Early Release Science of the exoplanet WASP-39b with JWST NIRSpec PRISM.

Transmission spectroscopy1-3 of exoplanets has revealed signatures of water vapour, aerosols and alkali metals in a few dozen exoplanet atmospheres4,5. However, these previous inferences with the Hubble and Spitzer Space Telescopes were hindered by the observations' relatively narrow wavelength range and spectral resolving power, which precluded the unambiguous identification of other chemical species-in particular the primary carbon-bearing molecules6,7. Here we report a broad-wavelength 0.5-5.5 µm atmospheric transmission spectrum of WASP-39b8, a 1,200 K, roughly Saturn-mass, Jupiter-radius exoplanet, measured with the JWST NIRSpec's PRISM mode9 as part of the JWST Transiting Exoplanet Community Early Release Science Team Program10-12. We robustly detect several chemical species at high significance, including Na (19σ), H2O (33σ), CO2 (28σ) and CO (7σ). The non-detection of CH4, combined with a strong CO2 feature, favours atmospheric models with a super-solar atmospheric metallicity. An unanticipated absorption feature at 4 µm is best explained by SO2 (2.7σ), which could be a tracer of atmospheric photochemistry. These observations demonstrate JWST's sensitivity to a rich diversity of exoplanet compositions and chemical processes.

Modes of delivery of genetic testing services and the uptake of cancer risk management strategies in BRCA1 and BRCA2 carriers.

BRCA testing services are now offered by various healthcare providers, thus it is important to evaluate whether the implementation of cancer risk management (CRM) strategies varies by service provider. Using a registry-based sample of 795 female BRCA mutation carriers, we explored the association between uptake of CRM strategies with duration of genetic counseling (GC) sessions, provider type, and other demographic and clinical variables. All participants completed a baseline questionnaire. Information about uptake of CRM strategies was collected for a subset of 438 participants who completed additional questions. Summary statistics and Pearson chi-squared analysis were used to examine the associations between demographic and clinical variables with service delivery factors and with the uptake of various CRM strategies. Overall uptake of CRM strategies was high across all provider types. However, GC sessions were longer when provided by a genetics professional than by another provider (p < 0.001). Furthermore, higher frequencies of uptake of most CRM strategies were associated with longer GC sessions and when testing was performed by a genetics professional. Identification of factors to optimize delivery of these specialized GC services is important to maximize implementation of CRM strategies in BRCA carriers.

Patient-led training on patient safety: a pilot study to test the feasibility and acceptability of an educational intervention.

BACKGROUND: Training in patient safety is an important element of medical education. Most educational interventions on patient safety training adopt a 'health-professional lens' with limited consideration on the impact of safety lapses on the patient and their families and little or no involvement of patients in the design or delivery of the training. AIMS: This paper describes a pilot study to test the feasibility and acceptability of implementing a patient-led educational intervention to facilitate safety training amongst newly qualified doctors. METHOD: Patients and/or carers who had experienced harm during their care shared narratives of their stories with trainees; this was followed by a focused discussion on patient safety issues exploring the causes and consequences of safety incidents and lessons to be learned from these. RESULTS: The intervention, which will be further tested in an NIHR-funded randomised controlled trial (RCT), was successfully implemented into an existing training programme and found acceptance amongst the patients and trainees. CONCLUSION: The pilot study proved to be a useful step in refining the intervention for the RCT including identifying appropriate outcome measures and highlighting organisational issues.

Frequency of mutations in mismatch repair genes in a population-based study of women with ovarian cancer.

BACKGROUND: Mutations in genes for hereditary non-polyposis colorectal cancer (HNPCC) in ovarian cancer patients remains poorly defined. We sought to estimate the frequency and characteristics of HNPCC gene mutations in a population-based sample of women with epithelial ovarian cancer. METHODS: The analysis included 1893 women with epithelial ovarian cancer ascertained from three population-based studies. Full-germline DNA sequencing of the coding regions was performed on three HNPCC genes, MLH1, MSH2 and MSH6. Collection of demographic, clinical and family history information was attempted in all women. RESULTS: Nine clearly pathogenic mutations were identified, including five in MSH6, two each in MLH1 and MSH2. In addition, 28 unique predicted pathogenic missense variants were identified in 55 patients. Pathogenic mutation carriers had an earlier mean age at diagnosis of ovarian cancer, overrepresentation of cancers with non-serous histologies and a higher number of relatives with HNPCC-related cancers. CONCLUSIONS: Our findings suggest that fewer than 1% of women with ovarian cancer harbour a germline mutation in the HNPCC genes, with overrepresentation of MSH6 mutations. This represents a lower-range estimate due to the large number of predicted pathogenic variants in which pathogenicity could not definitively be determined. Identification of mismatch repair gene mutations has the potential to impact screening and treatment decisions in these women.

