Metadata-conditioned generative models to synthesize anatomically-plausible 3D brain MRIs.

Recent advances in generative models have paved the way for enhanced generation of natural and medical images, including synthetic brain MRIs. However, the mainstay of current AI research focuses on optimizing synthetic MRIs with respect to visual quality (such as signal-to-noise ratio) while lacking insights into their relevance to neuroscience. To generate high-quality T1-weighted MRIs relevant for neuroscience discovery, we present a two-stage Diffusion Probabilistic Model (called BrainSynth) to synthesize high-resolution MRIs conditionally-dependent on metadata (such as age and sex). We then propose a novel procedure to assess the quality of BrainSynth according to how well its synthetic MRIs capture macrostructural properties of brain regions and how accurately they encode the effects of age and sex. Results indicate that more than half of the brain regions in our synthetic MRIs are anatomically plausible, i.e., the effect size between real and synthetic MRIs is small relative to biological factors such as age and sex. Moreover, the anatomical plausibility varies across cortical regions according to their geometric complexity. As is, the MRIs generated by BrainSynth significantly improve the training of a predictive model to identify accelerated aging effects in an independent study. These results indicate that our model accurately capture the brain's anatomical information and thus could enrich the data of underrepresented samples in a study. The code of BrainSynth will be released as part of the MONAI project at https://github.com/Project-MONAI/GenerativeModels.

Prevalence and correlates of frailty among older people with and without HIV in rural Uganda.

BACKGROUND: The relationship between HIV and frailty, a predictor of poor outcomes in the face of stressors, remains unknown in older people in sub-Saharan Africa. METHODS: We analysed data from the Quality of Life and Ageing with HIV in Rural Uganda cohort study to estimate the prevalence and correlates of frailty among older people with HIV (PWH) on long-term antiretroviral therapy and among age and sex-similar HIV-uninfected comparators. Frailty was defined as a self-report of 3 or 4 (and pre-frailty as 1 or 2) of the following phenotypic variables: weight loss, exhaustion, low activity, and slowness. We estimated the prevalence of frailty and pre-frailty and fitted logistic regression models to estimate the association between HIV and frailty, adjusting for sociodemographic factors, depression, and other comorbidities. RESULTS: We enrolled 599 participants (49% women) with a mean age of 58 years. PWH had a similar prevalence of frailty (8.1% vs. 10.9%, p=0.24) but a lower prevalence of pre-frailty (54.2% vs. 63.2%, p=0.03) compared with their HIV-uninfected comparators. In multivariable regression models, people with depression (AOR 7.52 [95% CI: 3.67-15.40], p<0.001) and those with ≥1 comorbidities (AOR 3.15 [95% CI: 1.71-3.82], p<0.001) were more likely to be frail. HIV serostatus was not significantly associated with frailty (AOR 0.71 [95% CI: 0.37-1.34], p=0.29). CONCLUSION: Older PWH had a similar prevalence of frailty as those without HIV. These findings call for additional study of the factors that contribute to the robustness of older PWH in sub-Saharan Africa.

Quantitative Assessments of Tumor Activity in a General Oncologic PET/CT Population: Which Metric Minimizes Tracer Uptake Time Dependence?

