Summary Background The prostate-specific antigen (PSA) test is used to screen for prostate cancer but has a high false-positive rate that translates into unnecessary prostate biopsies and ...overdiagnosis of low-risk prostate cancers. We aimed to develop and validate a model to identify high-risk prostate cancer (with a Gleason score of at least 7) with better test characteristics than that provided by PSA screening alone. Methods The Stockholm 3 (STHLM3) study is a prospective, population-based, paired, screen-positive, diagnostic study of men without prostate cancer aged 50–69 years randomly invited by date of birth from the Swedish Population Register kept by the Swedish Tax Agency. Men with prostate cancer at enrolment were excluded from the study. The predefined STHLM3 model (a combination of plasma protein biomarkers PSA, free PSA, intact PSA, hK2, MSMB, MIC1, genetic polymorphisms 232 SNPs, and clinical variables age, family, history, previous prostate biopsy, prostate exam), and PSA concentration were both tested in all participants enrolled. The primary aim was to increase the specificity compared with PSA without decreasing the sensitivity to diagnose high-risk prostate cancer. The primary outcomes were number of detected high-risk cancers (sensitivity) and the number of performed prostate biopsies (specificity). The STHLM3 training cohort was used to train the STHLM3 model, which was prospectively tested in the STHLM3 validation cohort. Logistic regression was used to test for associations between biomarkers and clinical variables and prostate cancer with a Gleason score of at least 7. This study is registered with ISCRTN.com , number ISRCTN84445406. Findings The STHLM3 model performed significantly better than PSA alone for detection of cancers with a Gleason score of at least 7 (p<0·0001), the area under the curve was 0·56 (95% CI 0·55–0·60) with PSA alone and 0·74 (95% CI 0·72–0·75) with the STHLM3 model. All variables used in the STHLM3 model were significantly associated with prostate cancers with a Gleason score of at least 7 (p<0·05) in a multiple logistic regression model. At the same level of sensitivity as the PSA test using a cutoff of ≥3 ng/mL to diagnose high risk prostate cancer, use of the STHLM3 model could reduce the number of biopsies by 32% (95% CI 24–39) and could avoid 44% (35–54) of benign biopsies. Interpretation The STHLM3 model could reduce unnecessary biopsies without compromising the ability to diagnose prostate cancer with a Gleason score of at least 7, and could be a step towards personalised risk-based prostate cancer diagnostic programmes. Funding Stockholm County Council (Stockholms Läns Landsting).
•The number of reported COVID-19 cases was considerably lower than true cases.•Seroprevalence is an effective means of quantifying the extent of underreporting.•Seroprevalence studies can be a useful ...adjunct to other routine surveillance methods.
Reported confirmed cases represent a small portion of overall true cases for many infectious diseases. The undercounting of true cases can be considerable when a significant portion of infected individuals are asymptomatic or minimally symptomatic, as is the case with COVID-19. Seroprevalence studies are an efficient way to assess the extent to which true cases are undercounted during a large-scale outbreak and can inform efforts to improve case identification and reporting.
A longitudinal seroprevalence study of active duty U.S. military members was conducted from May 2020 through June 2021. A random selection of service member serum samples submitted to the Department of Defense Serum Repository was analyzed for the presence of antibodies reactive to SARS-CoV-2. The monthly seroprevalence rates were compared with those of cumulative confirmed cases reported during the study period.
Seroprevalence was 2.3% in May 2020 and increased to 74.0% by June 2021. The estimated true case count based on seroprevalence was 9.3 times greater than monthly reported cases at the beginning of the study period and fell to 1.7 by the end of the study.
In our sample, confirmed case counts significantly underestimated true cases of COVID-19. The increased availability of testing over the study period and enhanced efforts to detect asymptomatic and minimally symptomatic cases likely contributed to the fall in the seroprevalence to reported case ratio.
