Alzheimer's disease CSF biomarkers correlate with early pathology and alterations in neuronal and glial gene expression.

INTRODUCTION: Normal pressure hydrocephalus (NPH) patients undergoing cortical shunting frequently show early Alzheimer's disease (AD) pathology on cortical biopsy, which is predictive of progression to clinical AD. The objective of this study was to use samples from this cohort to identify cerebrospinal fluid  (CSF) biomarkers for AD-related central nervous system (CNS) pathophysiologic changes using tissue and fluids with early pathology, free of post mortem artifact. METHODS: We analyzed Simoa, proteomic, and metabolomic CSF data from 81 patients with previously documented pathologic and transcriptomic changes. RESULTS: AD pathology on biopsy correlates with CSF ß-amyloid-42/40, neurofilament light chain (NfL), and phospho-tau-181(p-tau181)/ß-amyloid-42, while several gene expression modules correlate with NfL. Proteomic analysis highlights seven core proteins that correlate with pathology and gene expression changes on biopsy, and metabolomic analysis of CSF identifies disease-relevant groups that correlate with biopsy data. DISCUSSION: As additional biomarkers are added to AD diagnostic panels, our work provides insight into the CNS pathophysiology these markers are tracking. HIGHLIGHTS: AD CSF biomarkers correlate with CNS pathology and transcriptomic changes. Seven proteins correlate with CNS pathology and gene expression changes. Inflammatory and neuronal gene expression changes correlate with YKL-40 and NPTXR, respectively. CSF metabolomic analysis identifies pathways that correlate with biopsy data. Fatty acid metabolic pathways correlate with ß-amyloid pathology.

BASHH standards for the management of sexual health in UK prisons.

People in prison often experience risk factors that can lead to poor sexual health which is compounded by social deprivation. In response, the British Association for Sexual Health and HIV (BASHH) has published the first national standards in the management of UK prisons, providing recommendations for commissioners, service providers, health care providers and people in prison. Nine standards have been devised which cover aspects of sexual health diagnosis and management, public health measures, and some reproductive health issues. The aim of these standards is to drive improvements in sexual health provision in prisons to ensure access to high quality care that is equitable to that which is provided to the general population.

Real world utilisation of doravirine among people living with human immunodeficiency virus in England (DRIVE-REAL).

BACKGROUND: Doravirine is a non-nucleoside reverse transcriptase inhibitor recommended for the treatment of virologically suppressed and treatment naïve people living with HIV. The DRIVE-REAL study aimed to describe the characteristics, treatment patterns, and virological outcomes of doravirine users in a real-world cohort in the UK. METHODS: A retrospective, observational, multi-centre chart review was conducted for 300 adults living with HIV initiating doravirine-containing antiretroviral therapy. RESULTS: At baseline 83% of individuals were male, 45% aged ≥50 years, 65% white ethnicity. Median time since HIV diagnosis was 12 years. 96% were antiretroviral therapy-experienced, 87% had a HIV viral load <50 copies/ml, and 15% had resistance to at least one antiretroviral drug. 66% had comorbidities, most commonly depression (26%), and 70% were taking at least one co-medication. At six months, 94% (n = 283/300) were still receiving doravirine. Viral load data were available for n = 266/300 individuals and 95% (n = 253/266) had viral load <50 copies/ml. CONCLUSIONS: Individuals initiating doravirine in this cohort are predominantly treatment-experienced white middle-aged males, with a high frequency of comorbidities and co-medication. The majority of individuals at 6 months remained on doravirine and maintained or achieved HIV viral suppression. This study provides epidemiologic characteristics that can inform clinical care and subsequent hypothesis-testing studies.

An analysis of RNA quality metrics in human brain tissue.

Human brain tissue studies have historically used a range of metrics to assess RNA quality. However, few large-scale cross-comparisons of pre-sequencing quality metrics with RNA-seq quality have been published. Here, we analyze how well metrics gathered before RNA sequencing (post-mortem interval (PMI) and RNA integrity number RIN) relate to analyses of RNA quality after sequencing (Percent of counts in Top Ten genes (PTT), 5' bias, and 3' bias) as well as with individual gene counts across the transcriptome. We conduct this analysis across four different human cortical brain tissue collections sequenced with varying library preparation protocols. PMI and RIN have a low inverse correlation, and both PMI and RIN show consistent and opposing correlations with PTT. Unlike PMI, RIN shows strong consistent correlations with measurements of 3' and 5' bias, and RIN also correlates with 3,933 genes across datasets, in comparison to 138 genes for PMI. Neuronal and immune response genes correlate positively and negatively with RIN respectively, suggesting that different gene sets have divergent relationships with RIN in brain tissue. In summary, these analyses suggest that conventional metrics of RNA quality have varying degrees of value, and that PMI has an overall minimal but reproducible effect on RNA quality.

Alzheimer's disease CSF biomarkers correlate with early pathology and alterations in neuronal and glial gene expression.

INTRODUCTION: Normal pressure hydrocephalus (NPH) patients undergoing cortical shunting frequently show early AD pathology on cortical biopsy, which is predictive of progression to clinical AD. The objective of this study was to use samples from this cohort to identify CSF biomarkers for AD-related CNS pathophysiologic changes using tissue and fluids with early pathology, free of post-mortem artifact. METHODS: We analyzed Simoa, proteomic, and metabolomic CSF data from 81 patients with previously documented pathologic and transcriptomic changes. RESULTS: AD pathology on biopsy correlates with CSF ß-amyloid-40/42, neurofilament light chain (NfL), and phospho-tau-181(p-tau181)/ß-amyloid-42, while several gene expression modules correlate with NfL. Proteomic analysis highlights 7 core proteins that correlate with pathology and gene expression changes on biopsy, and metabolomic analysis of CSF identifies disease-relevant groups that correlate with biopsy data.. DISCUSSION: As additional biomarkers are added to AD diagnostic panels, our work provides insight into the CNS pathophysiology these markers are tracking.