Pan-cancer analysis of fear of cancer recurrence among cancer survivors.

BACKGROUND: Fear of cancer recurrence (FCR) is a phenomenon estimated to affect a large portion of cancer survivors. This study sought to determine whether patients from a National Cancer Institute-designated institution had their clinical needs met relating to FCR. PATIENTS AND METHODS: Patients referred to the survivorship clinic completed The Clinical Needs Assessment Tool for Cancer Survivors (CNAT-CS). Correlations between responses were calculated and univariable and multivariable logistic regression was used to identify predictors of met or unmet needs related to FCR. RESULTS: Of 647 patients, 241 (37.2%) reported they did not have clinical needs related to FCR and 386 (59.7%) reported they had clinical needs related to FCR but that the needs had been met. Only 20 (3.09%) reported that clinical needs relating to FCR were unmet. According to univariate logistic regression, sex had no impact on FCR (P = 0.8427), nor did years since diagnosis (P = 0.1014). Results of multivariable regression indicate that the odds ratio of reported FCR as an unmet need (versus not a need) is 0.939; the odds decreased by 6% (P = 0.0023) for every year increase in age. For each unit increase in distress score, the odds of reporting FCR as an unmet need increased by 32% (P = 0.0007). CONCLUSIONS: This study is unique in not only examining the presence of FCR but also whether patients reported that their needs were met for FCR. The study found that most patients had clinical needs for FCR, but the needs were met at the time of the survey. Patients who report higher distress scores are more likely to report FCR as an unmet need. Therefore, cancer survivors reporting high distress scores in clinic visits should be evaluated for FCR.

Factors that influence mesenteric artery blood flow velocity in newborn preterm infants.

OBJECTIVES: To identify demographic and clinical variables that relate to the postnatal increase in intestinal blood flow velocity in preterm infants. STUDY DESIGN: Fasting or preprandial peak systolic velocity (PSV) and time-averaged mean velocity (TAMV) in the superior mesenteric artery were measured once each day for the first 5 days of life. We investigated the relationship between blood flow velocity and the following variables: birth weight, gestational age, feeding volumes, number of days to reach full feeding volumes, type of feeding given, continuous positive airway pressure (CPAP) administration and hyperalimentation (HAL) administration. RESULTS: Twenty-five infants with a mean birth weight of 1740 g and mean gestational age of 31.8 weeks were studied. There were significant increases in PSV (P < 0.001) and TAMV (P = 0.005) from postnatal day 1 to 5. The postnatal increase in TAMV and PSV was attenuated in infants administered CPAP or HAL for > or =3 days; the results remained significant after controlling for birth weight and gestational age. There was a significant correlation (P < 0.02) between volume of enteral feedings given on 2 of 5 days for TAMV, and on 1 of 5 days for PSV. CONCLUSIONS: These data support previous findings of significant increases in intestinal blood flow in preterm infants during the first week of life, and of inconsistent effects of enteral feeding volumes on fasting or preprandial intestinal blood flow. The reasons for, and the clinical implications of, attenuated increases in postnatal intestinal blood flow in infants on CPAP or HAL require further investigation.

Umbilical cord nucleated red blood cell counts: normal values and the effect of labor.

OBJECTIVE: To determine the umbilical cord blood nucleated red blood cell (UC-nRBC) count in uncomplicated pregnancies delivered by elective cesarean section or delivered vaginally. METHODS: A total of 57-term singleton pregnancies were studied: 33 with elective cesarean sections and 24 with vaginal deliveries. UC-nRBC was analyzed for its nucleated red blood cell counts. A logarithmic transformation of the data was used for statistical analysis. RESULTS: The mean+/-standard deviation (s.d.) for nucleated red blood cell per 100 white blood cells (nRBC/100WBC) from the elective cesarean section group was 7.8+/-7.4. The vaginal delivery group had a mean value of 9.3+/-10.5, which was not significantly different. A value of 22 nRBC/100WBC defined the upper 95% confidence limit. The correlation between absolute nRBC and nRBC/100 WBC was 0.97. CONCLUSION: Although chronic hypoxia is associated with elevated nRBC, the stress of uncomplicated labor does not change the level. This adds credence to its use as a marker for hypoxia preceding labor and delivery.

Differential association of STK11 and TP53 with KRAS mutation-associated gene expression, proliferation and immune surveillance in lung adenocarcinoma.

