Fetal structural anomalies, which are detected by ultrasonography, have a range of genetic causes, including chromosomal aneuploidy, copy number variations (CNVs; which are detectable by chromosomal ...microarrays), and pathogenic sequence variants in developmental genes. Testing for aneuploidy and CNVs is routine during the investigation of fetal structural anomalies, but there is little information on the clinical usefulness of genome-wide next-generation sequencing in the prenatal setting. We therefore aimed to evaluate the proportion of fetuses with structural abnormalities that had identifiable variants in genes associated with developmental disorders when assessed with whole-exome sequencing (WES).
In this prospective cohort study, two groups in Birmingham and London recruited patients from 34 fetal medicine units in England and Scotland. We used whole-exome sequencing (WES) to evaluate the presence of genetic variants in developmental disorder genes (diagnostic genetic variants) in a cohort of fetuses with structural anomalies and samples from their parents, after exclusion of aneuploidy and large CNVs. Women were eligible for inclusion if they were undergoing invasive testing for identified nuchal translucency or structural anomalies in their fetus, as detected by ultrasound after 11 weeks of gestation. The partners of these women also had to consent to participate. Sequencing results were interpreted with a targeted virtual gene panel for developmental disorders that comprised 1628 genes. Genetic results related to fetal structural anomaly phenotypes were then validated and reported postnatally. The primary endpoint, which was assessed in all fetuses, was the detection of diagnostic genetic variants considered to have caused the fetal developmental anomaly.
The cohort was recruited between Oct 22, 2014, and June 29, 2017, and clinical data were collected until March 31, 2018. After exclusion of fetuses with aneuploidy and CNVs, 610 fetuses with structural anomalies and 1202 matched parental samples (analysed as 596 fetus-parental trios, including two sets of twins, and 14 fetus-parent dyads) were analysed by WES. After bioinformatic filtering and prioritisation according to allele frequency and effect on protein and inheritance pattern, 321 genetic variants (representing 255 potential diagnoses) were selected as potentially pathogenic genetic variants (diagnostic genetic variants), and these variants were reviewed by a multidisciplinary clinical review panel. A diagnostic genetic variant was identified in 52 (8·5%; 95% CI 6·4–11·0) of 610 fetuses assessed and an additional 24 (3·9%) fetuses had a variant of uncertain significance that had potential clinical usefulness. Detection of diagnostic genetic variants enabled us to distinguish between syndromic and non-syndromic fetal anomalies (eg, congenital heart disease only vs a syndrome with congenital heart disease and learning disability). Diagnostic genetic variants were present in 22 (15·4%) of 143 fetuses with multisystem anomalies (ie, more than one fetal structural anomaly), nine (11·1%) of 81 fetuses with cardiac anomalies, and ten (15·4%) of 65 fetuses with skeletal anomalies; these phenotypes were most commonly associated with diagnostic variants. However, diagnostic genetic variants were least common in fetuses with isolated increased nuchal translucency (≥4·0 mm) in the first trimester (in three 3·2% of 93 fetuses).
WES facilitates genetic diagnosis of fetal structural anomalies, which enables more accurate predictions of fetal prognosis and risk of recurrence in future pregnancies. However, the overall detection of diagnostic genetic variants in a prospectively ascertained cohort with a broad range of fetal structural anomalies is lower than that suggested by previous smaller-scale studies of fewer phenotypes. WES improved the identification of genetic disorders in fetuses with structural abnormalities; however, before clinical implementation, careful consideration should be given to case selection to maximise clinical usefulness.
UK Department of Health and Social Care and The Wellcome Trust.
We report consensus recommendations on magnetic resonance imaging in active surveillance. These include image quality, T2-weighted imaging and other sequences for lesion measurement, and updated ...Prostate Cancer Radiological Estimation of Change in Sequential Evaluation score differentiating stable visible and nonvisible disease. Further research is needed to define significant lesion size changes.
The Prostate Cancer Radiological Estimation of Change in Sequential Evaluation (PRECISE) recommendations standardise the reporting of prostate magnetic resonance imaging (MRI) in patients on active surveillance (AS) for prostate cancer. An international consensus group recently updated these recommendations and identified the areas of uncertainty.
