How are HIV services in the UK currently identifying and managing patients with cognitive impairment? Results of a national survey.

OBJECTIVES: The 2018 British HIV Association (BHIVA) Standards of Care state that people living with HIV should be questioned annually for symptoms of cognitive or memory decline. If symptoms are identified, screening should be considered and services offered if impairment is detected. We examined the availability of services, along with current practices related to the screening and management of cognitive impairment in people living with HIV, in UK HIV services. METHODS: A survey was distributed via email to all UK HIV services leads on the BHIVA audit mailing list. Questions related to screening practices, referral pathways, and the management of patients with suspected cognitive impairment. Descriptive analyses were conducted on all data returned. RESULTS: In total, 190 surveys were distributed. Of the respondents, 39 (60.6%) stated that they undertook screening for cognitive impairment in their HIV service, and 30 (47.6%) reported not offering a specific service or referral pathway. Awareness of BHIVA screening guidelines was high (49 [84.48%]), yet 15 (30.6%) respondents stated that they were not followed in their service and 41 (71.9%) felt there was a need for training on screening, assessment, and management of cognitive impairment in patients with HIV within their department. CONCLUSIONS: Despite no directive, a substantial number of HIV services surveyed are routinely screening patients for cognitive impairment without guidance on when to screen and which screening tools should be used. A UK consensus on screening, along with guidance and training for services, may help to resolve this gap in service provision.

People with HIV and healthcare workers views on screening for cognitive impairment in people with HIV: A qualitative study.

OBJECTIVES: People with HIV are an ageing population with an increased risk of cognitive impairment. Although cognitive impairment is dependent upon assessment, the acceptability of screening for cognitive impairment is unclear. This study aimed to explore the views of people with HIV and healthcare workers regarding routine screening for cognitive impairment. METHODS: In-depth individual qualitative interviews were conducted with purposively sampled people with HIV and focus groups of healthcare workers from a UK HIV service. Verbatim pseudonymized transcripts were analysed using reflexive thematic analysis supported by NVivo. RESULTS: Twenty people with HIV were interviewed and 12 healthcare workers participated in three focus groups. People with HIV were concerned about developing cognitive issues and were receptive to routine screening. Screening was seen as relevant and an important part of managing health in older age. Healthcare workers expressed concerns regarding the capacity of HIV services to implement routine screening and questioned the validity of screening measures used. People with HIV felt that screening and subsequent detection of cognitive impairment, if present, may help them to prepare for future issues and promote active management strategies and care pathways that would support cognitive health. People with HIV felt that screening should be brief and delivered by the HIV service and that they should be given a choice of administration method. Indications of cognitive impairment detected by a brief screening assessment should be discussed face to face and followed up with a comprehensive assessment. CONCLUSIONS: People with HIV are concerned about cognitive impairment and would welcome regular screening for this as part of the holistic care provided by the HIV team. Both people with HIV and healthcare workers would like more information on cognitive impairment, its screening and ways to support cognitive health.

"A fog that impacts everything": a qualitative study of health-related quality of life in people living with HIV who have cognitive impairment.

BACKGROUND: Cognitive impairment (CI) in people living with HIV (PLWH) is an important health concern in the context of an ageing HIV population. Impacting 14-28% of PLWH, CI is associated with lower health-related quality of life (HRQoL), however, evaluation of the illness-specific factors comprising HRQoL in PLWH with CI have not been assessed. OBJECTIVE: We sought to contribute evidence toward an understanding of HRQoL and identify domains of HRQoL in PLWH with CI. METHODS: Qualitative interviews with 25 PLWH with objective CI related to HIV disease were conducted with participants attending HIV clinics in the UK. Clinically significant CI was defined based on The European AIDS Clinical Society guidelines, requiring: (i) subjective reporting of cognitive symptoms; (ii) symptoms to be related to HIV (e.g. potentially confounding non-HIV related conditions have been excluded or are being optimally managed) and; (iii) formal neuropsychological assessment confirming CI. Median age was 56 years (range 35-80); 18 participants were men (72%); 11 (44%) were white British and 8 (32%) were Black African; 14 (56%) were men that have sex with men and 10 (40%) were heterosexual; median number of years living with HIV was 17 (range 1-34); and all participants were on combination antiretroviral therapy. Analyses employed techniques from grounded theory, underpinned by an inductive, collaborative team-based approach. RESULTS: Findings revealed seven interrelated domains comprising HRQoL experiences were identified: Physical function, Cognition, Social connectedness, Physical and mental health, Stigma, Self-concept, and Control and acceptance, and each was defined by specific descriptive components. CONCLUSION: This study provides valuable insights on the factors that drive HRQoL in PLWH with CI and contribute to a body of evidence which provides targets for the development of targeted interventions to maintain or improve quality of life.