In oncologic PET, the SUV and standardized uptake ratio (SUR) of a viable tumor generally increase during the postinjection period. In contrast, the net influx rate (Ki ), which is derived from dynamic PET data, should remain relatively constant. Uptake-time-corrected SUV (cSUV) and SUR (cSUR) have been proposed as uptake-time-independent, static alternatives to Ki Our primary aim was to quantify the intrascan repeatability of Ki , SUV, cSUV, SUR, and cSUR among malignant lesions on PET/CT. An exploratory aim was to assess the ability of cSUR to estimate Ki Methods: This prospective, single-center study enrolled adults undergoing standard-of-care oncologic PET/CT. SUV and Ki images were reconstructed from dynamic PET data obtained before (∼35-50 min after injection) and after (∼75-90 min after injection) standard-of-care imaging. Tumors were manually segmented. Quantitative metrics were extracted. cSUVs and cSURs were calculated for a 60-min postinjection reference uptake time. The magnitude of the intrascan test-retest percent change (test-retest |%Δ|) was calculated. Coefficients of determination (R 2) and intraclass correlation coefficients (ICC) were also computed. Differences between metrics were assessed via the Wilcoxon signed-rank test (α, 0.05). Results: This study enrolled 78 subjects; 41 subjects (mean age, 63.8 y; 24 men) with 116 lesions were analyzed. For both tracers, SUVmax and maximum SUR (SURmax) had large early-to-late increases (i.e., poor intrascan repeatability). Among [18F]FDG-avid lesions (n = 93), there were no differences in intrascan repeatability (median test-retest |%Δ|; ICC) between the maximum Ki (Ki ,max) (13%; 0.97) and either the maximum cSUV (cSUVmax) (12%, P = 0.90; 0.96) or the maximum cSUR (cSURmax) (13%, P = 0.67; 0.94). For DOTATATE-avid lesions (n = 23), there were no differences in intrascan repeatability between the Ki ,max (11%; 0.98) and either the cSUVmax (13%, P = 0.41; 0.98) or the cSURmax (11%, P = 0.08; 0.94). The SUVmax, cSUVmax, SURmax, and cSURmax were all strongly correlated with the Ki ,max for both [18F]FDG (R 2, 0.81-0.92) and DOTATATE (R 2, 0.88-0.96), but the cSURmax provided the best agreement with the Ki ,max across early-to-late time points for [18F]FDG (ICC, 0.69-0.75) and DOTATATE (ICC, 0.90-0.91). Conclusion: Ki ,max, cSUVmax, and cSURmax had low uptake time dependence compared with SUVmax and SURmax The Ki ,max can be predicted from cSURmax.

Medical comorbidities and lower myelin content are associated with poor cognition in young adults with perinatally acquired HIV.

OBJECTIVE: Approximately 40% of adults living with HIV experience cognitive deficits. Little is known about the risk factors for cognitive impairment and its association with myelin content in young adults living with perinatally acquired HIV (YApHIV), which is assessed in our cross-sectional study. DESIGN: A prospective, observational cohort study. METHODS: All participants underwent an 11-test cognitive battery and completed medical and social history surveys. Cognitive impairment was defined as Z scores falling at least 1.5 SD below the mean in at least two domains. Twelve participants underwent myelin water imaging. Neuroimaging data were compared to age and sex-matched HIV-uninfected controls. Regression analyses were used to evaluate for risk factors of lower cognitive domain scores and association between myelin content and cognition in YApHIV. RESULTS: We enrolled 21 virally suppressed YApHIV across two sites in the United States. Ten participants (48%) met criteria for cognitive impairment. Participants with any non-HIV related medical comorbidity scored lower across multiple cognitive domains compared to participants without comorbidities. Myelin content did not differ between YApHIV and controls after adjusting for years of education. Lower cognitive scores were associated with lower myelin content in the cingulum and corticospinal tract in YApHIV participants after correcting for multiple comparisons. CONCLUSION: Poor cognition in YApHIV may be exacerbated by non-HIV related comorbidities as noted in older adults with horizontally acquired HIV. The corticospinal tract and cingulum may be vulnerable to the legacy effect of untreated HIV in infancy. Myelin content may be a marker of cognitive reserve in YApHIV.

Intranasal Administration of Bedaquiline-Loaded Fucosylated Liposomes Provides Anti-Tubercular Activity while Reducing the Potential for Systemic Side Effects.