A panel of 38 experts used the formal RAND/UCLA Appropriateness Method consensus methodology. Panellists scored 193 statements using a 1–9 agreement scale, where 9 means full agreement. A summary of agreement, uncertainty, or disagreement (derived from the group median score) and consensus (determined using the Interpercentile Range Adjusted for Symmetry method) was calculated for each statement and presented for discussion before individual rescoring.
Participants agreed that MRI scans must meet a minimum image quality standard (median 9) or be given a score of ‘X’ for insufficient quality. The current scan should be compared with both baseline and previous scans (median 9), with the PRECISE score being the maximum from any lesion (median 8). PRECISE 3 (stable MRI) was subdivided into 3-V (visible) and 3-NonV (nonvisible) disease (median 9). Prostate Imaging Reporting and Data System/Likert ≥3 lesions should be measured on T2-weighted imaging, using other sequences to aid in the identification (median 8), and whenever possible, reported pictorially (diagrams, screenshots, or contours; median 9). There was no consensus on how to measure tumour size. More research is needed to determine a significant size increase (median 9). PRECISE 5 was clarified as progression to stage ≥T3a (median 9).
The updated PRECISE recommendations reflect expert consensus opinion on minimal standards and reporting criteria for prostate MRI in AS.
Prostate-cancer biopsy directed at areas of MRI abnormality was compared with standard transrectal ultrasonographic biopsy for diagnostic specificity and sensitivity. MRI-targeted biopsy identified ...more high-risk cancers and fewer clinically insignificant tumors.
CONTEXT Between March and July 2009, the largest number of confirmed cases of 2009 influenza A(H1N1) infection occurred in North America. OBJECTIVE To describe characteristics, treatment, and ...outcomes of critically ill patients in Canada with 2009 influenza A(H1N1) infection. DESIGN, SETTING, AND PATIENTS A prospective observational study of 168 critically ill patients with 2009 influenza A(H1N1) infection in 38 adult and pediatric intensive care units (ICUs) in Canada between April 16 and August 12, 2009. MAIN OUTCOME MEASURES The primary outcome measures were 28-day and 90-day mortality. Secondary outcomes included frequency and duration of mechanical ventilation and duration of ICU stay. RESULTS Critical illness occurred in 215 patients with confirmed (n = 162), probable (n = 6), or suspected (n = 47) community-acquired 2009 influenza A(H1N1) infection. Among the 168 patients with confirmed or probable 2009 influenza A(H1N1), the mean (SD) age was 32.3 (21.4) years; 113 were female (67.3%) and 50 were children (29.8%). Overall mortality among critically ill patients at 28 days was 14.3% (95% confidence interval, 9.5%-20.7%). There were 43 patients who were aboriginal Canadians (25.6%). The median time from symptom onset to hospital admission was 4 days (interquartile range IQR, 2-7 days) and from hospitalization to ICU admission was 1 day (IQR, 0-2 days). Shock and nonpulmonary acute organ dysfunction was common (Sequential Organ Failure Assessment mean SD score of 6.8 3.6 on day 1). Neuraminidase inhibitors were administered to 152 patients (90.5%). All patients were severely hypoxemic (mean SD ratio of PaO2 to fraction of inspired oxygen FIO2 of 147 128 mm Hg) at ICU admission. Mechanical ventilation was received by 136 patients (81.0%). The median duration of ventilation was 12 days (IQR, 6-20 days) and ICU stay was 12 days (IQR, 5-20 days). Lung rescue therapies included neuromuscular blockade (28% of patients), inhaled nitric oxide (13.7%), high-frequency oscillatory ventilation (11.9%), extracorporeal membrane oxygenation (4.2%), and prone positioning ventilation (3.0%). Overall mortality among critically ill patients at 90 days was 17.3% (95% confidence interval, 12.0%-24.0%; n = 29). CONCLUSION Critical illness due to 2009 influenza A(H1N1) in Canada occurred rapidly after hospital admission, often in young adults, and was associated with severe hypoxemia, multisystem organ failure, a requirement for prolonged mechanical ventilation, and the frequent use of rescue therapies.Published online October 12, 2009 (doi:10.1001/jama.2009.1496).
