Children and Adolescents With Hybrid Diabetes: A Management Conundrum.

OBJECTIVE: Hybrid diabetes (HD); ie, insulin resistance with positive diabetes-associated autoantibodies (DAAs) is increasing in children. We aimed to compare the characteristics of children with HD with those with type 1 diabetes (T1DM) and type 2 diabetes (T2DM) at diagnosis and after 2 years. METHODS: A retrospective review of patients aged 0 to 19 years, with C-peptide and 4 DAA measurements available, who were diangosed with new-onset diabetes from 2016 to 2020 were included in the analysis. RESULTS: Overall, 102 subjects were included, 32 with T1DM, 21 with HD, and 49 with T2DM. Amongst the groups (T1DM vs HD vs T2DM), there were differences in the proportion of non-Hispanic Whites (81.3% vs 47.6% vs 16.4%, P < .001), frequency of family history of T2DM (37.5% vs 100% vs 85.4%, P < .001), acanthosis nigricans (0% vs 42.9% vs 93.9%, P <.001), median body mass index z-score (-0.55 vs 1.8 vs 2.4, P <.001), and median C-peptide (0.4 ng/mL vs 0.9 ng/mL vs 2.4 ng/mL, P <.001). At 2 years, differences were seen in median body mass index z-scores (0.3 vs 1.9 vs 2.3, P <.001), mean HDL-cholesterol (58.0 mg/dL vs 48.2 mg/dL vs 39.5 mg/dL, P <.001), and the use of basal insulin (100% vs 100% vs 74.4%, P <.001). CONCLUSION: Phenotypic and metabolic differences were seen in youth with T1DM, HD, and T2DM at diagnosis and follow-up. At 2 years, all subjects with HD remained insulin dependent whereas some with T2DM were not, indicating the need for targeted interventions to address the etiopathogenesis.

Data to Care Pilot Program in Chicago: Experience, Outcomes, and Direction for the Future.

CONTEXT: Data to Care (D2C) involves sharing HIV surveillance data between health care facilities and health departments to improve continuity of care for people living with HIV (PLWH). The Chicago Department of Public Health (CDPH) initiated a D2C pilot program at the University of Chicago Medicine (UCM) from June 2016 to September 2019. OBJECTIVES: To describe the proportion of patients reported by UCM as not in care who were able to be matched to CDPH enhanced HIV/AIDS Reporting System (eHARS) and to report the individual-level factors associated with matching and viral suppression. DESIGN: Retrospective program evaluation. SETTING: UCM, an academic health care center that provides HIV care to adults via a Ryan White clinic on the south side of Chicago. PARTICIPANTS: Adult PLWH who had received care at UCM but did not have current documented HIV care visit(s). MAIN OUTCOME MEASURE: Proportion of matched patients; factors associated with matching and viral suppression. RESULTS: Overall, 72.4% (n = 813/1123) of patients reported by UCM were matched by CDPH to eHARS. Individuals aged 40 to 49 years (odds ratio [OR] = 1.99; 95% confidence interval [CI], 1.10-3.62), 50 to 59 years (OR = 2.47; 95% CI, 1.37-4.47), and 60 years or older (OR = 6.18; 95% CI, 3.18-12.32) were more likely to match in eHARS. People who lived outside of Chicago (OR = 0.09; 95% CI, 0.05-0.15) or with unknown zip codes (OR = 0.08; 95% CI, 0.05-0.12) were less likely to match. Men who have sex with men and persons older than 50 years were more likely to be virally suppressed. CONCLUSIONS: D2C is an evidence-based strategy for reengagement of PLWH; however, program implementation relies on successful data matching. We found that a large proportion of patients from UCM were not matched, particularly those who were younger or lived outside of Chicago. Additional research is needed to understand ways to improve data matching to facilitate reengagement in HIV care.

High Rate of HIV Among Trauma Patients Participating in Routine Emergency Department Screening.

Limited published data suggest rates of HIV may be high among trauma patients. This study compares rates of HIV screening and diagnosis among trauma and medical patients at a Level 1 trauma center emergency department (ED) with a universal HIV screening program. This is a retrospective cross-sectional study of all ED encounters from May 1, 2018, through May 1, 2021. Duplicate encounters, encounters with repeat testing within one year, and patients younger than 18 or older than 65 were excluded. Chi-squared analysis was used to compare demographics, rates of HIV testing, new and known HIV infections, and linkage to care between trauma and medical patients. After exclusion criteria were applied, 147,430 encounters from 91,468 unique patients were analyzed. Trauma comprised 7,497 (5.4%) encounters. Trauma patients were less likely to be screened for HIV than medical patients (18.1% vs 25.6%; OR 0.64; 95%CI, 0.61-0.68, p < .01). Trauma patients had higher rates of HIV (2.2% vs 1.3%; OR 1.78; 95% CI, 1.22-2.58, p < .01). Both trauma and medical patients would benefit from strategies to increase screening. Including trauma patients in routine ED HIV screening should be a priority to increase diagnosis rate and linkage to care in key populations.

