Wilms' tumor 1 (WT1) antigen is overexpressed in Kaposi Sarcoma and is regulated by KSHV vFLIP.

In people living with HIV, Kaposi Sarcoma (KS), a vascular neoplasm caused by KS herpesvirus (KSHV/HHV-8), remains one of the most common malignancies worldwide. Individuals living with HIV, receiving otherwise effective antiretroviral therapy, may present with extensive disease requiring chemotherapy. Hence, new therapeutic approaches are needed. The Wilms' tumor 1 (WT1) protein is overexpressed and associated with poor prognosis in several hematologic and solid malignancies and has shown promise as an immunotherapeutic target. We found that WT1 was overexpressed in >90% of a total 333 KS biopsies, as determined by immunohistochemistry and image analysis. Our largest cohort from ACTG, consisting of 294 cases was further analyzed demonstrating higher WT1 expression was associated with more advanced histopathologic subtypes. There was a positive correlation between the proportion of infected cells within KS tissues, assessed by expression of the KSHV-encoded latency-associated nuclear antigen (LANA), and WT1 positivity. Areas with high WT1 expression showed sparse T-cell infiltrates, consistent with an immune evasive tumor microenvironment. We show that major oncogenic isoforms of WT1 are overexpressed in primary KS tissue and observed WT1 upregulation upon de novo infection of endothelial cells with KSHV. KSHV latent viral FLICE-inhibitory protein (vFLIP) upregulated total and major isoforms of WT1, but upregulation was not seen after expression of mutant vFLIP that is unable to bind IKKÆ´ and induce NFκB. siRNA targeting of WT1 in latent KSHV infection resulted in decreased total cell number and pAKT, BCL2 and LANA protein expression. Finally, we show that ESK-1, a T cell receptor-like monoclonal antibody that recognizes WT1 peptides presented on MHC HLA-A0201, demonstrates increased binding to endothelial cells after KSHV infection or induction of vFLIP expression. We propose that oncogenic isoforms of WT1 are upregulated by KSHV to promote tumorigenesis and immunotherapy directed against WT1 may be an approach for KS treatment.

Vaccination-Associated Myocarditis and Myocardial Injury.

SARS-CoV-2 vaccine-associated myocarditis/myocardial injury should be evaluated in the contexts of COVID-19 infection, other types of viral myocarditis, and other vaccine-associated cardiac disorders. COVID-19 vaccine-associated myocardial injury can be caused by an inflammatory immune cell infiltrate, but other etiologies such as microvascular thrombosis are also possible. The clinical diagnosis is typically based on symptoms and cardiac magnetic resonance imaging. Endomyocardial biopsy is confirmatory for myocarditis, but may not show an inflammatory infiltrate because of rapid resolution or a non-inflammatory etiology. Myocarditis associated with SARS-COVID-19 vaccines occurs primarily with mRNA platform vaccines, which are also the most effective. In persons aged >16 or >12 years the myocarditis estimated crude incidences after the first 2 doses of BNT162b2 and mRNA-1273 are approximately 1.9 and 3.5 per 100 000 individuals, respectively. These rates equate to excess incidences above control populations of approximately 1.2 (BNT162b2) and 1.9 (mRNA-1273) per 100 000 persons, which are lower than the myocarditis rate for smallpox but higher than that for influenza vaccines. In the studies that have included mRNA vaccine and SARS-COVID-19 myocarditis measured by the same methodology, the incidence rate was increased by 3.5-fold over control in COVID-19 compared with 1.5-fold for BNT162b2 and 6.2-fold for mRNA-1273. However, mortality and major morbidity are less and recovery is faster with mRNA vaccine-associated myocarditis compared to COVID-19 infection. The reasons for this include vaccine-associated myocarditis having a higher incidence in young adults and adolescents, typically no involvement of other organs in vaccine-associated myocarditis, and based on comparisons to non-COVID viral myocarditis an inherently more benign clinical course.

Age-related macular degeneration.