Cancer remains one of the leading causes of mortality worldwide, leading to increased interest in utilizing immunotherapy strategies for better cancer treatments. In the past decade, CD103
T cells ...have been associated with better clinical prognosis in patients with cancer. However, the specific immune mechanisms contributing toward CD103-mediated protective immunity remain unclear. Here, we show an unexpected and transient CD61 expression, which is paired with CD103 at the synaptic microclusters of T cells. CD61 colocalization with the T cell antigen receptor further modulates downstream T cell antigen receptor signaling, improving antitumor cytotoxicity and promoting physiological control of tumor growth. Clinically, the presence of CD61
tumor-infiltrating T lymphocytes is associated with improved clinical outcomes, mediated through enhanced effector functions and phenotype with limited evidence of cellular exhaustion. In conclusion, this study identified an unconventional and transient CD61 expression and pairing with CD103 on human immune cells, which potentiates a new target for immune-based cellular therapies.
10003 Background: A subset of children with INRGSS Stage MS neuroblastoma (NBL) may be observed without treatment, while others have rapidly evolving symptoms that can be life-threatening. ANBL1232 ...adapted a previously developed semi-quantitative objective scoring system (OSS) to assign a numeric value to symptoms and laboratory abnormalities. The goal was to standardize monitoring, therapy initiation, and treatment duration in this cohort. Methods: Patients with newly diagnosed Stage MS NBL were eligible for this prospective trial. An OSS score (OSSS) was assigned at enrollment; the total number was based on scoring in 5 systems: gastrointestinal (GI), respiratory, circulatory, renal, and hepatic. Within the 5 systems, individual clinical and laboratory parameters were scored as not present = 0, mild/moderate = 1 Grade 2 CTCAEv4.0 adverse event (AE) or severe = 2 (Grade ≥3 AE). The OSSS was the sum of highest score within each organ system (maximum score: 2 per system, 10 total). Asymptomatic MS patients with an OSSS < 2 who were either < 3 months (mo) of age without hepatomegaly or 3-18 mo of age with favorable biology tumors were eligible for observation without initial treatment. Observed patients underwent monthly physical examinations and laboratory assessments for the first 6 mo following diagnosis. Tumor imaging was performed every 3 mo for 1 year, then every 6-12 mo through 36 mo. An OSSS ≥2 or a protocol-defined increase in primary tumor size prompted initiation of therapy. Results: From July 2014 to February 2021, 89 eligible and evaluable patients with newly diagnosed stage MS NBL enrolled. Among these, 18 (20.2%; 5 male and 13 female) were eligible for observation. Observed patients were older at diagnosis (median age: 2.87 vs. 1.81 mo, p = 0.23) and more likely to have primary tumors without image-defined risk factors (62.5% vs. 30.0%, p = 0.0166) than those assigned to therapy up front. Nearly all observed patients (17/18) had abdominal/adrenal primaries. The initial OSSS was 0 in all observed patients. Median reported observation time was 36 mo (range: 1-36 mo); 13 patients completed all required monthly assessments for the first 6 mo. No patients in the observation cohort required initiation of therapy for an increase in OSSS. One patient with OSSS = 1 at mo 3 had complete GI symptom resolution by mo 5. Conclusions: An OSSS of 0 at diagnosis can aid in identifying a favorable group of patients with stage MS NBL who can be safely observed. No patients in the observation cohort developed evidence of organ dysfunction or OSSS > 1 despite frequent physical examination and comprehensive laboratory testing, suggesting that follow up may be safely liberalized in this population over time. Clinical and laboratory criteria implemented at diagnosis could be used to identify patients requiring prompt treatment. Clinical trial information: NCT02176967 .
DGAT2 plays a critical role in hepatic triglyceride production, and data suggests that inhibition of DGAT2 could prove to be beneficial in treating a number of disease states. This article documents ...the discovery and optimization of a selective small molecule inhibitor of DGAT2 as well as pharmacological proof of biology in a mouse model of triglyceride production.
To assess the additional cost of incorporating the detection and treatment of retinopathy of prematurity (ROP) into neonatal care services of Brazil's Unified Health System (SUS).
A deterministic ...decision-tree simulation model was built to estimate the direct costs of screening for and treating ROP in neonatal intensive-care units (NICUs), based on data for 869 preterm infants with birth weight less than 1 500 g examined in six governmental NICUs in the capital city of Rio de Janeiro, where coverage was 52% and 8% of infants were treated. All of the parameters from this study were extrapolated to Brazilian newborn estimates in 2010. Costs of screening and treatment were estimated considering staff, equipment and maintenance, and training based on published data and expert opinion. A budget impact analysis was performed considering the population of preterm newborns, screening coverage, and the incidence of treatable ROP. One- and two-way sensitivity analyses were performed.