Utility of the Signal-to-Cutoff Ratio and Antigen Index from Fourth- and Fifth-Generation HIV-1/HIV-2 Antigen/Antibody Assays for the Diagnosis of Acute HIV Infection: Applicability for Real-Time Use for Immediate Initiation of Antiretroviral Therapy.

Identification of individuals with acute HIV infection (AHI) and rapid initiation of antiretroviral therapy (ART) are priorities for HIV elimination efforts. Fourth- and fifth-generation HIV-1/HIV-2 antigen (Ag)/antibody (Ab) combination assays can quickly identify patients with AHI, but false-positive results can occur. Confirmatory nucleic acid amplification testing (NAAT) may not be rapidly available. We reviewed the data for 127 patients with positive fourth-generation ARCHITECT and fifth-generation Bio-Plex immunoassay results who had negative or indeterminate confirmatory Ab testing results, which yielded 38 patients with confirmed AHI and 89 patients with false-positive results. The receiver operating characteristic (ROC) curves showed excellent discriminatory power, with an area under the curve (AUC) for the signal-to-cutoff (S/CO) ratio of 0.970 (95% confidence interval [CI], 0.935 to 1.00) and an AUC for the Ag index (AI) of 0.968 (95% CI, 0.904 to 1.00). A threshold of 3.78 for the S/CO ratio would maximize the sensitivity (96.3%) and specificity (93.4%). The threshold for AI was 2.83 (sensitivity of 100% and specificity of 96.4%). The S/CO ratio was significantly correlated with the viral load (Spearman correlation coefficient, 0.486 [P = 0.014]), but the AI was not. The viral loads were all high, with a median of >2.8 million copies/mL. Two false-positive results with AI and S/CO ratio values markedly higher than the medians were observed, indicating that biological false-positive results can occur. Review of the S/CO ratio or AI may be used to improve the accuracy of AHI diagnosis prior to confirmatory NAAT results being available.

Association between patient-reported barriers and HIV clinic appointment attendance: A prospective cohort study.

The association between patients' confidence in their ability to attend appointments and future retention in care has not previously been studied in a general HIV clinic. A survey of potential and known risk factors for poor retention was developed using validated screening tools and administered to 105 patients at an HIV clinic. Retention in care was assessed prospectively using two definitions: (1) two appointments at least three months apart within one year ("HRSA/HAB retention") and (2) no missed appointments within one year ("missed visits retention"). Most patients were African American (86%) and male (59%). Although most patients were confident they could keep their HIV appointments (89%), fewer were retained (HRSA/HAB: 73%; missed visits: 56%). Patients' confidence in their ability to keep future appointments was not associated with retention. Employment was associated with lower odds of HRSA/HAB retention (aOR 0.26 [95% CI 0.09-0.77]), and childcare was a common barrier that was associated with lower odds of missed visits retention (aOR 0.06 [95% CI 0.006-0.62]). Other known risk factors for poor retention were inconsistently associated with retention in care.

"When you have an immune disease like HIV and there is a pandemic, you still have to pay your bills": COVID-19-related challenges among people living with HIV and lessons for care delivery.

COVID-19 has disrupted routine medical care and increased psychosocial and economic stressors on a global scale, yet the full impact on people living with HIV (PLWH) and the HIV continuum of care remains unknown. As the pandemic continues to pose a significant threat to PLWH and their care, this research qualitatively aimed to elicit COVID-19-related challenges and perspectives of PLWH during the early phase of the pandemic and to identify lessons learned and impactful strategies for facilitating HIV care. We recruited 32 PLWH who receive care at a large academic medical center for semi-structured remote interviews to assess psychological/structural stressors experienced during the pandemic and to discern strategies for improving care. Most participants identified as Black (91%) and heterosexual (56%). Overall, PLWH reported exacerbated mental health stressors (e.g., anxiety, depression, substance use). Most participants cited no issues with antiretroviral therapy (ART) adherence or retention in care, yet five participants reported appointment cancellations or physician inaccessibility. Participants provided specific feedback for facilitating continued engagement in care during the pandemic, including telemedicine and education/patient empowerment. By seeking participant-provided solutions, this study centered on PLWH's experiences and emphasized proactive HIV care strategies for prioritizing patient empowerment and healthcare adaptability during a rapidly evolving pandemic.

