Identification of Genes with Rare Loss of Function Variants Associated with Aggressive Prostate Cancer and Survival.

BACKGROUND: Prostate cancer (PrCa) is a substantial cause of mortality among men globally. Rare germline mutations in BRCA2 have been validated robustly as increasing risk of aggressive forms with a poorer prognosis; however, evidence remains less definitive for other genes. OBJECTIVE: To detect genes associated with PrCa aggressiveness, through a pooled analysis of rare variant sequencing data from six previously reported studies in the UK Genetic Prostate Cancer Study (UKGPCS). DESIGN, SETTING, AND PARTICIPANTS: We accumulated a cohort of 6805 PrCa cases, in which a set of ten candidate genes had been sequenced in all samples. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We examined the association between rare putative loss of function (pLOF) variants in each gene and aggressive classification (defined as any of death from PrCa, metastatic disease, stage T4, or both stage T3 and Gleason score ≥8). Secondary analyses examined staging phenotypes individually. Cox proportional hazards modelling and Kaplan-Meier survival analyses were used to further examine the relationship between mutation status and survival. RESULTS AND LIMITATIONS: We observed associations between PrCa aggressiveness and pLOF mutations in ATM, BRCA2, MSH2, and NBN (odds ratio = 2.67-18.9). These four genes and MLH1 were additionally associated with one or more secondary analysis phenotype. Carriers of germline mutations in these genes experienced shorter PrCa-specific survival (hazard ratio = 2.15, 95% confidence interval 1.79-2.59, p = 4 × 10-16) than noncarriers. CONCLUSIONS: This study provides further support that rare pLOF variants in specific genes are likely to increase aggressive PrCa risk and may help define the panel of informative genes for screening and treatment considerations. PATIENT SUMMARY: By combining data from several previous studies, we have been able to enhance knowledge regarding genes in which inherited mutations would be expected to increase the risk of more aggressive PrCa. This may, in the future, aid in the identification of men at an elevated risk of dying from PrCa.

Family History of Prostate Cancer and Survival Outcomes in the UK Genetic Prostate Cancer Study.

BACKGROUND: A family history (FH) of prostate cancer (PrCa) is associated with an increased likelihood of PrCa diagnosis. Conflicting evidence exists regarding familial PrCa and clinical outcomes among PrCa patients, including all-cause mortality/overall survival (OS), PrCa-specific survival (PCSS), aggressive histology, and stage at diagnosis. OBJECTIVE: To determine how the number, degree, and age of a PrCa patient's affected relatives are associated with OS and PCSS of those already diagnosed with PrCa. DESIGN, SETTING, AND PARTICIPANTS: The UK Genetic Prostate Cancer Study is a longitudinal, multi-institutional, observational study collecting baseline and follow-up clinical data since 1992. We examined OS and PCSS in 16340 men by degree and number of relatives with prostate and genetically related cancers (breast, ovarian, and colorectal). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was all-cause mortality among PrCa patients. The risk of death with respect to FH was assessed by calculating hazard ratios from Cox proportional hazard regression models, adjusting for relevant factors. RESULTS AND LIMITATIONS: A stronger FH was inversely associated with the risk of all-cause and PrCa-specific mortality. This association was greater in those with an increasing number (p-trend < 0.001) and increasing closeness (p-trend < 0.001) of the diagnosed relatives. Patients with at least one first-degree relative were at a lower risk of all-cause mortality than those with no FH (hazard ratio = 0.82 [95% confidence interval 0.75-0.89]). The population is largely of European ancestry, and this may cause an issue with representation and generalisation. Data are missing on epidemiological risk factors for death such as smoking and on comorbidities. Recall of family members' diagnoses may affect the classification of FH in unconfirmed cases. CONCLUSIONS: Based on the investigation of the type and timing of relatives' cancers, it is likely that reductions in mortality are due almost completely to a greater awareness of the disease. This study provides information for clinicians guiding patients and their relatives based on their familial risk. It shows the importance of screening and awareness programmes, which are likely to improve survival among men with an FH. PATIENT SUMMARY: We were interested in how a family history of prostate cancer affects survival in prostate cancer patients. We studied 16340 patients, categorised them according to the strength of their family history, and found that the stronger their family history, the better they did in terms of overall survival. We looked at the type and timing of patients' diagnoses compared with those of their relatives and found that this effect is likely to be explained by awareness, which indicates the importance of screening and awareness programmes.