Age-related macular degeneration is an increasingly important public health issue due to ageing populations and increased longevity. Age-related macular degeneration affects individuals older than 55 years and threatens high-acuity central vision required for important tasks such as reading, driving, and recognising faces. Advances in retinal imaging have identified biomarkers of progression to late age-related macular degeneration. New treatments for neovascular age-related macular degeneration offer potentially longer-lasting effects, and progress is being made towards a treatment for atrophic late age-related macular degeneration. An effective intervention to slow progression in the earlier stages of disease, or to prevent late age-related macular degeneration development remains elusive, and our understanding of underlying mechanistic pathways continues to evolve.

Efficacy of the mRNA-1273 SARS-CoV-2 Vaccine at Completion of Blinded Phase.

BACKGROUND: At interim analysis in a phase 3, observer-blinded, placebo-controlled clinical trial, the mRNA-1273 vaccine showed 94.1% efficacy in preventing coronavirus disease 2019 (Covid-19). After emergency use of the vaccine was authorized, the protocol was amended to include an open-label phase. Final analyses of efficacy and safety data from the blinded phase of the trial are reported. METHODS: We enrolled volunteers who were at high risk for Covid-19 or its complications; participants were randomly assigned in a 1:1 ratio to receive two intramuscular injections of mRNA-1273 (100 µg) or placebo, 28 days apart, at 99 centers across the United States. The primary end point was prevention of Covid-19 illness with onset at least 14 days after the second injection in participants who had not previously been infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The data cutoff date was March 26, 2021. RESULTS: The trial enrolled 30,415 participants; 15,209 were assigned to receive the mRNA-1273 vaccine, and 15,206 to receive placebo. More than 96% of participants received both injections, 2.3% had evidence of SARS-CoV-2 infection at baseline, and the median follow-up was 5.3 months in the blinded phase. Vaccine efficacy in preventing Covid-19 illness was 93.2% (95% confidence interval [CI], 91.0 to 94.8), with 55 confirmed cases in the mRNA-1273 group (9.6 per 1000 person-years; 95% CI, 7.2 to 12.5) and 744 in the placebo group (136.6 per 1000 person-years; 95% CI, 127.0 to 146.8). The efficacy in preventing severe disease was 98.2% (95% CI, 92.8 to 99.6), with 2 cases in the mRNA-1273 group and 106 in the placebo group, and the efficacy in preventing asymptomatic infection starting 14 days after the second injection was 63.0% (95% CI, 56.6 to 68.5), with 214 cases in the mRNA-1273 group and 498 in the placebo group. Vaccine efficacy was consistent across ethnic and racial groups, age groups, and participants with coexisting conditions. No safety concerns were identified. CONCLUSIONS: The mRNA-1273 vaccine continued to be efficacious in preventing Covid-19 illness and severe disease at more than 5 months, with an acceptable safety profile, and protection against asymptomatic infection was observed. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; COVE ClinicalTrials.gov number, NCT04470427.).

A whole food, plant-based randomized controlled trial in metastatic breast cancer: feasibility, nutrient, and patient-reported outcomes.

PURPOSE: Quality of life (QOL) is among the most important outcomes for women with metastatic breast cancer (MBC), and it predicts survival. QOL is negatively impacted by cognitive impairment, fatigue, and weight gain. We assessed whether a whole food, plant-based (WFPB) diet-promoting weight loss is feasible and might improve QOL. METHODS: Women with MBC on stable systemic treatments were randomized 2:1 to 1) WFPB dietary intervention (n = 21) or 2) usual care (n = 11) for 8 weeks. Participants attended weekly education visits and consumed an ad libitum WFPB diet (3 prepared meals/day provided). Patient-reported outcomes and 3-day food records were assessed at baseline and 8 weeks. The effects of WFPB diet on changes in outcomes were assessed by analysis of covariance model controlling for baseline. RESULTS: 20 intervention and 10 control participants completed the trial. Intervention participants were highly adherent to the WFPB diet (94.3 % total calories on-plan). Intervention group nutrient intakes changed significantly including dietary fat (35.8 % to 20.4 % percent calories from fat, p < 0.001) and fiber content (12.7 to 30.8 g fiber/1000 kcal, p < 0.001). Perceived cognitive function (FACT-Cog total + 16.1; 95 % confidence interval [CI] = 0.8-31.7; p = 0.040) and emotional well-being (FACT-B emotional well-being subscale + 2.3; CI = 0.5-4.1; p = 0.016) improved in the WFPB versus the control group. Fatigue, measured by the BFI, improved within the WFPB group for fatigue severity (M = 4.7 ± 2.5[SD] to 3.7 ± 2.3, p = 0.047) and fatigue at its worst (5.8 ± 2.8 to 4.4 ± 2.4, p = 0.011). CONCLUSIONS: Significant dietary changes in this population are feasible and may improve QOL by improving treatment-related symptoms. Additional study is warranted. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03045289. Registered 7 February 2017.