Facilitators and Barriers to Smart Insulin Pen Use: A Mixed-Method Study of Multidisciplinary Stakeholders From Diabetes Teams in the United States.

This study sought to identify barriers and facilitators to successful smart insulin pen (SIP) use and gauge prescribing practices and integration into clinical practice by assessing provider and care team perspectives at participating endocrinology clinics within the T1D Exchange Quality Improvement Collaborative. The identified provider-related, patient-related, and clinic- and operational-level barriers and facilitators varied based on clinic knowledge, capacity, and resources. High-impact barriers included insurance coverage and prescribing processes; high-impact facilitators included improved diabetes clinic visit quality and use of SIPs as an alternative to insulin pump therapy. Findings indicated the need for provider and care team education and training on proper SIP features, use, and prescribing.

Partner Notification Services for Patients with Established and New HIV Infection Leads to Diagnosis and Linkage of HIV-Positive Partners.

Offering people living with HIV the opportunity to refer partners for HIV testing is an efficient way of identifying new HIV diagnoses. This report describes the outcomes of physician-led partner services at an urban academic center. Patients with HIV VL > 1000 copies/mL in both inpatient and outpatient settings were offered partner notification services (PNS). Of referred partners, 8.7% had a new diagnosis of HIV. New HIV+ partners were as likely to be referred by patients with existing HIV diagnoses as new diagnoses (p = 0.61), and as likely to be referred by patients interviewed while hospitalized as those in the clinic (p = 0.61).

"That same stigma...that same hatred and negativity:" a qualitative study to understand stigma and medical mistrust experienced by people living with HIV diagnosed with COVID-19.

BACKGROUND: The COVID-19 and HIV epidemics have exacerbated existing inequities among vulnerable groups and severely impacted communities of color. People living with HIV (PLWH), who may already face stigma or discrimination, are at risk of experiencing further stigma as a result of COVID-19, which can result in medical mistrust. METHODS: We performed qualitative interviews between June and August 2020 among 32 PLWH, including 10 individuals diagnosed with COVID-19. A majority of participants perceived themselves as having an increased risk of contracting COVID-19 due to their HIV status. RESULTS: Of those who tested positive for COVID-19, the majority regarded their HIV diagnosis as having a more profound impact on their lives but found similarities between COVID-19 stigma and HIV-related stigma. Many participants also expressed mistrust. CONCLUSIONS: These results can be used to better understand the perspectives of PLWH during the COVID-19 pandemic and have important implications for potential COVID-19 vaccine hesitancy and future health crises.

A Clinical Informatics Approach to Reengagement in HIV Care in the Emergency Department.

Emergency department visits provide an opportunity to reengage people living with HIV (PLWH) who are out of care. We developed an electronic medical record-based algorithm to identify PLWH in the emergency department and inpatient settings and utilized a trained HIV care navigator to reengage PLWH in these settings. The algorithm identified 420 PLWH during the 14-month observation period. Of these, 56 patients were out of care. Out-of-care individuals were significantly younger than those in care (mean age: 38.6 ± 15.5 vs 46.3 ±14.8 years, P < .001) and more likely to be uninsured (7.1% [4/56] vs 1.8% [6/337], P = .02). Among out-of-care patients, 66.1% (37/56) were reengaged in care. Only 21.4% (12/56) of out-of-care patients had previously received outpatient HIV care at our institution. This project demonstrates the feasibility of using an electronic medical record alert and HIV care navigator to reengage PLWH seeking emergency medical care.

Travel Time to Clinic but not Neighborhood Crime Rate is Associated with Retention in Care Among HIV-Positive Patients.

Using geospatial analysis, we examined the relationship of distance between a patient's residence and clinic, travel time to clinic, and neighborhood violent crime rates with retention in care or viral suppression among people living with HIV (PLWH). For HIV-positive patients at a large urban clinic, we measured distance and travel time between home and clinic and violent crime rate within a two block radius of the travel route. Kruskal-Wallis rank sum was used to compare outcomes between groups. Over the observation period, 2008-2016, 219/602 (36%) patients were retained in care. Median distance from clinic was 3.6 (IQR 2.1-5.6) miles versus 3.9 (IQR 2.7-6.1) miles among those retained versus not retained in care, p = 0.06. Median travel time by car was 15.9 (IQR 9.6-22.9) versus 17.1 (IQR 12.0-24.6) minutes for those retained versus not retained, p = 0.04. Violent crime rate along travel route was not associated with retention. There was no significant association between travel time or distance and viral suppression.