In Rio de Janeiro, unit costs per newborn were US$ 18 for each examination, US$ 398 per treatment, and US$ 29 for training. The estimated cost of ROP diagnosis and treatment for all at-risk infants NICUs was US$ 80 per infant. The additional cost to the SUS for one year would be US$ 556 640 for a ROP program with 52% coverage, increasing to US$ 856 320 for 80% coverage, and US$ 1.07 million or 100% coverage.
The results of this study indicate that providing ROP care is affordable within the framework of the SUS in Brazil, and might be feasible elsewhere in Latin America, considering the evidence of the effectiveness of ROP treatment and the social benefits achieved.
We aimed to evaluate differences in outcome between patients admitted to intensive care unit (ICU) after elective versus acute surgery in a multinational cohort of very old patients (≥80 years; VIP). ...Predictors of mortality, with special emphasis on frailty, were assessed.
In total, 5063 VIPs were included in this analysis, 922 were admitted after elective surgery or intervention, 4141 acutely, with 402 after acute surgery. Differences were calculated using Mann-Whitney-U test and Wilcoxon test. Univariate and multivariable logistic regression were used to assess associations with mortality.
Compared patients admitted after acute surgery, patients admitted after elective surgery suffered less often from frailty as defined as CFS (28% vs 46%; p < 0.001), evidenced lower SOFA scores (4 ± 5 vs 7 ± 7; p < 0.001). Presence of frailty (CFS >4) was associated with significantly increased mortality both in elective surgery patients (7% vs 12%; p = 0.01), in acute surgery (7% vs 12%; p = 0.02).
VIPs admitted to ICU after elective surgery evidenced favorable outcome over patients after acute surgery even after correction for relevant confounders. Frailty might be used to guide clinicians in risk stratification in both patients admitted after elective and acute surgery.
Trial registration: NCT03134807. Registered 1st May 2017.
•We evaluated differences in outcome between VIPs admitted to ICU after elective versus acute intervention•VIPs after elective intervention evidenced favorable outcome after correction for relevant confounders•Frailty might be used to guide clinicians in risk stratification in both patients admitted after elective and acute surgery.
Abstract
Background
Intensive care unit (ICU) patients age 90 years or older represent a growing subgroup and place a huge financial burden on health care resources despite the benefit being unclear. ...This leads to ethical problems. The present investigation assessed the differences in outcome between nonagenarian and octogenarian ICU patients.
Methods
We included 7900 acutely admitted older critically ill patients from two large, multinational studies. The primary outcome was 30-day-mortality, and the secondary outcome was ICU-mortality. Baseline characteristics consisted of frailty assessed by the Clinical Frailty Scale (CFS), ICU-management, and outcomes were compared between octogenarian (80–89.9 years) and nonagenarian (
>
90 years) patients. We used multilevel logistic regression to evaluate differences between octogenarians and nonagenarians.
Results
The nonagenarians were 10% of the entire cohort. They experienced a higher percentage of frailty (58% vs 42%;
p
< 0.001), but lower SOFA scores at admission (6
+
5 vs. 7
+
6;
p
< 0.001). ICU-management strategies were different. Octogenarians required higher rates of organ support and nonagenarians received higher rates of life-sustaining treatment limitations (40% vs. 33%;
p
< 0.001). ICU mortality was comparable (27% vs. 27%;
p
= 0.973) but a higher 30-day-mortality (45% vs. 40%;
p
= 0.029) was seen in the nonagenarians. After multivariable adjustment nonagenarians had no significantly increased risk for 30-day-mortality (aOR 1.25 (95% CI 0.90–1.74;
p
= 0.19)).
Conclusion
After adjustment for confounders, nonagenarians demonstrated no higher 30-day mortality than octogenarian patients. In this study, being age 90 years or more is no particular risk factor for an adverse outcome. This should be considered– together with illness severity and pre-existing functional capacity - to effectively guide triage decisions.
Trial registration
NCT03134807
and
NCT03370692
.
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