Decline in Hepatitis C Virus (HCV) Incidence in Men Who Have Sex With Men Living With Human Immunodeficiency Virus: Progress to HCV Microelimination in the United Kingdom?

BACKGROUND: Modeling of the London hepatitis C virus (HCV) epidemic in men who have sex with men (MSM) and are living with human immunodeficiency virus (HIV) suggested that early access to direct-acting antiviral (DAA) treatment may reduce incidence. With high rates of linkage to care, microelimination of HCV within MSM living with HIV may be realistic ahead of 2030 World Health Organization targets. We examined trends in HCV incidence in the pre- and post-DAA eras for MSM living with HIV in London and Brighton, United Kingdom. METHODS: A retrospective cohort study was conducted at 5 HIV clinics in London and Brighton between 2013 and 2018. Each site reported all acute HCV episodes during the study period. Treatment timing data were collected. Incidence rates and reinfection proportion were calculated. RESULTS: A total of.378 acute HCV infections were identified, comprising 292 first infections and 86 reinfections. Incidence rates of acute HCV in MSM living with HIV peaked at 14.57/1000 person-years of follow-up (PYFU; 95% confidence interval [CI], 10.95-18.20) in 2015. Rates fell to 4.63/1000 PYFU (95% CI, 2.60 to 6.67) by 2018. Time from diagnosis to starting treatment declined from 29.8 (2013) to 3.7 months (2018). CONCLUSIONS: We observed a 78% reduction in the incidence of first HCV episode and a 68% reduction in overall HCV incidence since the epidemic peak in 2015, which coincides with wider access to DAAs in England. Further interventions to reduce transmission, including earlier access to treatment and for reinfection, are likely needed for microelimination to be achieved in this population.

Nonviral Liver Disease Burden in People Living With HIV and Elevated Transaminases: A Cross-Sectional Study.

INTRODUCTION: Because of improved life expectancy in people living with HIV (PLWH), liver disease is increasingly being recognized. We assessed nonviral chronic liver disease burden in PLWH. METHODS: The HIV non-virAL liver disease study (2014-2021) prospectively recruited PLWH with elevated serum alanine aminotransferase levels and negative hepatitis serology. Clinically significant hepatic fibrosis (CSHF) was defined as liver stiffness measurement of >7.1 kPa and hazardous alcohol use as Alcohol Use Disorders Identification Test score ≥ 8. Primary outcome was prevalence/predictors of CSHF. RESULTS: Total recruited were n = 274, 92% male, median age 52 (45-59) years, and 96% having undetectable HIV viral load. Overall, n = 97 (35%) had hazardous alcohol use, n = 72 (26%) had metabolic syndrome, and 17%-27% had exposure to hepatotoxic antiretrovirals. Prevalence of CSHF was 20% (n = 54), prevalence of cirrhosis (liver stiffness measurement > 12.5 kPa) being 7% (19/274). Risk factors for CSHF were hazardous alcohol use in 44% (n = 24), metabolic syndrome in 46% (n = 25), and hepatotoxic antiretrovirals in 56% (n = 30), most having more than one risk factor. Independent predictors of CSHF were serum high-density lipoprotein (odds ratio [OR] 0.220; 95% confidence interval [CI]: 0.061 to 0.790, P = 0.020) (inverse relationship); serum aspartate aminotransferase (OR 1.033, 95% CI: 1.001 to 1.067, P = 0.045), and didanosine use (OR 2.878, 95% CI: 1.228 to 6.774, P = 0.015). Moderate-severe hepatic steatosis was identified in 52% (n = 142). FIB-4 and aspartate aminotransferase-to-platelet ratio index performed poorly in predicting CSHF (positive predictive value 27.3% and 30.6%, respectively) and advanced fibrosis (≥F3) (positive predictive value 17.6% and 5.9%, respectively). CONCLUSION: In this study, 20% of PLWH had CSHF associated with high prevalence of hazardous alcohol use/metabolic syndrome/potentially hepatotoxic antiretrovirals. These potentially modifiable risk factors need addressing.

Altered oxidative neurometabolic response to methylene blue in bipolar disorder revealed by quantitative neuroimaging.

BACKGROUND: Cerebral mitochondrial and hemodynamic abnormalities have been implicated in Bipolar Disorder pathophysiology, likely contributing to neurometabolic vulnerability-leading to worsen clinical outcomes and mood instability. To investigate neurometabolic vulnerability in patients with BD, we combined multi-modal quantitative MRI assessment of cerebral oxygenation with acute administration of Methylene Blue, a neurometabolic/hemodynamic modulator acting on cerebral mitochondria. METHODS: Fifteen euthymic patients with chronic BD-type 1, and fifteen age/gender-matched healthy controls underwent two separate MRI sessions in a single-blinded randomized cross-over design, each after intravenous infusion of either MB (0.5 mg/kg) or placebo. MRI-based measures of Cerebral Blood Flow and Oxygen Extraction Fraction were integrated to compute Cerebral Metabolic Rate of Oxygen in Frontal Lobe, Anterior Cingulate, and Hippocampus-implicated in BD neurometabolic pathophysiology. Inter-daily variation in mood rating was used to assess mood instability. RESULTS: A decrease in global CBF and CMRO2 was observed after acutely administrating MB to all participants. Greater regional CMRO2 reductions were observed after MB, in patients compared to controls in FL (mean = -14.2 ± 19.5 % versus 2.3 ± 14.8 %), ACC (mean = -14.8 ± 23.7 % versus 2.4 ± 15.7 %). The effects on CMRO2 in those regions were primarily driven by patients with longer disease duration and higher mood instability. LIMITATIONS: Sample size; medications potentially impacting on response to MB. CONCLUSIONS: An altered neurometabolic response to MB, a mitochondrial/hemodynamic modulator, was observed in patients, supporting the hypothesis of vulnerability to neurometabolic stress in BD. Integrating quantitative imaging of cerebral oxygen metabolism with a mitochondrial-targeting pharmacological challenge could provide a novel biomarker of neurometabolic and cerebrovascular pathophysiology in BD.