A whole-food, plant-based randomized controlled trial in metastatic breast cancer: weight, cardiometabolic, and hormonal outcomes.

PURPOSE: Breast cancer treatment is associated with weight gain, and obesity and its related cardiometabolic and hormonal risk factors have been associated with poorer outcomes. Dietary intervention may address these risk factors, but limited research has been done in the setting of metastatic breast cancer requiring systemic therapy. METHODS: Women with metastatic breast cancer on stable treatment were randomized 2:1 to an 8-week intervention (n = 21) or control (n = 11). The intervention included weekly assessment visits and an ad libitum whole-food, plant-based (WFPB) diet with provided meals. Cardiometabolic, hormonal, and cancer markers were assessed at baseline, 4 weeks, and 8 weeks. RESULTS: Within the intervention group, mean weight decreased by 6.6% (p < 0.01) after 8 weeks. Fasting insulin decreased from 16.8 uIU/L to 11.2 uIU/L (p < 0.01), concurrent with significantly reduced insulin resistance. Total cholesterol decreased from 193.6 mg/dL to 159 mg/dL (p < 0.01), and low-density lipoprotein (LDL) cholesterol decreased from 104.6 mg/dL to 82.2 mg/dL (p < 0.01). Total testosterone was unchanged, but free testosterone trended lower within the intervention group (p = 0.08) as sex hormone binding globulin increased from 74.3 nmol/L to 98.2 nmol/L (p < 0.01). There were no significant differences in cancer progression markers at week 8, although mean CA 15-3, CA 27.29, and CEA were lower in the intervention group (p = 0.53, p = 0.23, and p = 0.54, respectively) compared to control, when adjusted for baseline. CONCLUSION: WFPB dietary changes during treatment for metastatic breast cancer are well tolerated and significantly improve weight, cardiometabolic and hormonal parameters. Longer studies are warranted to assess the durability of changes. Trial registration First registered at Clinicaltrials.gov (NCT03045289) on February 7, 2017.

SARS-CoV-2-specific T cells associate with inflammation and reduced lung function in pulmonary post-acute sequalae of SARS-CoV-2.

As of January 2022, at least 60 million individuals are estimated to develop post-acute sequelae of SARS-CoV-2 (PASC) after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While elevated levels of SARS-CoV-2-specific T cells have been observed in non-specific PASC, little is known about their impact on pulmonary function which is compromised in the majority of these individuals. This study compares frequencies of SARS-CoV-2-specific T cells and inflammatory markers with lung function in participants with pulmonary PASC and resolved COVID-19 (RC). Compared to RC, participants with respiratory PASC had between 6- and 105-fold higher frequencies of IFN-γ- and TNF-α-producing SARS-CoV-2-specific CD4+ and CD8+ T cells in peripheral blood, and elevated levels of plasma CRP and IL-6. Importantly, in PASC participants the frequency of TNF-α-producing SARS-CoV-2-specific CD4+ and CD8+ T cells, which exhibited the highest levels of Ki67 indicating they were activity dividing, correlated positively with plasma IL-6 and negatively with measures of lung function, including forced expiratory volume in one second (FEV1), while increased frequencies of IFN-γ-producing SARS-CoV-2-specific T cells associated with prolonged dyspnea. Statistical analyses stratified by age, number of comorbidities and hospitalization status demonstrated that none of these factors affect differences in the frequency of SARS-CoV-2 T cells and plasma IL-6 levels measured between PASC and RC cohorts. Taken together, these findings demonstrate elevated frequencies of SARS-CoV-2-specific T cells in individuals with pulmonary PASC are associated with increased systemic inflammation and decreased lung function, suggesting that SARS-CoV-2-specific T cells contribute to lingering pulmonary symptoms. These findings also provide mechanistic insight on the pathophysiology of PASC that can inform development of potential treatments to reduce symptom burden.