While mutations in the KRAS oncogene are among the most prevalent in human cancer, there are few successful treatments to target these tumors. It is also likely that heterogeneity in KRAS-mutant tumor biology significantly contributes to the response to therapy. We hypothesized that the presence of commonly co-occurring mutations in STK11 and TP53 tumor suppressors may represent a significant source of heterogeneity in KRAS-mutant tumors. To address this, we utilized a large cohort of resected tumors from 442 lung adenocarcinoma patients with data including annotation of prevalent driver mutations (KRAS and EGFR) and tumor suppressor mutations (STK11 and TP53), microarray-based gene expression and clinical covariates, including overall survival (OS). Specifically, we determined impact of STK11 and TP53 mutations on a new KRAS mutation-associated gene expression signature as well as previously defined signatures of tumor cell proliferation and immune surveillance responses. Interestingly, STK11, but not TP53 mutations, were associated with highly elevated expression of KRAS mutation-associated genes. Mutations in TP53 and STK11 also impacted tumor biology regardless of KRAS status, with TP53 strongly associated with enhanced proliferation and STK11 with suppression of immune surveillance. These findings illustrate the remarkably distinct ways through which tumor suppressor mutations may contribute to heterogeneity in KRAS-mutant tumor biology. In addition, these studies point to novel associations between gene mutations and immune surveillance that could impact the response to immunotherapy.

An international data set for CMML validates prognostic scoring systems and demonstrates a need for novel prognostication strategies.

Since its reclassification as a distinct disease entity, clinical research efforts have attempted to establish baseline characteristics and prognostic scoring systems for chronic myelomonocytic leukemia (CMML). Although existing data for baseline characteristics and CMML prognostication have been robustly developed and externally validated, these results have been limited by the small size of single-institution cohorts. We developed an international CMML data set that included 1832 cases across eight centers to establish the frequency of key clinical characteristics. Of note, we found that the majority of CMML patients were classified as World Health Organization CMML-1 and that a 7.5% bone marrow blast cut-point may discriminate prognosis with higher resolution in comparison with the existing 10%. We additionally interrogated existing CMML prognostic models and found that they are all valid and have comparable performance but are vulnerable to upstaging. Using random forest survival analysis for variable discovery, we demonstrated that the prognostic power of clinical variables alone is limited. Last, we confirmed the independent prognostic relevance of ASXL1 gene mutations and identified the novel adverse prognostic impact imparted by CBL mutations. Our data suggest that combinations of clinical and molecular information may be required to improve the accuracy of current CMML prognostication.

Calpain inhibition mediates autophagy-dependent protection against polyglutamine toxicity.

Over recent years, accumulated evidence suggests that autophagy induction is protective in animal models of a number of neurodegenerative diseases. Intense research in the field has elucidated different pathways through which autophagy can be upregulated and it is important to establish how modulation of these pathways impacts upon disease progression in vivo and therefore which, if any, may have further therapeutic relevance. In addition, it is important to understand how alterations in these target pathways may affect normal physiology when constitutively modulated over a long time period, as would be required for treatment of neurodegenerative diseases. Here we evaluate the potential protective effect of downregulation of calpains. We demonstrate, in Drosophila, that calpain knockdown protects against the aggregation and toxicity of proteins, like mutant huntingtin, in an autophagy-dependent fashion. Furthermore, we demonstrate that, overexpression of the calpain inhibitor, calpastatin, increases autophagosome levels and is protective in a mouse model of Huntington's disease, improving motor signs and delaying the onset of tremors. Importantly, long-term inhibition of calpains did not result in any overt deleterious phenotypes in mice. Thus, calpain inhibition, or activation of autophagy pathways downstream of calpains, may be suitable therapeutic targets for diseases like Huntington's disease.

Cellular and molecular characterization of a murine non-union model.

PURPOSE: We have developed a method to study the molecular and cellular events underlying delayed skeletal repair in a model that utilizes distraction osteogenesis. METHODS: The clinical states of delayed union and non-union were reproduced in this murine model by altering distraction parameters such as the inclusion and exclusion of a latency phase and variations in the rate and rhythm of distraction. Radiographic, cellular, and molecular analyses were performed on the distraction tissues. RESULTS: Eliminating the latency period delayed bony union, but did not appreciably alter the extent of platelet endothelial cell adhesion marker (PECAM) immunostaining. Following elimination of a latency phase and a threefold increase in the rate of distraction, there was a further delay in bone regeneration and a higher rate of non-union (60%). Instead of bone, the distraction gap was comprised of adipose or fibrous tissue. Once again, despite the rigorous distraction protocol, we detected equivalent PECAM staining within the distraction gap. In a minority of cases, cartilage and osseous tissues occupied the distraction gap likely by a prolonged process of endochondral ossification. CONCLUSIONS: Here, we have altered the mechanical environment in such a way to reproducibly create delays in skeletal regeneration. These delays in skeletal tissue regeneration appear to develop even in the presence of endothelial cells, which suggests that mechanisms other than a disruption to the vascular network can account for some cases of non-union.