Incidence and Clinical Features of Pneumomediastinum and Pneumothorax in COVID-19 Pneumonia.

BACKGROUND: Pneumothorax (PTX) and pneumomediastinum (PM), collectively termed here "air leak", are now well described complications of severe COVID-19 pneumonia across several case series. The incidence is thought to be approximately 1% but is not definitively known. OBJECTIVES: To report the incidence and describe the demographic features, risk factors and outcomes of patients with air leak as a complication of COVID-19. METHODS: A retrospective observational study on all adult patients with COVID-19 admitted to Watford General Hospital, West Hertfordshire NHS Trust between March 1st 2020 and Feb 28th 2021. Patients with air leak were identified after reviewing both chest radiographs (CXRs) and axial imaging (CT Thorax) with confirmatory radiology reports inclusive of the terms PTX and/or PM. RESULTS: Air leak occurred with an incidence of 0.56%. Patients with air leak were younger and had evidence of more severe disease at presentation, including a higher median CRP and number of abnormal zones affected on chest radiograph. Asthma was a significant risk factor in the development of air leak (OR 13.4 [4.7-36.4]), both spontaneously and following positive pressure ventilation. CPAP and IMV were also associated with a greater than six fold increase in the risk of air leak (OR 6.4 [2.5-16.6] and 9.8 [3.7-27.8] respectively). PTX, with or without PM, in the context of COVID-19 pneumonia was almost universally fatal whereas those with alone PM had a lower risk of death. CONCLUSION: Despite the global vaccination programme, patients continue to develop severe COVID-19 disease and may require respiratory support. This study demonstrates the importance of identifying that deterioration in such patients may be resultant from PTX or PM, particularly in asthmatics and those managed with positive pressure ventilation.

Necrotizing enterocolitis and congenital heart disease.

Necrotizing enterocolitis (NEC) remains a prominent surgical emergency among infant population, associated with a significant mortality, as well as various subsequent morbidities. Congenital heart disease (CHD) has an increased associated incidence with NEC in infant population. Recent research has provided insight into the pathophysiology of NEC in patients with CHD and how this differs from those without CHD. The deviation from normal circulatory physiology has a suggested association in the pathophysiology of NEC in CHD, which may have implications for the risk factors of NEC in infants with CHD, the effect on outcomes of NEC, and whether alternative approaches to management may need to be considered in comparison to classical NEC. This review aims to highlight studies that provide insight and awareness into the relationship between NEC and CHD, in order that clinicians may direct themselves more clearly toward optimal management for infants in this category.

The effect of antivirals on COVID-19: a systematic review.

INTRODUCTION: Coronavirus Disease 2019 is a contagious infection that has infected millions worldwide. The objective of this systematic review is to identify studies pertaining to antivirals, both as sole and combined therapies, in COVID-19 patients and review the clinical outcomes of these treatment methods. AREAS COVERED: A systematic review was conducted using Preferred Reporting Items or Systematic Reviews and Meta-analysis (PRISMA) guidelines. A literature search was done on Medline, Global Health, and EMBASE using keywords and MeSH terms relevant to COVID- 19 and antivirals. Limits were put on date to obtain articles between December 2019 to May 2020 (the time at which the search was performed). 776 articles were identified and screened. After screening, 16 studies were included. The narrative synthesis revealed three key themes (1) Use of antivirals only (such as lopinavir, umifenovir, and remdesivir), (2) Use of lopinavir-ritonavir alongside other treatments, and (3) Use of other antivirals in combination with other treatments. EXPERT OPINION: Using antivirals in combination with other treatments has potential; however, further randomized controlled trials with larger sample sizes are required to identify the best candidate components that should comprise combined treatments for COVID-19. This should optimize treatment efficacy and improve patient outcomes.

Relationship of self-reported body size and shape with risk for prostate cancer: A UK case-control study.

