Differential associations of depression-related phenotypes with cardiometabolic risks: Polygenic analyses and exploring shared genetic variants and pathways.

BACKGROUND: Numerous studies have suggested associations between depression and cardiometabolic (CM) diseases. However, little is known about the mechanism underlying this comorbidity, and whether the relationship differs by depression subtypes. METHODS: Using polygenic risk scores (PRS) and linkage disequilibrium (LD) score regression, we investigated the genetic overlap of various depression-related phenotypes with a comprehensive panel of 20 CM traits. GWAS results for major depressive disorder (MDD) were taken from the PGC and CONVERGE studies, with the latter focusing on severe melancholic depression. GWAS results on general depressive symptoms (DS) and neuroticism were also included. We identified the shared genetic variants and inferred enriched pathways. We also looked for drugs over-represented among the top-shared genes, with an aim to finding repositioning opportunities for comorbidities. RESULTS: We found significant genetic overlap between MDD, DS, and neuroticism with cardiometabolic traits. In general, positive polygenic associations with CM abnormalities were observed except for MDD-CONVERGE. Counterintuitively, PRS representing severe melancholic depression was associated with reduced CM risks. Enrichment analyses of shared SNPs revealed many interesting pathways such as those related to inflammation that underlie the comorbidity of depressive and CM traits. Using a gene-set analysis approach, we also revealed several repositioning candidates with literature support (e.g., bupropion). CONCLUSIONS: Our study highlights shared genetic bases of depression with CM traits, and suggests the associations vary by depression subtypes, which may have implications in targeted prevention of cardiovascular events for patients. Identification of shared genetic factors may also guide drug discovery for the comorbidities.

Variation in harms and benefits of prostate-specific antigen screening for prostate cancer by socio-clinical risk factors: A rapid review.

Objective: To analyse the latest evidence on the relative harms and benefits of screening and diagnostic pathways with close examination of (i) men aged 50 years or older, (ii) men whose ethnicity places them at higher risk and (iii) men with a family history. Methods: We conducted a literature search using PubMed and Cochrane Central Register of Controlled Trials (CENTRAL) databases and other sources, from January 1990 to 25 January 2023. Two independent reviewers selected for randomised controlled trials (RCTs) and cohort studies which met our inclusion criteria. Results: Twenty-eight articles were selected, from six trials, including the Göteborg trial-reported separately from European Randomised Study of Screening for Prostate Cancer (ERSPC). Prostate-specific antigen (PSA)-based screening led to the increased detection of low-grade cancer and reduction of advanced/metastatic disease but had contradictory effects on prostate cancer (PCa)-specific mortality (no difference or reduced), possibly due to issues of contamination or compliance. Screening men from a relatively young age (50-55) reduced risk of PCa-specific mortality in a subanalysis of an 18-year follow-up study and in a 17-year cohort study from the main Göteborg trial. Moreover, one Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial analysis reported a trend of reduced risk of PCa-specific mortality for men with a family history who were screened. [Correction added on 05 March 2024, after first online publication: "Cancer Screening Trial" has been added to the preceding sentence.] However, we did not find relevant studies for ethnicity. Conclusion: Under current UK practice, the choice to conduct a PSA test relies on a shared decision-making approach guided by known risk factors. However, we found there was a lack of strong evidence on the harms and benefits of PSA screening by socio-clinical risk factors and suggest further research is required to understand the long-term impact of screening on high-risk populations in the current diagnostic setting.

The impact of pre-biopsy MRI and additional testing on prostate cancer screening outcomes: A rapid review.

Objective: This work aims to examine the latest evidence on the impact of pre-biopsy MRI, in addition to prostate-specific antigen (PSA) testing, on health outcomes and quality of life. Methods: We conducted a literature search including PubMed and Cochrane Central Register of Controlled Trials (CENTRAL) databases, with a limited scan of (i) guidelines and (ii) references from trial reports, from January 2005 to 25th January 2023. Two independent reviewers selected randomised controlled trials (RCT) and cohort studies which met our inclusion criteria. Results: One hundred thirty-seven articles were identified, and seven trial articles were selected. Trial interventions were as follows: (i) PSA blood test, (ii) additional tests such as pre-biopsy multiparametric magnetic resonance imaging (mpMRI) and Biparametric MRI (bpMRI), and (iii) MRI targeted biopsy and standard biopsy. Compared with standard biopsy, MRI-based interventions led to increased detection of clinically significant cancers in three studies and decreased detection of clinically insignificant cancer (Gleason grade 3 + 3) in four studies. However, PROstate Magnetic resonance Imaging Study (PROMIS) and Stockholm3 with MRI (STHLM3-MRI) studies reported different trends depending on the scenario studied in PROMIS (MRI triage and MRI directed biopsy vs. MRI triage and standard biopsy) and thresholds used in STHLM3-MRI (≥0·11 and ≥0·15). MRI also helped 8%-49% of men avoid biopsy, in six out of seven studies, but not in STHLM3-MRI at ≥0.11. Interestingly, the proportion of men who experienced sepsis and UTI was low across studies. Conclusion: This review found that a combination of approaches, centred on the use of pre-biopsy MRI, may improve the detection of clinically significant cancers and reduce (i) the diagnosis of clinically insignificant cancers and (ii) unnecessary biopsies, compared with PSA testing and standard biopsy alone. However, the impact of such interventions on longer term outcomes such as prostate cancer-specific mortality has not yet been assessed.