Abstract Background Many young children with type 1 diabetes mellitus (T1DM) do not consume a healthful diet; exactly why this occurs despite T1DM education remains poorly understood. Objective This ...study describes parents’ perceptions of healthful eating for T1DM in young children and identifies factors related to parents’ dietary management. Design A cross-sectional, mixed-methods study was performed. Parents completed a questionnaire, 3-day weighed diet record, and a semi-structured interview regarding their perceptions of healthful eating for T1DM and their dietary management practices. Participants/setting Twenty-three families, recruited from a pediatric diabetes clinic in the midwestern United States between February 2012 and April 2013, participated. Eligible families had a child with T1DM who was 1 to 6 years old, at least 6 months from diagnosis, and was following an intensive insulin regimen. Statistical analyses performed Mean scores and percentages were calculated from the diet diaries and parent questionnaires, and parents’ interviews were coded to identify common themes. Results Results showed that while parents may believe they know what constitutes a healthful diet for T1DM, they do not always feed their child a healthful diet. Parent-identified barriers to healthful eating included limited time to prepare homemade meals, perceived higher costs of healthier foods, the influence of peers on children’s food preferences, and picky eating. Parents also discussed a desire not to limit their child’s diet or make their child “feel different,” which many parents said often led them to give into their child’s requests for less healthful food options. Conclusions Parents of young children with T1DM identified several barriers to healthful eating that are common for all parents, such as time constraints, expense, and child food preferences. However, unique themes emerged, including parents’ desire not to limit their child’s diet or make their child “feel different.” Nutrition components of T1DM education should include psychological and behavioral strategies to help parents manage these unique concerns.
The health risks associated with living in houses insulated with asbestos are unknown. Loose-fill asbestos was used to insulate some houses in the Australian Capital Territory (ACT). We compared the ...incidence of mesothelioma and other cancers in residents of the ACT who did and did not live in these houses.
Our cohort study included all ACT residents identified using Medicare enrolment data. These data were linked to addresses of affected residential properties in the ACT to ascertain exposure. We followed up residents by linking data to the Australian Cancer Database and National Death Index. Outcomes were diagnosis of mesothelioma and selected other cancers. Effects were estimated for males and females separately using standardised incidence ratios (SIRs), adjusting for age and calendar time of diagnosis.
Between Nov 1, 1983, and Dec 31, 2013, 1 035 578 ACT residents were identified from the Medicare database. Of these, 17 248 (2%) had lived in an affected property, including seven (2%) of 285 people diagnosed with mesothelioma. The adjusted incidence of mesothelioma in males who had lived at an affected property was 2·5 times that of unexposed males (SIR 2·54, 95% CI 1·02–5·24). No mesotheliomas were reported among females who had lived at an affected property. Among individuals who had lived at an affected property, there was an elevated incidence of colorectal cancer in women (SIR 1·73, 95% CI 1·29–2·26) and prostate cancer in men (1·29, 1·07–1·54); colorectal cancer was increased, although not significantly, in males (SIR 1·32, 95% CI 0·99–1·72), with no significant increase in the other cancers studied.
Residential asbestos insulation is likely to be unsafe. Our findings have important health, social, financial, and legal implications for governments and communities in which asbestos has been used to insulate houses.
ACT Government.
Aims Aldosterone antagonism reduces cardiovascular morbidity and mortality in patients with left ventricular (LV) systolic dysfunction and heart failure or diabetes after acute myocardial infarction ...(AMI). The mechanism of this effect is unclear. We performed a contrast-enhanced cardiac magnetic resonance study to assess the effects of eplerenone on LV remodeling after AMI. Methods One hundred patients (mean age, 58.9 ± 12 years; 77% male) with LV systolic dysfunction but without heart failure or diabetes were randomized to 24 weeks' double-blind treatment with eplerenone or placebo started 1 to 14 days after AMI. Contrast-enhanced cardiac magnetic resonance was performed, and plasma concentrations of matrix metalloproteinase-2 (MMP-2) and MMP-9 were measured before randomization and at 12 and 24 weeks. Results Baseline LV ejection fraction was, by chance, significantly higher in eplerenone than in placebo-treated patients. Eplerenone had no effect on the primary end point (change in LV end-systolic volume index); after covariate adjustment, the primary end point fell by 6.1 ± 2.7 mL/m2 with eplerenone compared to placebo ( P = .027), and LV end-diastolic volume index fell by 7.5 ± 3.4 mL/m2 ( P = .031); eplerenone did not significantly influence LV ejection fraction. Eplerenone, after covariate adjustment, significantly decreased MMP-2 and increased MMP-9 over 24 weeks relative to placebo. Conclusions In a population of patients with AMI with high uptake of contemporary antiremodeling therapy, eplerenone provides modest incremental protection against LV remodeling, only after covariate adjustment.