INTRODUCTION: Previous evidence has suggested a relationship between male self-reported body size and the risk of developing prostate cancer. In this UK-wide case-control study, we have explored the possible association of prostate cancer risk with male self-reported body size. We also investigated body shape as a surrogate marker for fat deposition around the body. As obesity and excessive adiposity have been linked with increased risk for developing a number of different cancers, further investigation of self-reported body size and shape and their potential relationship with prostate cancer was considered to be appropriate. OBJECTIVE: The study objective was to investigate whether underlying associations exist between prostate cancer risk and male self-reported body size and shape. METHODS: Data were collected from a large case-control study of men (1928 cases and 2043 controls) using self-administered questionnaires. Data from self-reported pictograms of perceived body size relating to three decades of life (20's, 30's and 40's) were recorded and analysed, including the pattern of change. The associations of self-identified body shape with prostate cancer risk were also explored. RESULTS: Self-reported body size for men in their 20's, 30's and 40's did not appear to be associated with prostate cancer risk. More than half of the subjects reported an increase in self-reported body size throughout these three decades of life. Furthermore, no association was observed between self-reported body size changes and prostate cancer risk. Using 'symmetrical' body shape as a reference group, subjects with an 'apple' shape showed a significant 27% reduction in risk (Odds ratio = 0.73, 95% C.I. 0.57-0.92). CONCLUSIONS: Change in self-reported body size throughout early to mid-adulthood in males is not a significant risk factor for the development of prostate cancer. Body shape indicative of body fat distribution suggested that an 'apple' body shape was protective and inversely associated with prostate cancer risk when compared with 'symmetrical' shape. Further studies which investigate prostate cancer risk and possible relationships with genetic factors known to influence body shape may shed further light on any underlying associations.

Homeobox B13 G84E Mutation and Prostate Cancer Risk.

BACKGROUND: The homeobox B13 (HOXB13) G84E mutation has been recommended for use in genetic counselling for prostate cancer (PCa), but the magnitude of PCa risk conferred by this mutation is uncertain. OBJECTIVE: To obtain precise risk estimates for mutation carriers and information on how these vary by family history and other factors. DESIGN, SETTING, AND PARTICIPANTS: Two-fold: a systematic review and meta-analysis of published risk estimates, and a kin-cohort study comprising pedigree data on 11983 PCa patients enrolled during 1993-2014 from 189 UK hospitals and who had been genotyped for HOXB13 G84E. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Relative and absolute PCa risks. Complex segregation analysis with ascertainment adjustment to derive age-specific risks applicable to the population, and to investigate how these vary by family history and birth cohort. RESULTS AND LIMITATIONS: A meta-analysis of case-control studies revealed significant heterogeneity between reported relative risks (RRs; range: 0.95-33.0, p<0.001) and differences by case selection (p=0.007). Based on case-control studies unselected for PCa family history, the pooled RR estimate was 3.43 (95% confidence interval [CI] 2.78-4.23). In the kin-cohort study, PCa risk for mutation carriers varied by family history (p<0.001). There was a suggestion that RRs decrease with age, but this was not significant (p=0.068). We found higher RR estimates for men from more recent birth cohorts (p=0.004): 3.09 (95% CI 2.03-4.71) for men born in 1929 or earlier and 5.96 (95% CI 4.01-8.88) for men born in 1930 or later. The absolute PCa risk by age 85 for a male HOXB13 G84E carrier varied from 60% for those with no PCa family history to 98% for those with two relatives diagnosed at young ages, compared with an average risk of 15% for noncarriers. Limitations include the reliance on self-reported cancer family history. CONCLUSIONS: PCa risks for HOXB13 G84E mutation carriers are heterogeneous. Counselling should not be based on average risk estimates but on age-specific absolute risk estimates tailored to individual mutation carriers' family history and birth cohort. PATIENT SUMMARY: Men who carry a hereditary mutation in the homeobox B13 (HOXB13) gene have a higher than average risk for developing prostate cancer. In our study, we examined a large number of families of men with prostate cancer recruited across UK hospitals, to assess what other factors may contribute to this risk and to assess whether we could create a precise model to help in predicting a man's prostate cancer risk. We found that the risk of developing prostate cancer in men who carry this genetic mutation is also affected by a family history of prostate cancer and their year of birth. This information can be used to assess more personalised prostate cancer risks to men who carry HOXB13 mutations and hence better counsel them on more personalised risk management options, such as tailoring prostate cancer screening frequency.