenin nuclear translocation and TCF/LEF-dependent gene transactivation. Mutations in Wnt downstream signalling components have revealed diverse functions thought to be carried out by Wnt ligands themselves. However, redundancy between the 19 mammalian Wnt proteins and 10 FZD receptors and Wnt hydrophobicity have made it difficult to attribute these functions directly to Wnt ligands. For example, individual mutations in Wnt ligands have not revealed homeostatic phenotypes in the intestinal epithelium-an archetypal canonical, Wnt pathway-dependent, rapidly self-renewing tissue, the regeneration of which is fueled by proliferative crypt Lgr5
intestinal stem cells (ISCs). R-spondin ligands (RSPO1-RSPO4) engage distinct LGR4-LGR6, RNF43 and ZNRF3 receptor classes, markedly potentiate canonical Wnt/β-catenin signalling, and induce intestinal organoid growth in vitro and Lgr5
ISCs in vivo. However, the interchangeability, functional cooperation and relative contributions of Wnt versus RSPO ligands to in vivo canonical Wnt signalling and ISC biology remain unknown. Here we identify the functional roles of Wnt and RSPO ligands in the intestinal crypt stem-cell niche. We show that the default fate of Lgr5
ISCs is to differentiate, unless both RSPO and Wnt ligands are present. However, gain-of-function studies using RSPO ligands and a new non-lipidated Wnt analogue reveal that these ligands have qualitatively distinct, non-interchangeable roles in ISCs. Wnt proteins are unable to induce Lgr5
ISC self-renewal, but instead confer a basal competency by maintaining RSPO receptor expression that enables RSPO ligands to actively drive and specify the extent of stem-cell expansion. This functionally non-equivalent yet cooperative interaction between Wnt and RSPO ligands establishes a molecular precedent for regulation of mammalian stem cells by distinct priming and self-renewal factors, with broad implications for precise control of tissue regeneration.
IMPORTANCE: The number of deaths from cervical cancer in the United States has decreased substantially since the implementation of widespread cervical cancer screening and has declined from 2.8 to ...2.3 deaths per 100 000 women from 2000 to 2015. OBJECTIVE: To update the US Preventive Services Task Force (USPSTF) 2012 recommendation on screening for cervical cancer. EVIDENCE REVIEW: The USPSTF reviewed the evidence on screening for cervical cancer, with a focus on clinical trials and cohort studies that evaluated screening with high-risk human papillomavirus (hrHPV) testing alone or hrHPV and cytology together (cotesting) compared with cervical cytology alone. The USPSTF also commissioned a decision analysis model to evaluate the age at which to begin and end screening, the optimal interval for screening, the effectiveness of different screening strategies, and related benefits and harms of different screening strategies. FINDINGS: Screening with cervical cytology alone, primary hrHPV testing alone, or cotesting can detect high-grade precancerous cervical lesions and cervical cancer. Screening women aged 21 to 65 years substantially reduces cervical cancer incidence and mortality. The harms of screening for cervical cancer in women aged 30 to 65 years are moderate. The USPSTF concludes with high certainty that the benefits of screening every 3 years with cytology alone in women aged 21 to 29 years substantially outweigh the harms. The USPSTF concludes with high certainty that the benefits of screening every 3 years with cytology alone, every 5 years with hrHPV testing alone, or every 5 years with both tests (cotesting) in women aged 30 to 65 years outweigh the harms. Screening women older than 65 years who have had adequate prior screening and women younger than 21 years does not provide significant benefit. Screening women who have had a hysterectomy with removal of the cervix for indications other than a high-grade precancerous lesion or cervical cancer provides no benefit. The USPSTF concludes with moderate to high certainty that screening women older than 65 years who have had adequate prior screening and are not otherwise at high risk for cervical cancer, screening women younger than 21 years, and screening women who have had a hysterectomy with removal of the cervix for indications other than a high-grade precancerous lesion or cervical cancer does not result in a positive net benefit. CONCLUSIONS AND RECOMMENDATION: The USPSTF recommends screening for cervical cancer every 3 years with cervical cytology alone in women aged 21 to 29 years. (A recommendation) The USPSTF recommends screening every 3 years with cervical cytology alone, every 5 years with hrHPV testing alone, or every 5 years with hrHPV testing in combination with cytology (cotesting) in women aged 30 to 65 years. (A recommendation) The USPSTF recommends against screening for cervical cancer in women younger than 21 years. (D recommendation) The USPSTF recommends against screening for cervical cancer in women older than 65 years who have had adequate prior screening and are not otherwise at high risk for cervical cancer. (D recommendation) The USPSTF recommends against screening for cervical cancer in women who have had a hysterectomy with removal of the cervix and do not have a history of a high-grade precancerous lesion or cervical cancer. (D recommendation)