Genes implicated by a methylome-wide schizophrenia study in neonatal blood show differential expression in adult brain samples.

Schizophrenia is a disabling disorder involving genetic predisposition in combination with environmental influences that likely act via dynamic alterations of the epigenome and the transcriptome but its detailed pathophysiology is largely unknown. We performed cell-type specific methylome-wide association study of neonatal blood (N = 333) from individuals who later in life developed schizophrenia and controls. Suggestively significant associations (P < 1.0 × 10-6) were detected in all cell-types and in whole blood with methylome-wide significant associations in monocytes (P = 2.85 × 10-9-4.87 × 10-9), natural killer cells (P = 1.72 × 10-9-7.82 × 10-9) and B cells (P = 3.8 × 10-9). Validation of methylation findings in post-mortem brains (N = 596) from independent schizophrenia cases and controls showed significant enrichment of transcriptional differences (enrichment ratio = 1.98-3.23, P = 2.3 × 10-3-1.0 × 10-5), with specific highly significant differential expression for, for example, BDNF (t = -6.11, P = 1.90 × 10-9). In addition, expression difference in brain significantly predicted schizophrenia (multiple correlation = 0.15-0.22, P = 3.6 × 10-4-4.5 × 10-8). In summary, using a unique design combining pre-disease onset (neonatal) blood methylomic data and post-disease onset (post-mortem) brain transcriptional data, we have identified genes of likely functional relevance that are associated with schizophrenia susceptibility, rather than confounding disease associated artifacts. The identified loci may be of clinical value as a methylation-based biomarker for early detection of increased schizophrenia susceptibility.

Clinical performance of predicting late age-related macular degeneration development using multimodal imaging.

BACKGROUND: To examine whether the clinical performance of predicting late age-related macular degeneration (AMD) development is improved through using multimodal imaging (MMI) compared to using colour fundus photography (CFP) alone, and how this compares with a basic prediction model using well-established AMD risk factors. METHODS: Individuals with AMD in this study underwent MMI, including optical coherence tomography (OCT), fundus autofluorescence, near-infrared reflectance and CFP at baseline, and then at 6-monthly intervals for 3-years to determine MMI-defined late AMD development. Four retinal specialists independently assessed the likelihood that each eye at baseline would progress to MMI-defined late AMD over 3-years with CFP, and then with MMI. Predictive performance with CFP and MMI were compared to each other, and to a basic prediction model using age, presence of pigmentary abnormalities, and OCT-based drusen volume. RESULTS: The predictive performance of the clinicians using CFP [AUC = 0.75; 95% confidence interval (CI) = 0.68-0.82] improved when using MMI (AUC = 0.79; 95% CI = 0.72-0.85; p = 0.034). However, a basic prediction model outperformed clinicians using either CFP or MMI (AUC = 0.85; 95% CI = 0.78-91; p ≤ 0.002). CONCLUSIONS: Clinical performance for predicting late AMD development was improved by using MMI compared to CFP. However, a basic prediction model using well-established AMD risk factors outperformed retinal specialists, suggesting that such a model could further improve personalised counselling and monitoring of individuals with the early stages of AMD in clinical practice.

Concussion diagnosis and recovery in relation to collegiate athletic department classification: a LIMBIC MATARS consortium investigation.