GATA1-mutant clones are frequent and often unsuspected in babies with Down syndrome: identification of a population at risk of leukemia.

Transient abnormal myelopoiesis (TAM), a preleukemic disorder unique to neonates with Down syndrome (DS), may transform to childhood acute myeloid leukemia (ML-DS). Acquired GATA1 mutations are present in both TAM and ML-DS. Current definitions of TAM specify neither the percentage of blasts nor the role of GATA1 mutation analysis. To define TAM, we prospectively analyzed clinical findings, blood counts and smears, and GATA1 mutation status in 200 DS neonates. All DS neonates had multiple blood count and smear abnormalities. Surprisingly, 195 of 200 (97.5%) had circulating blasts. GATA1 mutations were detected by Sanger sequencing/denaturing high performance liquid chromatography (Ss/DHPLC) in 17 of 200 (8.5%), all with blasts >10%. Furthermore low-abundance GATA1 mutant clones were detected by targeted next-generation resequencing (NGS) in 18 of 88 (20.4%; sensitivity ∼0.3%) DS neonates without Ss/DHPLC-detectable GATA1 mutations. No clinical or hematologic features distinguished these 18 neonates. We suggest the term "silent TAM" for neonates with DS with GATA1 mutations detectable only by NGS. To identify all babies at risk of ML-DS, we suggest GATA1 mutation and blood count and smear analyses should be performed in DS neonates. Ss/DPHLC can be used for initial screening, but where GATA1 mutations are undetectable by Ss/DHPLC, NGS-based methods can identify neonates with small GATA1 mutant clones.

Understanding the lived experience research priorities for improving health-related quality of life in people living with HIV with cognitive impairment.

BACKGROUND: People living with HIV experience higher rates of cognitive impairment (CI), and at younger ages, than the general population. These individuals report poor health-related quality of life (HRQL), however, interventions aimed at assisting people living with HIV to live well with CI do not currently exist and represent an important un-met need in this population. OBJECTIVE: This study aimed to identify the lived experience research priorities for improving HRQL and identify interventions to support priority areas. METHODS: A Research Advisory Group was established with 15 lived experience, academic, healthcare, and third sector professionals. Additionally, two semi-structured focus groups were undertaken, with health and third sector professionals and people living with HIV with CI. Participants were asked to rank factors impacting HRQL, identified in prior research, in terms of priority and intervention development. Findings were analysed using a combination of conventional and summative content analysis. Study findings were feedback to our Research Advisory Group. RESULTS: Five people living with HIV with CI, recruited through third sector agencies [Male 80%; median age 59 (range 56-78); White British 60%; homosexual 60%], and three healthcare and third sector participants (66% third sector professionals from two local HIV charities; 33% HIV-specific clinical psychologist) took part in two focus groups and ranked interventions targeting improvement in physical function, social connectedness, cognition and perceived control over cognitive health as priority areas. Findings were then fed back to the Research Advisory Group who recommended the development of an illness-specific cognitive rehabilitation programme and improved information provision as important avenues for intervention development. CONCLUSION: Given the absence of meaningful patient and public involvement, intervention, and support guidelines for people living with HIV with CI, this provides a roadmap for future research in this important and growing area of HIV clinical care.

Cognitive impairment in people living with HIV: mechanisms, controversies, and future perspectives.

Despite the dramatic decrease in HIV-associated neurocognitive impairment (NCI) in the combined antiretroviral treatment (cART) era, subtler neuropsychological complications remain prevalent. In this review, we discuss the changing pathophysiology of HIV-associated NCI, considering recent evidence of HIV neuropathogenesis, and the pivotal role of cART. Furthermore, we address the multifactorial nature of NCI in people living with HIV, including legacy and ongoing insults to the brain, as well as host-specific factors. We also summarize the ongoing debate about the refinement of diagnostic criteria, exploring the strengths and limitations of these recent approaches. Finally, we present current research in NCI management in people living with HIV and highlight the need for using both pharmacological and nonpharmacological pathways toward a holistic approach.

Analysis of GATA1 mutations in Down syndrome transient myeloproliferative disorder and myeloid leukemia.