IMPORTANCE: By 2020, approximately 12.3 million individuals in the United States older than 50 years are expected to have osteoporosis. Osteoporotic fractures, particularly hip fractures, are ...associated with limitations in ambulation, chronic pain and disability, loss of independence, and decreased quality of life, and 21% to 30% of patients who experience a hip fracture die within 1 year. The prevalence of primary osteoporosis (ie, osteoporosis without underlying disease) increases with age and differs by race/ethnicity. With the aging of the US population, the potential preventable burden is likely to increase in future years. OBJECTIVE: To update the 2011 US Preventive Services Task Force (USPSTF) recommendation on screening for osteoporosis. EVIDENCE REVIEW: The USPSTF reviewed the evidence on screening for and treatment of osteoporotic fractures in men and women, as well as risk assessment tools, screening intervals, and efficacy of screening and treatment in subgroups. The screening population was postmenopausal women and older men with no known previous osteoporotic fractures and no known comorbid conditions or medication use associated with secondary osteoporosis. FINDINGS: The USPSTF found convincing evidence that bone measurement tests are accurate for detecting osteoporosis and predicting osteoporotic fractures in women and men. The USPSTF found adequate evidence that clinical risk assessment tools are moderately accurate in identifying risk of osteoporosis and osteoporotic fractures. The USPSTF found convincing evidence that drug therapies reduce subsequent fracture rates in postmenopausal women. The USPSTF found that the evidence is inadequate to assess the effectiveness of drug therapies in reducing subsequent fracture rates in men without previous fractures. CONCLUSIONS AND RECOMMENDATION: The USPSTF recommends screening for osteoporosis with bone measurement testing to prevent osteoporotic fractures in women 65 years and older. (B recommendation) The USPSTF recommends screening for osteoporosis with bone measurement testing to prevent osteoporotic fractures in postmenopausal women younger than 65 years at increased risk of osteoporosis, as determined by a formal clinical risk assessment tool. (B recommendation) The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for osteoporosis to prevent osteoporotic fractures in men. (I statement)
IMPORTANCE: Perinatal depression, which is the occurrence of a depressive disorder during pregnancy or following childbirth, affects as many as 1 in 7 women and is one of the most common ...complications of pregnancy and the postpartum period. It is well established that perinatal depression can result in adverse short- and long-term effects on both the woman and child. OBJECTIVE: To issue a new US Preventive Services Task Force (USPSTF) recommendation on interventions to prevent perinatal depression. EVIDENCE REVIEW: The USPSTF reviewed the evidence on the benefits and harms of preventive interventions for perinatal depression in pregnant or postpartum women or their children. The USPSTF reviewed contextual information on the accuracy of tools used to identify women at increased risk of perinatal depression and the most effective timing for preventive interventions. Interventions reviewed included counseling, health system interventions, physical activity, education, supportive interventions, and other behavioral interventions, such as infant sleep training and expressive writing. Pharmacological approaches included the use of nortriptyline, sertraline, and omega-3 fatty acids. FINDINGS: The USPSTF found convincing evidence that counseling interventions, such as cognitive behavioral therapy and interpersonal therapy, are effective in preventing perinatal depression. Women with a history of depression, current depressive symptoms, or certain socioeconomic risk factors (eg, low income or young or single parenthood) would benefit from counseling interventions and could be considered at increased risk. The USPSTF found adequate evidence to bound the potential harms of counseling interventions as no greater than small, based on the nature of the intervention and the low likelihood of serious harms. The USPSTF found inadequate evidence to assess the benefits and harms of other noncounseling interventions. The USPSTF concludes with moderate certainty that providing or referring pregnant or postpartum women at increased risk to counseling interventions has a moderate net benefit in preventing perinatal depression. CONCLUSIONS AND RECOMMENDATION: The USPSTF recommends that clinicians provide or refer pregnant and postpartum persons who are at increased risk of perinatal depression to counseling interventions. (B recommendation)