Characterisation of CCT271850, a selective, oral and potent MPS1 inhibitor, used to directly measure in vivo MPS1 inhibition vs therapeutic efficacy.

BACKGROUND: The main role of the cell cycle is to enable error-free DNA replication, chromosome segregation and cytokinesis. One of the best characterised checkpoint pathways is the spindle assembly checkpoint, which prevents anaphase onset until the appropriate attachment and tension across kinetochores is achieved. MPS1 kinase activity is essential for the activation of the spindle assembly checkpoint and has been shown to be deregulated in human tumours with chromosomal instability and aneuploidy. Therefore, MPS1 inhibition represents an attractive strategy to target cancers. METHODS: To evaluate CCT271850 cellular potency, two specific antibodies that recognise the activation sites of MPS1 were used and its antiproliferative activity was determined in 91 human cancer cell lines. DLD1 cells with induced GFP-MPS1 and HCT116 cells were used in in vivo studies to directly measure MPS1 inhibition and efficacy of CCT271850 treatment. RESULTS: CCT271850 selectively and potently inhibits MPS1 kinase activity in biochemical and cellular assays and in in vivo models. Mechanistically, tumour cells treated with CCT271850 acquire aberrant numbers of chromosomes and the majority of cells divide their chromosomes without proper alignment because of abrogation of the mitotic checkpoint, leading to cell death. We demonstrated a moderate level of efficacy of CCT271850 as a single agent in a human colorectal carcinoma xenograft model. CONCLUSIONS: CCT271850 is a potent, selective and orally bioavailable MPS1 kinase inhibitor. On the basis of in vivo pharmacodynamic vs efficacy relationships, we predict that more than 80% inhibition of MPS1 activity for at least 24 h is required to achieve tumour stasis or regression by CCT271850.

Human Parthenogenetic Embryonic Stem Cell-Derived Neural Stem Cells Express HLA-G and Show Unique Resistance to NK Cell-Mediated Killing.

Parent-of-origin imprints have been implicated in the regulation of neural differentiation and brain development. Previously we have shown that, despite the lack of a paternal genome, human parthenogenetic (PG) embryonic stem cells (hESCs) can form proliferating neural stem cells (NSCs) that are capable of differentiation into physiologically functional neurons while maintaining allele-specific expression of imprinted genes. Since biparental ("normal") hESC-derived NSCs (N NSCs) are targeted by immune cells, we characterized the immunogenicity of PG NSCs. Flow cytometry and immunocytochemistry revealed that both N NSCs and PG NSCs exhibited surface expression of human leukocyte antigen (HLA) class I but not HLA-DR molecules. Functional analyses using an in vitro mixed lymphocyte reaction assay resulted in less proliferation of peripheral blood mononuclear cells (PBMC) with PG compared with N NSCs. In addition, natural killer (NK) cells cytolyzed PG less than N NSCs. At a molecular level, expression analyses of immune regulatory factors revealed higher HLA-G levels in PG compared with N NSCs. In line with this finding, MIR152, which represses HLA-G expression, is less transcribed in PG compared with N cells. Blockage of HLA-G receptors ILT2 and KIR2DL4 on natural killer cell leukemia (NKL) cells increased cytolysis of PG NSCs. Together this indicates that PG NSCs have unique immunological properties due to elevated HLA-G expression.

Structural requirements for enzymatic activities of foamy virus protease-reverse transcriptase.

Reverse transcriptases (RTs) are pivotal in the life cycle of retroviruses and convert the genomic viral RNA into double-stranded DNA. The RT polymerase domain is subdivided into fingers, palm, thumb, and the connection subdomain, which links the polymerase to the C-terminal RNase H domain. In contrast to orthoretroviruses, mature RT of foamy viruses harbors the protease (PR) domain at its N-terminus (PR-RT). Therefore and due to low homology to other RTs, it is difficult to define the boundaries and functions of the (sub)domains. We introduced N- and C-terminal deletions into simian foamy virus PR-RT to investigate the impact of the truncations on the catalytic activities. Both, the RNase H domain and the connection subdomain contribute substantially to polymerase integrity and stability as well as to polymerase activity and substrate binding. The 42 amino acids long region C-terminal of the PR is important for polymerase stability and activity. PR activation via binding of PR-RT to viral RNA requires the presence of the full length PR-RT including the RNase H domain. In vitro, the cleavage efficiencies of FV PR for the Gag and Pol cleavage site are comparable, even though in virus particles only the Pol site is cleaved to completion suggesting that additional factors control PR activity and that virus maturation needs to be strictly regulated.