Liposomal formulations of antibiotics for inhalation offer the potential for the delivery of high drug doses, controlled drug release kinetics in the lung, and an excellent safety profile. In this study, we evaluated the in vivo performance of a liposomal formulation for the poorly soluble, antituberculosis agent, bedaquiline. Bedaquiline was encapsulated within monodisperse liposomes of ∼70 nm at a relatively high drug concentration (∼3.6 mg/mL). Formulations with or without fucose residues, which bind to C-type lectin receptors and mediate a preferential binding to macrophage mannose receptor, were prepared, and efficacy was assessed in an in vivo C3HeB/FeJ mouse model of tuberculosis infection (H37Rv strain). Seven intranasal instillations of 5 mg/kg bedaquiline formulations administered every second day resulted in a significant reduction in lung burden (∼0.4-0.6 Δlog10 CFU), although no differences between fucosylated and nonfucosylated formulations were observed. A pharmacokinetic study in healthy, noninfected Balb/c mice demonstrated that intranasal administration of a single dose of 2.5 mg/kg bedaquiline liposomal formulation (fucosylated) improved the lung bioavailability 6-fold compared to intravenous administration of the same formulation at the same dose. Importantly, intranasal administration reduced systemic concentrations of the primary metabolite, N-desmethyl-bedaquiline (M2), compared with both intravenous and oral administration. This is a clinically relevant finding as the M2 metabolite is associated with a higher risk of QT-prolongation in predisposed patients. The results clearly demonstrate that a bedaquiline liposomal inhalation suspension may show enhanced antitubercular activity in the lung while reducing systemic side effects, thus meriting further nonclinical investigation.

Dynamics of peripheral T cell exhaustion and monocyte subpopulations in neurocognitive impairment and brain atrophy in chronic HIV infection.

BACKGROUND: HIV-associated neurocognitive disorders (HAND) is hypothesized to be a result of myeloid cell-induced neuro-inflammation in the central nervous system that may be initiated in the periphery, but the contribution of peripheral T cells in HAND pathogenesis remains poorly understood. METHODS: We assessed markers of T cell activation (HLA-DR + CD38+), immunosenescence (CD57 + CD28-), and immune-exhaustion (TIM-3, PD-1 and TIGIT) as well as monocyte subsets (classical, intermediate, and non-classical) by flow cytometry in peripheral blood derived from individuals with HIV on long-term stable anti-retroviral therapy (ART). Additionally, normalized neuropsychological (NP) composite test z-scores were obtained and regional brain volumes were assessed by magnetic resonance imaging (MRI). Relationships between proportions of immune phenotypes (of T-cells and monocytes), NP z-scores, and brain volumes were analyzed using Pearson correlations and multiple linear regression models. RESULTS: Of N = 51 participants, 84.3% were male, 86.3% had undetectable HIV RNA < 50 copies/ml, median age was 52 [47, 57] years and median CD4 T cell count was 479 [376, 717] cells/uL. Higher CD4 T cells expressing PD-1 + and/or TIM-3 + were associated with lower executive function and working memory and higher CD8 T cells expressing PD-1+ and/or TIM-3+ were associated with reduced brain volumes in multiple regions (putamen, nucleus accumbens, cerebellar cortex, and subcortical gray matter). Furthermore, higher single or dual frequencies of PD-1 + and TIM-3 + expressing CD4 and CD8 T-cells correlated with higher CD16 + monocyte numbers. CONCLUSIONS: This study reinforces evidence that T cells, particularly those with immune exhaustion phenotypes, are associated with neurocognitive impairment and brain atrophy in people living with HIV on ART. Relationships revealed between T-cell immune exhaustion and inflammatory in CD16+ monocytes uncover interrelated cellular processes likely involved in the immunopathogenesis of HAND.

Peptide-Carrier Conjugation.

To produce antibodies against synthetic peptides, it is necessary to couple them to a protein carrier. This chapter provides a nonspecialist overview of peptide-carrier conjugation. Furthermore, a protocol for coupling cysteine-containing peptides to bovine serum albumin is outlined.

Fmoc Solid-Phase Peptide Synthesis.