IMPORTANCE: An estimated 12% of adults 18 years or older and 8% of adolescents aged 12 to 17 years report unhealthy use of prescription or illegal drugs in the US. OBJECTIVE: To update its 2008 ...recommendation, the USPSTF commissioned reviews of the evidence on screening by asking questions about drug use and interventions for unhealthy drug use in adults and adolescents. POPULATION: This recommendation statement applies to adults 18 years or older, including pregnant and postpartum persons, and adolescents aged 12 to 17 years in primary care settings. This statement does not apply to adolescents or adults who have a currently diagnosed drug use disorder or are currently undergoing or have been referred for drug use treatment. This statement applies to settings and populations for which services for accurate diagnosis, effective treatment, and appropriate care can be offered or referred. EVIDENCE ASSESSMENT: In adults, the USPSTF concludes with moderate certainty that screening by asking questions about unhealthy drug use has moderate net benefit when services for accurate diagnosis of unhealthy drug use or drug use disorders, effective treatment, and appropriate care can be offered or referred. In adolescents, because of the lack of evidence, the USPSTF concludes that the benefits and harms of screening for unhealthy drug use are uncertain and that the balance of benefits and harms cannot be determined. RECOMMENDATION: The USPSTF recommends screening by asking questions about unhealthy drug use in adults 18 years or older. Screening should be implemented when services for accurate diagnosis, effective treatment, and appropriate care can be offered or referred. (Screening refers to asking questions about unhealthy drug use, not testing biological specimens.) (B recommendation) The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for unhealthy drug use in adolescents. (I statement)
IMPORTANCE: More than 35% of men and 40% of women in the United States are obese. Obesity is associated with health problems such as increased risk for coronary heart disease, type 2 diabetes, ...various types of cancer, gallstones, and disability. Obesity is also associated with an increased risk for death, particularly among adults younger than 65 years. OBJECTIVE: To update the US Preventive Services Task Force (USPSTF) 2012 recommendation on screening for obesity in adults. EVIDENCE REVIEW: The USPSTF reviewed the evidence on interventions (behavioral and pharmacotherapy) for weight loss or weight loss maintenance that can be provided in or referred from a primary care setting. Surgical weight loss interventions and nonsurgical weight loss devices (eg, gastric balloons) are considered to be outside the scope of the primary care setting. FINDINGS: The USPSTF found adequate evidence that intensive, multicomponent behavioral interventions in adults with obesity can lead to clinically significant improvements in weight status and reduce the incidence of type 2 diabetes among adults with obesity and elevated plasma glucose levels; these interventions are of moderate benefit. The USPSTF found adequate evidence that behavior-based weight loss maintenance interventions are of moderate benefit. The USPSTF found adequate evidence that the harms of intensive, multicomponent behavioral interventions (including weight loss maintenance interventions) in adults with obesity are small to none. Therefore, the USPSTF concludes with moderate certainty that offering or referring adults with obesity to intensive behavioral interventions or behavior-based weight loss maintenance interventions has a moderate net benefit. CONCLUSIONS AND RECOMMENDATION: The USPSTF recommends that clinicians offer or refer adults with a body mass index of 30 or higher to intensive, multicomponent behavioral interventions. (B recommendation)
(Abstracted from JAMA 2018;320:674–686)The number of deaths from cervical cancer in the United States has decreased substantially since the 1960s and especially during the last 2 decades because of ...the implementation of widespread cervical cancer screening. Most cases of this cancer occur in women who have not been adequately screened.
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