Children with Down syndrome (DS) up to the age of 4 years are at a 150-fold excess risk of developing myeloid leukemia (ML-DS). Approximately 4%-5% of newborns with DS develop transient myeloproliferative disorder (TMD). Blast cell structure and immunophenotype are similar in TMD and ML-DS. A mutation in the hematopoietic transcription factor GATA1 is present in almost all cases. Here, we show that simple techniques detect GATA1 mutations in the largest series of TMD (n = 134; 88%) and ML-DS (n = 103; 85%) cases tested. Furthermore, no significant difference in the mutational spectrum between the 2 disorders was seen. Thus, the type of GATA1 sequence mutation is not a reliable tool and is not prognostic of which patients with TMD are probable to develop ML-DS.

Health-Related Quality of Life in People Living With HIV With Cognitive Symptoms: Assessing Relevant Domains and Associations.

This study aimed to validate and assess a comprehensive set of illness-specific health-related quality of life (HRQL) domains in people living with HIV (PLWH) with cognitive symptoms. One hundred and three HIV patients with cognitive symptoms (n = 93 male, 90.3%) were identified from two UK HIV clinics and complete a series of validated scales measuring seven HRQL domains identified as important to HRQL by PLWH with cognitive impairment. These included: physical functioning, cognition, social connectedness, self-concept, HIV stigma, acceptance of and perceived control over cognitive health, and physical and mental health and wellbeing. Exploratory factor analysis confirmed that domain total scores loaded onto one main factor, representing HRQL. Scale cut-off scores revealed a significant proportion of patients scored outside the normal range on single domains (between 26.2% and 79.6%), and many patients on multiple domains (40.8% on 4 or more domains). We found evidence of poor HRQL across domains in the majority of PLWH with cognitive symptoms and identified domains driving these experiences. This provides targets for intervention development and clinical action to maintain or improve HRQL in PLWH with cognitive symptoms or impairment.

Perturbed hematopoiesis in the Tc1 mouse model of Down syndrome.

Trisomy of human chromosome 21 (Hsa21) results in Down syndrome (DS), a disorder that affects many aspects of physiology, including hematopoiesis. DS children have greatly increased rates of acute lymphoblastic leukemia and acute megakaryoblastic leukemia (AMKL); DS newborns present with transient myeloproliferative disorder (TMD), a preleukemic form of AMKL. TMD and DS-AMKL almost always carry an acquired mutation in GATA1 resulting in exclusive synthesis of a truncated protein (GATA1s), suggesting that both trisomy 21 and GATA1 mutations are required for leukemogenesis. To gain further understanding of how Hsa21 contributes to hematopoietic abnormalities, we examined the Tc1 mouse model of DS, which carries an almost complete freely segregating copy of Hsa21, and is the most complete model of DS available. We show that although Tc1 mice do not develop leukemia, they have macrocytic anemia and increased extramedullary hematopoiesis. Introduction of GATA1s into Tc1 mice resulted in a synergistic increase in megakaryopoiesis, but did not result in leukemia or a TMD-like phenotype, demonstrating that GATA1s and trisomy of approximately 80% of Hsa21 perturb megakaryopoiesis but are insufficient to induce leukemia.

Down syndrome--recent progress and future prospects.

Down syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and is associated with a number of deleterious phenotypes, including learning disability, heart defects, early-onset Alzheimer's disease and childhood leukaemia. Individuals with DS are affected by these phenotypes to a variable extent; understanding the cause of this variation is a key challenge. Here, we review recent research progress in DS, both in patients and relevant animal models. In particular, we highlight exciting advances in therapy to improve cognitive function in people with DS and the significant developments in understanding the gene content of Hsa21. Moreover, we discuss future research directions in light of new technologies. In particular, the use of chromosome engineering to generate new trisomic mouse models and large-scale studies of genotype-phenotype relationships in patients are likely to significantly contribute to the future understanding of DS.

Quality of life in people living with HIV-associated neurocognitive disorder: A scoping review study.

Quality of life (QoL) is recognized as an essential end point in the disease management of chronic conditions such as HIV with calls to include good QoL as a 'fourth 90' in the 90-90-90 testing and treatment targets introduced by World Health Organization in 2016. Cognitive impairments impact a broad spectrum of experiences and are a common issue effecting people living with HIV (PLWH). Despite this, few studies have examined QoL in PLWH who also have a cognitive disorder. This study aimed to synthesize and describe what is known about QoL in those living with HIV-associated neurocognitive disorders (HAND). A scoping review of peer-reviewed literature was conducted to identify how QoL has been investigated and measured in PLWH with HAND, and how PLWH with HAND report and describe their QoL. We searched PsychInfo, Medline, Scopus, and Web of Science along with hand-searching reference lists from relevant studies found. Included studies were those published in English after 1st January 2003 which included PLWH with cognitive impairment not due to other pre-existing conditions. Fifteen articles met criteria for inclusion. Two studies measured QoL as a primary aim, with others including QoL assessment as part of a broader battery of outcomes. The MOS-HIV and SF-36 were the most commonly used measures of overall QoL, with findings generally suggestive of poorer overall QoL in PLWH with HAND, compared to PLWH without cognitive impairment. Studies which examined dimensions of QoL focused exclusively on functionality, level of independence, and psychological QoL domains. There is a considerable dearth of research examining QoL in PLWH with HAND. The initiatives which advocate for healthy aging and improved QoL in PLWH must be extended to include and understand the experiences those also living with cognitive impairment. Research is needed to understand the broad experiential impacts of living with these two complex, chronic conditions, to ensure interventions are meaningful to patients and potential benefits are not missed.