Synthetic peptides are important as drugs and in research. Currently, the method of choice for producing these compounds is solid-phase peptide synthesis. Here, we describe the scope and limitations of Fmoc solid-phase peptide synthesis. Furthermore, we provide a detailed protocol for Fmoc peptide synthesis.

The Multifaceted Interactions of Dictyostelium Atg1 with Mitochondrial Function, Endocytosis, Growth, and Development.

Autophagy is a degradative recycling process central to the maintenance of homeostasis in all eukaryotes. By ensuring the degradation of damaged mitochondria, it plays a key role in maintaining mitochondrial health and function. Of the highly conserved autophagy proteins, autophagy-related protein 1 (Atg1) is essential to the process. The involvement of these proteins in intracellular signalling pathways, including those involving mitochondrial function, are still being elucidated. Here the role of Atg1 was investigated in the simple model organism Dictyostelium discoideum using an atg1 null mutant and mutants overexpressing or antisense-inhibiting atg1. When evaluated against the well-characterised outcomes of mitochondrial dysfunction in this model, altered atg1 expression resulted in an unconventional set of phenotypic outcomes in growth, endocytosis, multicellular development, and mitochondrial homeostasis. The findings here show that Atg1 is involved in a tightly regulated signal transduction pathway coordinating energy-consuming processes such as cell growth and multicellular development, along with nutrient status and energy production. Furthermore, Atg1's effects on energy homeostasis indicate a peripheral ancillary role in the mitochondrial signalling network, with effects on energy balance rather than direct effects on electron transport chain function. Further research is required to tease out these complex networks. Nevertheless, this study adds further evidence to the theory that autophagy and mitochondrial signalling are not opposing but rather linked, yet strictly controlled, homeostatic mechanisms.

Recent advances in the development of antimicrobial peptides against ESKAPE pathogens.

Multi-drug resistant ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) are a global health threat. The severity of the problem lies in its impact on mortality, therapeutic limitations, the threat to public health, and the costs associated with managing infections caused by these resistant strains. Effectively addressing this challenge requires innovative approaches to research, the development of new antimicrobials, and more responsible antibiotic use practices globally. Antimicrobial peptides (AMPs) are a part of the innate immune system of all higher organisms. They are short, cationic and amphipathic molecules with broad-spectrum activity. AMPs interact with the negatively charged bacterial membrane. In recent years, AMPs have attracted considerable interest as potential antibiotics. However, AMPs have low bioavailability and short half-lives, which may be circumvented by chemical modification. This review presents recent in vitro and in silico strategies for the modification of AMPs to improve their stability and application in preclinical experiments.

A positive affect intervention alters leukocyte DNA methylation in sexual minority men with HIV who use methamphetamine.

OBJECTIVE: This epigenomics sub-study embedded within a randomized controlled trial examined whether an evidenced-based behavioral intervention model that decreased stimulant use altered leukocyte DNA methylation (DNAm). METHODS: Sexual minority men with HIV who use methamphetamine were randomized to a five-session positive affect intervention (n = 32) or an attention-control condition (n = 21), both delivered during three months of contingency management for stimulant abstinence. All participants exhibited sustained HIV virologic control - an HIV viral load less than 40 copies/mL at baseline and six months post-randomization. The Illumina EPIC BeadChip measured leukocyte methylation of cytosine-phosphate-guanosine (CpG) sites mapping onto five a priori candidate genes of interest (i.e., ADRB2, BDNF, FKBP5, NR3C1, OXTR). Functional DNAm pathways and soluble markers of immune dysfunction were secondary outcomes. RESULTS: Compared to the attention-control condition, the positive affect intervention significantly decreased methylation of CpG sites on genes that regulate ß2 adrenergic and oxytocin receptors. There was an inconsistent pattern for the direction of the intervention effects on methylation of CpG sites on genes for glucocorticoid receptors and brain-derived neurotrophic factor. Pathway analyses adjusting for the false discovery rate (padj < 0.05) revealed significant intervention-related alterations in DNAm of Reactome pathways corresponding to neural function as well as dopamine, glutamate, and serotonin release. Positive affect intervention effects on DNAm were accompanied by significant reductions in the self-reported frequency of stimulant use. CONCLUSIONS: There is an epigenetic signature of an evidence-based behavioral intervention model that reduced stimulant use, which will guide the identification of biomarkers for treatment responses.