PURPOSE: We investigated time to reach concussion diagnosis and recovery milestones in collegiate athletes relative to their schools' National Collegiate Athletic Association (NCAA) classification. METHODS: We retrospectively examined 849 (43.1% female) concussion cases from 11 NCAA institutions (Division I Power 5 [n = 4], Division I Non-Power 5 [n = 4], and Division II/III [n = 3]) from the 2015-16 to 2019-20 athletic seasons. Our primary outcome measures were days to reach specific clinical milestones following concussion. RESULTS: Median (IQR) time from injury to diagnosis was significantly longer at Division II/III institutions (1 [0-4] days) compared to Division I Power 5 (0 [0-1] days) and Division I Non-Power 5 (0 [0-1] days) institutions (p < 0.001). Likewise, Division II/III athletes (15 [11-22] days) took significantly longer to return to sport after concussion than Division I Power 5 (10 [7-16] days) and Division I Non-Power 5 (11 [7-18.5] days) athletes (p < 0.001). CONCLUSION: Division II/III athletes had delayed concussion diagnoses and return to sport timelines compared to Division I athletes. Our results suggest that differences in sports medicine resources across NCAA divisions may influence injury recognition and recovery in collegiate athletes with concussion.

Sport Type and Risk of Subsequent Injury in Collegiate Athletes Following Concussion: a LIMBIC MATARS Consortium Investigation.

OBJECTIVE: To investigate the association between sport type (collision, contact, non-contact) and subsequent injury risk following concussion in collegiate athletes. MATERIALS AND METHODS: This retrospective chart review of 248 collegiate athletes with diagnosed concussions (age: 20.0 ± 1.4 years; height: 179.6 ± 10.9 cm; mass: 79.0 ± 13.6 kg, 63% male) from NCAA athletic programs (n = 11) occurred between the 2015-2020 athletic seasons. Acute injuries that occurred within six months following concussion were evaluated. Subsequent injuries were grouped by lower extremity, upper extremity, trunk, or concussion. The independent variable was sport type: collision, contact, non-contact. A Cox proportional hazard model was used to assess the risk of subsequent injury between sport types. RESULTS: Approximately 28% (70/248) of athletes sustained a subsequent acute injury within six months post-concussion. Collision sport athletes had a significantly higher risk of sustaining any injury (HR: 0.41, p < 0.001, 95% CI: 0.28, 0.62), lower extremity (HR: 0.55, p = 0.04, 95% CI: 0.32, 0.97), and upper extremity (HR: 0.41, p = 0.01, 95% CI: 0.20, 0.81) injuries following concussion. No differences between sport types were observed for other injuries. CONCLUSION: Collision sport athletes had a higher rate of any subsequent injury, lower, and upper extremity injuries following concussion. Future research should focus on sport-specific secondary injury prevention efforts.

Physical activity and recovery following concussion in collegiate athletes: a LIMBIC MATARS Consortium Investigation.

OBJECTIVE: To investigate whether routine daily activities (RDA), non-prescribed exercise (Non-ERx), or prescribed exercise (ERx) were associated with recovery from sport-related concussion (SRC) in collegiate athletes. MATERIALS AND METHODS: Data for this cross-sectional, retrospective chart review of collegiate athletes diagnosed with SRC (n = 285[39.6% female], age = 19.5 ± 1.4 years) were collected during the 2015-16 to 2019-20 athletic seasons. The independent variable was group (RDA, Non-ERx, ERx). Dependent variables included days from date of diagnosis to symptom resolution (Dx-SR) and SR to return to sport (SR-RTS). RESULTS: Those in the Non-ERx group took nearly 1.3 times longer to achieve SR (IRR = 1.28, 95% CI: 1.11, 1.46) and, 1.8 times longer for RTS (IRR = 1.82, 95% CI: 1.11, 2.71) when compared to those in the RDA group. No other comparisons were significant. CONCLUSION: Collegiate athletes in the Non-ERx group took approximately 1 week longer to achieve SR as compared to the RDA and ERx groups. Our findings suggest that if exercise is recommended following SRC, it must be clearly and specifically prescribed. If exercise parameters cannot be prescribed, or monitored, RDA appear to be similarly beneficial during recovery for collegiate athletes with concussion.

The association between longitudinal declines in speech sound accuracy and speech intelligibility in speakers with amyotrophic lateral sclerosis.