Assessment and Management of HIV-Associated Cognitive Impairment: Experience from a Multidisciplinary Memory Service for People Living with HIV.

As the HIV population ages, the prevalence of cognitive impairment (CI) is increasing, yet few services exist for the assessment and management of these individuals. Here we provide an initial description of a memory assessment service for people living with HIV and present data from a service evaluation undertaken in the clinic. We conducted an evaluation of the first 52 patients seen by the clinic. We present patient demographic data, assessment outcomes, diagnoses given and interventions delivered to those seen in the clinic. 41 patients (79%) of those seen in the clinic had objective CI: 16 (31%) met criteria for HIV-associated Neurocognitive Disorder (HAND), 2 (4%) were diagnosed with dementia, 14 (27%) showed CI associated with mental illness and/or drugs/alcohol, 7 (13%) had CI which was attributed to factors other than HIV and in 2 (4%) patients the cause remains unclear. 32 (62%) patients showed some abnormality on Magnetic Resonance Imaging (MRI) brain scans. Patients attending the clinic performed significantly worse than normative scores on all tests of global cognition and executive function. Interventions offered to patients included combination antiretroviral therapy modification, signposting to other services, case management, further health investigations and in-clinic advice. Our experience suggests that the need exists for specialist HIV memory services and that such a model of working can be successfully implemented into HIV patient care. Further work is needed on referral criteria and pathways. Diagnostic processes and treatment offered needs to consider and address the multifactorial aetiology of CI in HIV and this is essential for effective assessment and management.

Coexistence of LMPP-like and GMP-like leukemia stem cells in acute myeloid leukemia.

The relationships between normal and leukemic stem/progenitor cells are unclear. We show that in ∼80% of primary human CD34+ acute myeloid leukemia (AML), two expanded populations with hemopoietic progenitor immunophenotype coexist in most patients. Both populations have leukemic stem cell (LSC) activity and are hierarchically ordered; one LSC population gives rise to the other. Global gene expression profiling shows the LSC populations are molecularly distinct and resemble normal progenitors but not stem cells. The more mature LSC population most closely mirrors normal granulocyte-macrophage progenitors (GMP) and the immature LSC population a previously uncharacterized progenitor functionally similar to lymphoid-primed multipotential progenitors (LMPPs). This suggests that in most cases primary CD34+ AML is a progenitor disease where LSCs acquire abnormal self-renewal potential.

Heat shock protein 27 functions in inflammatory gene expression and transforming growth factor-beta-activated kinase-1 (TAK1)-mediated signaling.

Heat shock protein (HSP) 27 has long been known to be a component of the p38 mitogen-activated protein kinase (MAPK) signaling pathway. p38 MAPK has important functions in the inflammatory response, but the role of HSP27 in inflammation has remained unknown. We have used small interfering RNAs to suppress HSP27 expression in HeLa cells and fibroblasts and found that it is required for pro-inflammatory cell signaling and the expression of pro-inflammatory genes. HSP27 is needed for the activation by interleukin (IL)-1 of TAK1 and downstream signaling by p38 MAPK, JNK, and their activators (MKK-3, -4, -6, -7) and IKKbeta. IL-1-induced ERK activation appears to be independent of HSP27. HSP27 is required for both IL-1 and TNF-induced signaling pathways for which the most upstream common signaling protein is TAK1. HSP27 is also required for IL-1-induced expression of the pro-inflammatory mediators, cyclooxygenase-2, IL-6, and IL-8. HSP27 functions to drive cyclooxygenase-2 and IL-6 expression by augmenting the activation of the kinase downstream of p38 MAPK, MK2, resulting in stabilization of cyclooxygenase-2 and IL-6 mRNAs. The mechanism may not occur in cells of myeloid lineage because HSP27 protein was undetectable in human monocytes and murine macrophages.