Abstract Objective This study used a market-basket approach to examine the availability and cost of a standard food shopping list (R-TFP) vs a healthier food shopping list (H-TFP) in the grocery ...stores used by a sample of 23 families of young children with type 1 diabetes mellitus (T1DM). Methods The researchers used frequency counts to measure availability. The average cost of the R-TFP and H-TFP was compared using paired t test. Results Small or independent markets had the highest percentage of missing foods (14%), followed by chain supermarkets (3%) and big box stores (2%). There was a significant difference in average cost for the R-TFP vs the H-TFP ($324.71 and $380.07, respectively; P < .001). Conclusions and Implications Families may encounter problems finding healthier foods and/or incur greater costs for healthier foods. Nutrition education programs for T1DM need to teach problem solving to help families overcome these barriers.
Abstract Objective To present results for a parent-based educational intervention targeting mealtime behaviors plus nutrition among families of young children (mean age, 5.0 ± 1.2 years) with type 1 ...diabetes mellitus (T1DM). Methods The researchers recruited 9 caregivers who participated in the 6-session intervention and completed baseline and posttreatment assessments, which included dietary intake, acceptability of diet changes, mealtime behavior, and mean blood glucose values. Results Children's mean daily blood glucose levels decreased from 185 ± 46 mg/dL to 159 ± 40 mg/dL ( P < .001). There were also decreases in problematic parent and child mealtime behaviors. There was no change in children's dietary intake indicators that could be detected. Conclusions and Implications It appears promising that this targeted behavior plus nutrition intervention can improve glycemic control and behavior for young children with type 1 diabetes mellitus. Larger, randomized controlled trials will clarify significant results, limitations, and sustainability. Techniques within the program may have application to current practice.
Genetic disorders and congenital anomalies are the leading causes of infant mortality. Diagnosis of most genetic diseases in neonatal and paediatric intensive care units (NICU and PICU) is not ...sufficiently timely to guide acute clinical management. We used rapid whole-genome sequencing (STATseq) in a level 4 NICU and PICU to assess the rate and types of molecular diagnoses, and the prevalence, types, and effect of diagnoses that are likely to change medical management in critically ill infants.
We did a retrospective comparison of STATseq and standard genetic testing in a case series from the NICU and PICU of a large children's hospital between Nov 11, 2011, and Oct 1, 2014. The participants were families with an infant younger than 4 months with an acute illness of suspected genetic cause. The intervention was STATseq of trios (both parents and their affected infant). The main measures were the diagnostic rate, time to diagnosis, and rate of change in management after standard genetic testing and STATseq.
20 (57%) of 35 infants were diagnosed with a genetic disease by use of STATseq and three (9%) of 32 by use of standard genetic testing (p=0·0002). Median time to genome analysis was 5 days (range 3-153) and median time to STATseq report was 23 days (5-912). 13 (65%) of 20 STATseq diagnoses were associated with de-novo mutations. Acute clinical usefulness was noted in 13 (65%) of 20 infants with a STATseq diagnosis, four (20%) had diagnoses with strongly favourable effects on management, and six (30%) were started on palliative care. 120-day mortality was 57% (12 of 21) in infants with a genetic diagnosis.
In selected acutely ill infants, STATseq had a high rate of diagnosis of genetic disorders. Most diagnoses altered the management of infants in the NICU or PICU. The very high infant mortality rate indicates a substantial need for rapid genomic diagnoses to be allied with a novel framework for precision medicine for infants in NICU and PICU who are diagnosed with genetic diseases to improve outcomes.
Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Human Genome Research Institute, and National Center for Advancing Translational Sciences.