Plasma galectin-9 relates to cognitive performance and inflammation among adolescents with vertically acquired HIV.

OBJECTIVE: Adolescents with perinatally acquired HIV (AWH) are at an increased risk of poor cognitive development yet the underlying mechanisms remain unclear. Circulating galectin-9 (Gal-9) has been associated with increased inflammation and multimorbidity in adults with HIV despite antiretroviral therapy (ART); however, the relationship between Gal-9 in AWH and cognition remain unexplored. DESIGN: A cross-sectional study of two independent age-matched cohorts from India [AWH on ART ( n  = 15), ART-naive ( n  = 15), and adolescents without HIV (AWOH; n  = 10)] and Myanmar [AWH on ART ( n  = 54) and AWOH ( n  = 22)] were studied. Adolescents from Myanmar underwent standardized cognitive tests. METHODS: Plasma Gal-9 and soluble mediators were measured by immunoassays and cellular immune markers by flow cytometry. We used Mann-Whitney U tests to determine group-wise differences, Spearman's correlation for associations and machine learning to identify a classifier of cognitive status (impaired vs. unimpaired) built from clinical (age, sex, HIV status) and immunological markers. RESULTS: Gal-9 levels were elevated in ART-treated AWH compared with AWOH in both cohorts (all P  < 0.05). Higher Gal-9 in AWH correlated with increased levels of inflammatory mediators (sCD14, TNFα, MCP-1, IP-10, IL-10) and activated CD8 + T cells (all P  < 0.05). Irrespective of HIV status, higher Gal-9 levels correlated with lower cognitive test scores in multiple domains [verbal learning, visuospatial learning, memory, motor skills (all P  < 0.05)]. ML classification identified Gal-9, CTLA-4, HVEM, and TIM-3 as significant predictors of cognitive deficits in adolescents [mean area under the curve (AUC) = 0.837]. CONCLUSION: Our results highlight a potential role of Gal-9 as a biomarker of inflammation and cognitive health among adolescents with perinatally acquired HIV.

Neuropsychiatric and Laboratory Outcomes of Hepatitis C Treatment in an Early-Treated HIV Cohort in Thailand.

Background: Hepatitis C virus (HCV) coinfection may further compromise immunological and cognitive function in people with HIV (PWH). This study compared laboratory and neuropsychiatric measures across the periods of HCV seroconversion and direct-acting antiviral (DAA) therapy with sustained virologic response (SVR) among PWH who initiated antiretroviral therapy (ART) during acute HIV infection (AHI) and acquired HCV after 24 weeks of ART. Methods: Participants from the RV254 AHI cohort underwent paired laboratory and neuropsychiatric assessments during regular follow-up. The former included measurements of CD4 + and CD8 + T-cell counts, HIV RNA, liver enzymes, and lipid profiles. The latter included the Patient Health Questionnaire-9 (PHQ-9), Distress Thermometer (DT), and a 4-test cognitive battery that evaluated psychomotor speed, executive function, fine motor speed and dexterity. The raw scores in the battery were standardized and averaged to create an overall performance (NPZ-4) score. Parameters of HCV-coinfected participants were compared across HCV seroconversion and DAA treatment groups. Results: Between 2009 and 2022, 79 of 703 RV254 participants acquired HCV after ≥ 24 weeks of ART; 53 received DAA, and 50 (94%) achieved SVR. All participants were Thai males (median age: 30 years); 34 (68%) denied past intravenous drug use, and 41 (82%) had a history of other sexually transmitted infections during follow-up. Following SVR, aspartate transferase (AST) and alanine transaminase (ALT) decreased (p < 0.001), while total cholesterol, low-density lipoprotein, and triglycerides increased (p < 0.01). The median CD4+/CD8 + ratio increased from 0.91 to 0.97 (p = 0.012). NPZ-4 improved from 0.75 to 0.91 (p = 0.004). The median DT score increased from 1.7 to 2.7 (p = 0.045), but the PHQ-9 score remained unchanged. Conclusion: HCV coinfection is common in this group of high-risk PWH, highlighting the need for regular screening, early diagnosis, and treatment. There was a modest improvement in the CD4+/CD8 + T-cell ratio and cognitive performance after DAA therapy in patients who achieved SVR. Future studies should examine potential neuropsychiatric impacts during early HCV infection as well as the longer-term neuropsychiatric outcomes after DAA treatment with SVR.