The purpose of this study was to examine how neurodegeneration secondary to amyotrophic lateral sclerosis (ALS) impacts speech sound accuracy over time and how speech sound accuracy, in turn, is related to speech intelligibility. Twenty-one participants with ALS read the Bamboo Passage over multiple data collection sessions across several months. Phonemic and orthographic transcriptions were completed for all speech samples. The percentage of phonemes accurately produced was calculated across each phoneme, sound class (i.e. consonants versus vowels), and distinctive feature (i.e. features involved in Manner of Articulation, Place of Articulation, Laryngeal Voicing, Tongue Height, and Tongue Advancement). Intelligibility was determined by calculating the percentage of words correctly transcribed orthographically by naive listeners. Linear mixed effects models were conducted to assess the decline of each distinctive feature over time and its impact on intelligibility. The results demonstrated that overall phonemic production accuracy had a nonlinear relationship with speech intelligibility and that a subset of features (i.e. those dependent on precise lingual and labial constriction and/or extensive lingual and labial movement) were more important for intelligibility and were more impacted over time than other features. Furthermore, findings revealed that consonants were more strongly associated with intelligibility than vowels, but consonants did not significantly differ from vowels in their decline over time. These findings have the potential to (1) strengthen mechanistic understanding of the physiological constraints imposed by neuronal degeneration on speech production and (2) inform the timing and selection of treatment and assessment targets for individuals with ALS.

Predictive Factors for Biopsy-Negative Giant Cell Arteritis and Alternative Diagnoses in a Neuro-Ophthalmology Context.

Giant cell arteritis is a challenging diagnosis for patients given the high prevalence of negative temporal artery biopsies (TAB). Despite the lack of histopathological evidence of giant cell arteritis in the TAB, patients can still have TAB-negative giant cell arteritis. The purpose of this paper is to analyse the predictors for TAB-negative giant cell arteritis and the alternative diagnosis of biopsy-negative patients without a giant cell arteritis diagnosis. A retrospective electronic database review of all TABs performed at the Royal Victorian Eye and Ear Hospital from February 2015 to May 2020. Logistic regression analysis was performed to determine predictive factors for a diagnosis of TAB-negative giant cell arteritis. In all cases, a clinical diagnosis of TAB-negative giant cell arteritis was determined by a neuro-ophthalmologist. Alternative diagnoses for negative TABs were identified and explored. A total of 368 TABs were analysed with 287 (78%) negative for histopathological evidence of GCA. Twenty-seven (9.4%) patients were diagnosed and treated as TAB-negative giant cell arteritis. The clinical predictors of a TAB-negative giant cell arteritis diagnosis were the presence of jaw claudication (OR 2.77, 95% CI 1.10-6.98) and CRP (OR 1.02, 95% CI 1.00-1.03). Alternative diagnoses included non-specific headache, non-arteritic anterior ischaemic optic neuropathy, retinal vessel occlusions, and ocular nerve palsies. Predictive factors for a diagnosis of TAB-negative giant cell arteritis were jaw claudication and an elevated CRP. Several alternative diagnoses can be considered for patients with a negative TAB in a neuro-ophthalmology context.

Sex Differences in Subclinical Atherosclerosis and Systemic Immune Activation/Inflammation Among People With Human Immunodeficiency Virus in the United States.

BACKGROUND: Among people with HIV (PWH), sex differences in presentations of atherosclerotic cardiovascular disease (ASCVD) may be influenced by differences in coronary plaque parameters, immune/inflammatory biomarkers, or relationships therein. METHODS: REPRIEVE, a primary ASCVD prevention trial, enrolled antiretroviral therapy (ART)-treated PWH. At entry, a subset of US participants underwent coronary computed tomography angiography (CTA) and immune phenotyping (n = 755 CTA; n = 725 CTA + immune). We characterized sex differences in coronary plaque and immune/inflammatory biomarkers and compared immune-plaque relationships by sex. Unless noted otherwise, analyses adjust for ASCVD risk score. RESULTS: The primary analysis cohort included 631 males and 124 females. ASCVD risk was higher among males (median: 4.9% vs 2.1%), while obesity rates were higher among females (48% vs 21%). Prevalence of any plaque and of plaque with either ≥1 visible noncalcified portion or vulnerable features (NC/V-P) was lower among females overall and controlling for relevant risk factors (RR [95% CI] for any plaque: .67 [.50, .92]; RR for NC/V-P: .71 [.51, 1.00] [adjusted for ASCVD risk score and body mass index]). Females showed higher levels of IL-6, hs-CRP, and D-dimer and lower levels of Lp-PLA2 (P < .001 for all). Higher levels of Lp-PLA2, MCP-1, and oxLDL were associated with higher plaque (P < .02) and NC/V-P prevalence, with no differences by sex. Among females but not males, D-dimer was associated with higher prevalence of NC/V-P (interaction P = .055). CONCLUSIONS: Among US PWH, females had a lower prevalence of plaque and NC/V-P, as well as differences in key immune/inflammatory biomarkers. Immune-plaque relationships differed by sex for D-dimer but not other tested parameters. Clinical Trial Registration. ClinicalTrials.gov; identifier: NCT0234429 (date of initial registration: 22 January 2015).