N3-alkylation during formation of quinazolin-4-ones from condensation of anthranilamides and orthoamides.

Dimethylformamide dimethylacetal (DMFDMA) is widely used as a source of electrophilic one-carbon units at the formate oxidation level; however, electrophilic methylation with this reagent is previously unreported. Reaction of anthranilamide with DMFDMA at 150 °C for short periods gives mainly quinazolin-4-one. However, prolonged reaction with dimethylformamide di(primary-alkyl)acetals leads to subsequent alkylation at N(3). 3-Substituted anthranilamides give 8-substituted 3-alkylquinazolin-4-ones. Condensation of anthranilamides with dimethylacetamide dimethylacetal provides 2,3-dimethylquinazolin-4-ones. In these reactions, the source of the N(3)-alkyl group is the O-alkyl group of the orthoamides. By contrast, reaction with the more sterically crowded dimethylformamide di(isopropyl)acetal diverts the alkylation to the oxygen, giving 4-isopropoxyquinazolines, along with N(3)-methylquinazolin-4-ones where the methyl is derived from N-Me of the orthoamides. Reaction of anthranilamide with the highly sterically demanding dimethylformamide di(t-butyl)acetal gives largely quinazolin-4-one, whereas dimethylformamide di(neopentyl)acetal forms a mixture of quinazolin-4-one and N(3)-methylquinazolin-4-one. The observations are rationalised in terms of formation of intermediate cationic electrophiles (alkoxymethylidene-N,N-dimethylammonium) by thermal elimination of the corresponding alkoxide from the orthoamides. These are the first observations of orthoamides as direct alkylating agents.

Green care in first-episode psychosis: short report of a mixed-methods evaluation of a 'woodland group' in an early intervention service.

AIMS AND METHOD: In the context of increasing recognition of the role of nature in well-being, but limited evidence for specific patient groups, we describe a mixed-methods evaluation of a 10-week green care intervention (a woodland group) for 18- to 30-year-olds who had experienced a first episode of psychosis. Data were collected using the Questionnaire on the Process of Recovery (QPR), semi-structured service evaluation questionnaires, the NHS Friends and Family Test (FFT), and focus group analysis. RESULTS: All participants present at week 10 (n = 5) would recommend this group to others; 4/8 participants showed reliable improvement on QPR outcome measures. Thematic analysis identified themes of connection with nature and others, development of a sense of well-being and 'peacefulness' and new perspectives on psychotic experience. CLINICAL IMPLICATIONS: This small retrospective evaluation describes patient-reported benefits, feasibility and acceptability of green care interventions within early intervention in psychosis services (EIS).

Connecting brain and body: Transdiagnostic relevance of connective tissue variants to neuropsychiatric symptom expression.

The mind is embodied; thoughts and feelings interact with states of physiological arousal and physical integrity of the body. In this context, there is mounting evidence for an association between psychiatric presentations and the expression variant connective tissue, commonly recognised as joint hypermobility. Joint hypermobility is common, frequently under-recognised, significantly impacts quality of life, and can exist in isolation or as the hallmark of hypermobility spectrum disorders (encompassing joint hypermobility syndrome and hypermobile Ehlers-Danlos syndrome). In this narrative review, we appraise the current evidence linking psychiatric disorders across the lifespan, beginning with the relatively well-established connection with anxiety, to hypermobility. We next consider emerging associations with affective illnesses, eating disorders, alongside less well researched links with personality disorders, substance misuse and psychosis. We then review related findings relevant to neurodevelopmental disorders and stress-sensitive medical conditions. With growing understanding of mind-body interactions, we discuss potential aetiopathogenetic contributions of dysautonomia, aberrant interoceptive processing, immune dysregulation and proprioceptive impairments in the context of psychosocial stressors and genetic predisposition. We examine clinical implications of these evolving findings, calling for increased awareness amongst healthcare professionals of the transdiagnostic nature of hypermobility and related disorders. A role for early screening and detection of hypermobility in those presenting with mental health and somatic symptoms is further highlighted, with a view to facilitate preventative approaches alongside longer-term holistic management strategies. Finally, suggestions are offered for directions of future scientific exploration which may be key to further delineating fundamental mind-body-brain interactions.

The role of ibrutinib in COVID-19 hyperinflammation: A case report.

Immune modulation in COVID-19 is emerging as an important therapeutic strategy as increasing evidence suggests that inflammatory pathways are implicated in lung damage. Bruton tyrosine kinase inhibitors (BTKi), such as ibrutinib, are commonly used to treat indolent B-cell neoplasms and chronic graft-versus-host disease (GvHD). Given their potential to suppress pulmonary inflammatory cytokines and lessen acute lung injury, this could be applicable in the context of hospitalised COVID-19 patients. We describe an 81 year-old male receiving ibrutinib for Waldenstrom macroglobulinaemia (WM) who was hospitalised with COVID-19. On stopping the BTKi due to concerns of additional immunosuppression, he required non-invasive ventilation (NIV) in the intensive care unit (ICU) and demonstrated prompt clinical recovery when ibrutinib was reinstated. Continuing ibrutinib in patients with COVID-19 may be advantageous given its immunomodulatory properties and withdrawal of ibrutinib therapy may be detrimental. Further evidence is required to explore the potential therapeutic impact of BTKis and other immunomodulatory agents on the clinical course of COVID-19 as is currently being carried out in a number of clinical trials.