Mindfulness-Based Stress Reduction for Symptom Management in Older Individuals with HIV-Associated Neurocognitive Disorder.

The growing number of people aging with HIV represents a group vulnerable to the symptom burdens of HIV-associated neurocognitive disorder (HAND). Among younger groups, Mindfulness-Based Stress Reduction (MBSR) has been shown to help people living with HIV manage HIV-related and other life stress, and although there is some theoretical and empirical evidence that it may be effective among those with cognitive deficits, the approach has not been studied in older populations with HAND. Participants (n = 180) 55 years or older with HIV and cognitive impairment were randomly assigned to either an 8-week MBSR arm or a waitlist control. We assessed the impact of MBSR compared to a waitlist control on psychological outcomes [stress, anxiety, depression, and quality of life (QOL)] and cognitive metrics (e.g., speed of information processing, working memory, attention, impulsivity) measured at baseline, immediately post intervention (8 weeks) and one month later (16 weeks). Intent to treat analyses showed significant improvement in the MBSR group compared to control on symptoms of depression from baseline to 8 weeks, however, the difference was not sustained at 16 weeks. The MBSR group also showed improvement in perceived QOL from baseline to 16 weeks compared to the waitlist control group. Cognitive performance did not differ between the two treatment arms. MBSR shows promise as a tool to help alleviate the symptom burden of depression and low QOL in older individuals living with HAND and future work should address methods to better sustain the beneficial impact on depression and QOL.

Unusual imaging findings associated with abdominal pediatric germ cell tumors.

Germ cell tumors of childhood are tumors arising from germline cells in gonadal or extragonadal locations. Extragonadal germ cell tumors are characteristically located in the midline, arising intracranially or in the mediastinum, retroperitoneum, or pelvis. These tumors are generally easily diagnosed due to typical sites of origin, characteristic imaging findings, and laboratory markers. However, germ cell tumors can be associated with unusual clinical syndromes or imaging features that can perplex the radiologist. This review will illustrate atypical imaging/clinical manifestations and complications of abdominal germ cell tumors in childhood. These features include unusual primary tumors such as multifocal primaries; local complications such as ovarian torsion or ruptured dermoid; atypical presentations of metastatic disease associated with burned-out primary tumor, growing teratoma syndrome, and gliomatosis peritonei; endocrine manifestations such as precocious puberty and hyperthyroidism; and antibody mediated paraneoplastic syndrome such as anti-N-methyl-D-aspartate-receptor antibody-mediated encephalitis. This review aims to illustrate unusual imaging features associated with the primary tumor, metastatic disease, or distant complications of abdominal germ cell tumors of childhood.

Leveraging qualitative approaches to guide sustainable international research collaborations.