Antiretroviral Therapy Intensification for Neurocognitive Impairment in Human Immunodeficiency Virus.

BACKGROUND: Neurocognitive impairment (NCI) in people with HIV (PWH) on antiretroviral therapy (ART) is common and may result from persistent HIV replication in the central nervous system. METHODS: A5324 was a randomized, double-blind, placebo-controlled, 96-week trial of ART intensification with dolutegravir (DTG) + MVC, DTG + Placebo, or Dual - Placebo in PWH with plasma HIV RNA <50 copies/mL on ART and NCI. The primary outcome was the change on the normalized total z score (ie, the mean of individual NC test z scores) at week 48. RESULTS: Of 357 screened, 191 enrolled: 71% male, 51% Black race, 22% Hispanic ethnicity; mean age 52 years; mean CD4+ T-cells 681 cells/µL. Most (65%) had symptomatic HIV-associated NC disorder. Study drug was discontinued due to an adverse event in 15 (8%) and did not differ between arms (P = .17). Total z score, depressive symptoms, and daily functioning improved over time in all arms with no significant differences between them at week 48 or later. Adjusting for age, sex, race, study site, efavirenz use, or baseline z score did not alter the results. Body mass index modestly increased over 96 weeks (mean increase 0.32 kg/m2, P = .006) and did not differ between arms (P > .10). CONCLUSIONS: This is the largest, randomized, placebo-controlled trial of ART intensification for NCI in PWH. The findings do not support empiric ART intensification as a treatment for NCI in PWH on suppressive ART. They also do not support that DTG adversely affects cognition, mood, or weight.

Cardiotoxicity and pharmacogenetics of doxorubicin in black Zimbabwean breast cancer patients.

AIMS: Doxorubicin-induced cardiotoxicity (DIC) is a significant cause of mortality in cancer care. This study was conducted to establish the frequency of DIC in Zimbabwean breast cancer patients on doxorubicin and to test the DIC predictive power of genetic biomarkers. METHODS: A cohort of 50 Zimbabwean breast cancer patients treated with doxorubicin were followed up for 12 months with serial echocardiography and genotyped for UGTA1A6*4, SLC28A3 and RARG. Eleven per cent of the patients experienced DIC. RESULTS: The frequencies of SLC28A3 (rs7853758), UGT1A6*4 (rs17863783) and RARG (rs2229774) were 60.7%, 17.9% and 14.3%, respectively. No association between DIC and the three variants was observed. CONCLUSIONS: This is the first study on the prevalence of DIC and associated genetic biomarker predictive evaluation in Zimbabwean breast cancer patients. The genetic frequencies observed in our study were different to those reported in other populations. A larger sample size with a longer follow-up time will be necessary in future studies.

Development of a new quantum trajectory molecular dynamics framework.

An extension to the wave packet description of quantum plasmas is presented, where the wave packet can be elongated in arbitrary directions. A generalized Ewald summation is constructed for the wave packet models accounting for long-range Coulomb interactions and fermionic effects are approximated by purpose-built Pauli potentials, self-consistent with the wave packets used. We demonstrate its numerical implementation with good parallel support and close to linear scaling in particle number, used for comparisons with the more common wave packet employing isotropic states. Ground state and thermal properties are compared between the models with differences occurring primarily in the electronic subsystem. Especially, the electrical conductivity of dense hydrogen is investigated where a 15% increase in DC conductivity can be seen in our wave packet model compared with other models. This article is part of the theme issue 'Dynamic and transient processes in warm dense matter'.