Lumacaftor and ivacaftor combination treatment showed efficacy in patients aged 12 years or older with cystic fibrosis homozygous for F508del-cystic fibrosis transmembrane conductance regulator ...(CFTR) in placebo-controlled studies and patients aged 6-11 years with cystic fibrosis homozygous for F508del-CFTR in an open-label study. We report efficacy and safety of lumacaftor and ivacaftor in patients with cystic fibrosis aged 6-11 years homozygous for F508del-CFTR.
In this phase 3, randomised, double-blind, placebo-controlled, multicentre study, patients were enrolled at 54 hospitals and medical centres in nine countries (the USA, Australia, Belgium, Canada, Denmark, France, Germany, Sweden, and the UK). Eligible patients weighed at least 15 kg, with a confirmed diagnosis of cystic fibrosis, percent predicted forced expiratory volume in 1 s (FEV
) of 70 or more, and lung clearance index
(LCI
) of 7·5 or more at screening (values less than these thresholds were permitted at day 1). All patients were tested for CFTR genotype at screening; eligible patients had to have the F508del-CFTR mutation on both alleles. Exclusion criteria included any comorbidity or laboratory abnormality that might confound the study results or pose additional risk to the patient. Patients were stratified by weight (<25 kg vs ≥25 kg) and ppFEV
severity (<90 vs ≥90) determined at the screening visit, and randomly assigned 1:1 to treatment using an interactive web response system to receive 200 mg lumacaftor and 250 mg ivacaftor every 12 hours or placebo for 24 weeks. Patients, all site personnel including the investigator and the site monitor, and the study team were blinded, with the exception of site personnel needing this information in the event of medical emergency or pregnancy and patient safety and regulatory affairs personnel to meet serious adverse event reporting requirements. The primary endpoint was the mean absolute change in LCI
from all on-treatment study visits up to and including week 24. All randomly assigned patients who were exposed to any amount of study drug, with treatment assignment as assigned were included in primary and other efficacy analyses. All patients who were exposed to any amount of study drug, with treatment assignment as treated, were included in the safety analysis. This study was registered with ClinicalTrials.gov, number NCT02514473.
Between July 23, 2015, and Sept 20, 2016, a total of 206 patients were enrolled and randomly assigned to receive lumacaftor and ivacaftor (n=104) or placebo (n=102). Two randomly assigned patients were never dosed with study drug (one in the placebo arm due to ineligibility arising from a streptococcal throat infection and one in the lumacaftor and ivacaftor arm due to withdrawal based on refusal to provide blood tests) and were not included in the analyses. 103 patients received at least one dose of lumacaftor and ivacaftor and 101 patients received at least one dose of placebo. For the primary endpoint, the average absolute change in LCI
from baseline over all study visits up to and including the week 24 visit, least squares mean difference was -1·09 units (95% CI -1·43 to -0·75, p<0·0001) for lumacaftor and ivacaftor versus placebo. For the key secondary endpoint of sweat chloride concentration, the least squares mean difference versus placebo was -20·8 mmol/L (95% CI -23·4 to -18·2, average absolute change at day 15/week 4; p<0·0001). The least squares mean difference compared with placebo in absolute change in ppFEV
from all on-treatment study visits until week 24 was 2·4 (95% CI 0·4-4·4, p=0·0182). 196 (96%) of 204 patients reported adverse events, most of which were mild (87 43%) or moderate (98 48%). Treatment was discontinued due to adverse events in three (3%) of 103 patients in the lumacaftor and ivacaftor group and two (2%) of 101 patients in the placebo group. Serious adverse events were reported in 13 (13%) of 103 patients in the lumacaftor and ivacaftor group and 11 (11%) of 101 patients in the placebo group.
Treatment with lumacaftor and ivacaftor was associated with statistically significant improvements in lung function, as measured by LCI
and ppFEV
, versus placebo in patients aged 6-11 years with cystic fibrosis homozygous for F508del-CFTR. The overall safety profile was consistent with previous phase 3 studies of lumacaftor and ivacaftor.
Vertex Pharmaceuticals.
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