Qualitative research approaches were used to launch an international research collaboration between the U. S. and Cambodia. Cambodian officials requested assistance in learning qualitative approaches to complement the research skills of Cambodian mental health providers. This article provides a description of how U. S. researchers responded to that request and engaged with Cambodian psychiatrists to explore mental health needs and interventions in both countries and initiate a sustainable relationship. The early focus on qualitative research methodologies may be an avenue that mitigates some of the challenges that can characterize international research. In this study, early communications involved developing a plan to teach qualitative methods while also collecting and analyzing data in both countries that would address the mental health concerns experienced by respective care providers. A case study exemplar was embedded with a scripted focus group guide to collect data from U. S. focus groups, then share with Cambodian psychiatrists. Components of hermeneutic phenomenological interviewing and descriptive content analysis were used to simultaneously teach and enact the research methods, gather data in both countries to analyze, and inspire participants to replicate the methods in their ongoing work. Cambodian psychiatrists were able to demonstrate competence in facilitating focus groups after being participant-observers. Researcher/practitioners from both U. S. and Cambodian teams gained new understandings about the mental health needs of their patients. The mutual engagement of a research focus is an effective way to establish cross-cultural relationships. The challenges of staying with stable teams over times remain, but the content shared and learned in a participatory structure yields understandings that cross cultural boundaries. Anticipated and unexpected challenges may be offset by an intention of reciprocity and mutual engagement. The use of qualitative methodologies, early and repeatedly, can facilitate relational understanding.

Phase 1 study of latozinemab in progranulin-associated frontotemporal dementia.

INTRODUCTION: Heterozygous mutations in the GRN gene lead to reduced progranulin (PGRN) levels in plasma and cerebrospinal fluid (CSF) and are causative of frontotemporal dementia (FTD) with > 90% penetrance. Latozinemab is a human monoclonal immunoglobulin G1 antibody that is being developed to increase PGRN levels in individuals with FTD caused by heterozygous loss-of-function GRN mutations. METHODS: A first-in-human phase 1 study was conducted to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of multiple-dose intravenous administration of latozinemab in eight symptomatic participants with FTD caused by a heterozygous loss-of-function GRN mutation (FTD-GRN). RESULTS: Latozinemab demonstrated favorable safety and PK/PD profiles. Multiple-dose administration of latozinemab increased plasma and CSF PGRN levels in participants with FTD-GRN to levels that approximated those seen in healthy volunteers. DISCUSSION: Data from the first-in-human phase 1 study support further development of latozinemab for the treatment of FTD-GRN. Highlights: GRN mutations decrease progranulin (PGRN) and cause frontotemporal dementia (FTD).Latozinemab is being developed as a PGRN-elevating therapy.Latozinemab demonstrated a favorable safety profile in a phase 1 clinical trial.Latozinemab increased PGRN levels in the CNS of symptomatic FTD-GRN participants.

HIV, Social Networks, and Loneliness among Older Adults in Uganda.

Loneliness among older adults has been identified as a major public health problem. Yet little is known about loneliness, or the potential role of social networks in explaining loneliness, among older people with HIV (PWH) in sub-Saharan Africa, where 70% of PWH reside. To explore this issue, we analyzed data from 599 participants enrolled in the Quality of Life and Ageing with HIV in Rural Uganda study, including older adults with HIV in ambulatory care and a comparator group of people without HIV of similar age and gender. The 3-item UCLA Loneliness Scale was used to measure loneliness, and HIV status was the primary explanatory variable. The study found no statistically significant correlation between loneliness and HIV status. However, individuals with HIV had smaller households, less physical and financial support, and were less socially integrated compared to those without HIV. In multivariable logistic regressions, loneliness was more likely among individuals who lived alone (aOR:3.38, 95% CI:1.47-7.76) and less likely among those who were married (aOR:0.34, 95% CI:0.22-0.53) and had a higher level of social integration (aOR:0.86, 95% CI: 0.79-0.92). Despite having smaller social networks and less support, older adults with HIV had similar levels of loneliness as those without HIV, which may be attributed to resiliency and access to HIV-related health services among individuals with HIV. Nonetheless, further research is necessary to better understand the mechanisms involved.