Evaluating whether Prostate Cancer UK's risk checker is a help or hindrance to prostate-specific antigen testing policy: a mixed-methods study.

BACKGROUND: The UK has an informed choice testing policy for prostate cancer. The prostate-specific antigen (PSA) blood test is available for free to any man aged ≥50 years who requests it and has been informed of the harms and benefits. This policy leads to differences in PSA testing rates, which can exacerbate health inequalities. AIM: To assess whether Prostate Cancer UK's risk checker helps men at risk of prostate cancer make an informed choice about the PSA test. DESIGN & SETTING: Mixed-methods study in the UK. METHOD: In total, 1181 men at risk, their partners, and clinical experts participated in surveys, focus groups, and one-to-one interviews. Data on risk checker completions by sociodemographic factors were analysed over time. Data from general practices that sent the risk checker to their patients were collected and analysed for service monitoring purposes. RESULTS: There was a strong assumption that testing must be good, and therefore a need to emphasise the pros and cons of the test and that having it was the patient's decision. Men believed their GP would invite them for PSA testing. On the impact of the risk checker, 79.6% of men who completed it had at least one prostate cancer risk factor; the average time they interacted with the information in the tool was 9 minutes 28 seconds; and 75.7% felt the tool had equipped them to make an informed choice. CONCLUSION: Online decision-making tools, such as the risk checker, can help reach men at high risk of prostate cancer and support them in making an informed choice about the PSA test.

The Effect of the COVID-19 Pandemic on Non-COVID-19 Deaths: Population-Wide Retrospective Cohort Study.

BACKGROUND: Health care avoidance in the COVID-19 pandemic has been widely reported. Yet few studies have investigated the dynamics of hospital avoidance behavior during pandemic waves and inferred its impact on excess non-COVID-19 deaths. OBJECTIVE: This study aimed to measure the impact of hospital avoidance on excess non-COVID-19 deaths in public hospitals in Hong Kong. METHODS: This was a retrospective cohort study involving 11,966,786 patients examined between January 1, 2016, and December 31, 2021, in Hong Kong. All data were linked to service, treatment, and outcomes. To estimate excess mortality, the 2-stage least squares method was used with daily tallies of emergency department (ED) visits and 28-day mortality. Records for older people were categorized by long-term care (LTC) home status, and comorbidities were used to explain the demographic and clinical attributes of excess 28-day mortality. The primary outcome was actual excess death in 2020 and 2021. The 2-stage least squares method was used to estimate the daily excess 28-day mortality by daily reduced visits. RESULTS: Compared with the prepandemic (2016-2019) average, there was a reduction in total ED visits in 2020 of 25.4% (548,116/2,142,609). During the same period, the 28-day mortality of non-COVID-19 ED deaths increased by 7.82% (2689/34,370) compared with 2016-2019. The actual excess deaths in 2020 and 2021 were 3143 and 4013, respectively. The estimated total excess non-COVID-19 28-day deaths among older people in 2020 to 2021 were 1958 (95% CI 1100-2820; no time lag). Deaths on arrival (DOAs) or deaths before arrival (DBAs) increased by 33.6% (1457/4336) in 2020, while non-DOA/DBAs increased only by a moderate 4.97% (1202/24,204). In both types of deaths, the increases were higher during wave periods than in nonwave periods. Moreover, non-LTC patients saw a greater reduction in ED visits than LTC patients across all waves, by more than 10% (non-LTC: 93,896/363,879, 25.8%; LTC: 7,956/67,090, 11.9%). Most of the comorbidity subsets demonstrated an annualized reduction in visits in 2020. Renal diseases and severe liver diseases saw notable increases in deaths. CONCLUSIONS: We demonstrated a statistical method to estimate hospital avoidance behavior during a pandemic and quantified the consequent excess 28-day mortality with a focus on older people, who had high frequencies of ED visits and deaths. This study serves as an informed alert and possible investigational guideline for health care professionals for hospital avoidance behavior and its consequences.

Implications of de novo mutations in guiding drug discovery: A study of four neuropsychiatric disorders.

Recent studies have suggested an important role of de novo mutations (DNMs) in neuropsychiatric disorders. As DNMs are not subject to elimination due to evolutionary pressure, they are likely to have greater disruptions on biological functions. While a number of sequencing studies have been performed on neuropsychiatric disorders, the implications of DNMs for drug discovery remain to be explored. In this study, we employed a gene-set analysis approach to address this issue. Four neuropsychiatric disorders were studied, including schizophrenia (SCZ), autistic spectrum disorders (ASD), intellectual disability (ID) and epilepsy. We first identified gene-sets associated with different drugs, and analyzed whether the gene-set pertaining to each drug overlaps with DNMs more than expected by chance. We also assessed which medication classes are enriched among the prioritized drugs. We discovered that neuropsychiatric drug classes were indeed significantly enriched for DNMs of all four disorders; in particular, antipsychotics and antiepileptics were the most strongly enriched drug classes for SCZ and epilepsy respectively. Interestingly, we revealed enrichment of several unexpected drug classes, such as lipid-lowering agents for SCZ and anti-neoplastic agents. By inspecting individual hits, we also uncovered other interesting drug candidates or mechanisms (e.g. histone deacetylase inhibition and retinoid signaling) that might warrant further investigations. Taken together, this study provided evidence for the usefulness of DNMs in guiding drug discovery or repositioning.