Suicide Attempts and Ideation Among Veterans/Service Members and Non-Veterans Over 5 Years Following Traumatic Brain Injury: A Combined NIDILRR and VA TBI Model Systems Study.

OBJECTIVE: This study compared rates of suicide attempt (SA) and suicidal ideation (SI) during the first 5 years after traumatic brain injury (TBI) among veterans and service members (V/SMs) in the Veterans Affairs (VA) and the National Institute on Disability, Independent Living, and Rehabilitation Research (NIDILRR) Model Systems National Databases to each other and to non-veterans (non-Vs) in the NIDILRR database. SETTING: Twenty-one NIDILRR and 5 VA TBI Model Systems (TBIMS) inpatient rehabilitation facilities in the United States. PARTICIPANTS: Participants with TBI were discharged from rehabilitation alive, had a known military status recorded (either non-V or history of military service), and successful 1-, 2-, and/or 5-year follow-up interviews completed between 2009 and 2021. The year 1 cohort included 8737 unique participants (8347 with SA data and 3987 with SI data); the year 2 (7628 participants) and year 5 (4837 participants) cohorts both had similar demographic characteristics to the year 1 cohort. DESIGN: Longitudinal design with data collected across TBIMS centers at 1, 2, and 5 years post-injury. MAIN OUTCOMES AND MEASURES: History of SA in past year and SI in past 2 weeks assessed by the Patient Health Questionnaire-9 (PHQ-9). Patient demographics, injury characteristics, and rehabilitation outcomes were also assessed. RESULTS: Full sample rates of SA were 1.9%, 1.5%, and 1.6%, and rates of SI were 9.6%, 10.1%, and 8.7% (respectively at years 1, 2, and 5). There were significant differences among groups based on demographic, injury-related, mental/behavioral health, and functional outcome variables. Characteristics predicting SA/SI related to mental health history, substance use, younger age, lower functional independence, and greater levels of disability. CONCLUSIONS: Compared with participants with TBI in the NIDILRR system, higher rates of SI among V/SMs with TBI in the VA system appear associated with risk factors observed within this group, including mental/behavioral health characteristics and overall levels of disability.

A Network Analysis of the PART-O at 1 and 2 Years After TBI: A Veterans Affairs Model Systems Study.

OBJECTIVE: The construct of participation after traumatic brain injury (TBI) can be difficult to operationalize. Psychometric network analysis offers an empirical approach to visualizing and quantifying the associations between activities that comprise participation, elucidating the relations among the construct's components without assuming the presence of a latent common cause and generating a model to inform future measurement methods. The current research applied psychometric network analysis to the Participation Assessment with Recombined Tools-Objective (PART-O) within a sample of service members and veterans (SM/Vs) with a history of TBI at 1 and 2 years ( T1 and T2 ) postinjury. PARTICIPANTS: Participants ( N = 663) were SM/Vs with a history of TBI who completed comprehensive inpatient rehabilitation services at a Department of Veterans Affairs (VA) Polytrauma Rehabilitation Center (PRC). SETTING: Five VA PRCs. DESIGN: Cross-sectional, retrospective analysis of data from the VA TBI Model Systems study. MAIN MEASURES: PART-O. RESULTS: Network analysis demonstrated that the PART-O structure was generally consistent over time, but some differences emerged. The greatest difference observed was the association between "spending time with friends" and "giving emotional support" to others. This association was more than twice as strong at T2 as at T1 . The "out of the house" item was most central, as demonstrated by dense connections within its own subscale (Out and About) and items in other subscales (ie, Social Relations and Productivity). When examining items connecting the 3 subscales, the items related to giving emotional support, internet use, and getting out of the house emerged as the strongest connectors at T1 , and the internet was the strongest connector at T2 . CONCLUSION: Providing emotional support to others is associated with greater participation across multiple domains and is an important indicator of recovery. Being out and about, internet use, and engagement in productive activities such as school and work shared strong associations with Social Relations. Network analysis permits visual conceptualization of the dynamic constructs that comprise participation and has the potential to inform approaches to measurement and treatment.