Exploring the Feasibility of an Electronic Tool for Predicting Retention in HIV Care: Provider Perspectives.

Retention in care for people living with HIV (PLWH) is important for individual and population health. Preemptive identification of PLWH at high risk of lapsing in care may improve retention efforts. We surveyed providers at nine institutions throughout Chicago about their perspectives on using an electronic health record (EHR) tool to predict the risk of lapsing in care. Sixty-three percent (20/32) of providers reported currently assessing patients' risk for lapsing in care, and 91% (29/32) reported willingness to implement an EHR tool. When compared to those with other job roles, prescribers agreed (vs. neutral) that the tool would be less biased than personal judgment (OR 13.33, 95% CI 1.05, 169.56). Prescribers were also more likely to identify community health workers as persons who should deliver these interventions (OR 10.50, 95% CI 1.02, 108.58). Transportation, housing, substance use, and employment information were factors that providers wanted to be included in an EHR-based tool. Social workers were significantly more likely to indicate the inclusion of employment information as important (OR 10.50, 95% CI 1.11, 98.87) when compared to other participants. Acceptability of an EHR tool was high; future research should investigate barriers and evaluate the effectiveness of such a tool.

Patient Perspectives on Portal-Based Anxiety and Depression Screening in HIV Care: A Qualitative Study Using the Consolidated Framework for Implementation Research.

Electronic patient portals represent a promising means of integrating mental health assessments into HIV care where anxiety and depression are highly prevalent. Patient attitudes toward portal-based mental health screening within HIV clinics have not been well described. The aim of this formative qualitative study is to characterize the patient-perceived facilitators and barriers to portal-based anxiety and depression screening within HIV care in order to inform implementation strategies for mental health screening. Twelve adult HIV clinic patients participated in semi-structured interviews that were audio recorded and transcribed. The transcripts were coded using constructs from the Consolidated Framework for Implementation Research and analyzed thematically to identify the barriers to and facilitators of portal-based anxiety and depression screening. Facilitators included an absence of alternative screening methods, an approachable design, perceived adaptability, high compatibility with HIV care, the potential for linkage to treatment, an increased self-awareness of mental health conditions, the ability to bundle screening with clinic visits, and communicating an action plan for results. The barriers included difficulty navigating the patient portal system, a lack of technical support, stigmatization from the healthcare system, care team response times, and the novelty of using patient portals for communication. The patients in the HIV clinic viewed the use of a portal-based anxiety and depression screening tool as highly compatible with routine HIV care. Technical difficulties, follow-up concerns, and a fear of stigmatization were commonly perceived as barriers to portal use. The results of this study can be used to inform implementation strategies when designing or incorporating portal-based mental health screening into other HIV care settings.

Population-Level Portal-Based Anxiety and Depression Screening Perspectives in HIV Care Clinicians: Qualitative Study Using the Consolidated Framework for Implementation Research.

BACKGROUND: Depression and anxiety are common among people with HIV and are associated with inadequate viral suppression, disease progression, and increased mortality. However, depression and anxiety are underdiagnosed and undertreated in people with HIV owing to inadequate visit time and personnel availability. Conducting population-level depression and anxiety screening via the patient portal is a promising intervention that has not been studied in HIV care settings. OBJECTIVE: We aimed to explore facilitators of and barriers to implementing population-level portal-based depression and anxiety screening for people with HIV. METHODS: We conducted semistructured hour-long qualitative interviews based on the Consolidated Framework for Implementation Research with clinicians at an HIV clinic. RESULTS: A total of 10 clinicians participated in interviews. In total, 10 facilitators and 7 barriers were identified across 5 Consolidated Framework for Implementation Research domains. Facilitators included advantages of systematic screening outside clinic visits; the expectation that assessment frequency could be tailored to patient needs; evidence from the literature and previous experience in other settings; respect for patient privacy; empowering patients and facilitating communication about mental health; compatibility with clinic culture, workflows, and systems; staff beliefs about the importance of mental health screening and benefits for HIV care; engaging all clinic staff and leveraging their strengths; and clear planning and communication with staff. Barriers included difficulty in ensuring prompt response to suicidal ideation; patient access, experience, and comfort using the portal; limited availability of mental health services; variations in how providers use the electronic health record and communicate with patients; limited capacity to address mental health concerns during HIV visits; staff knowledge and self-efficacy regarding the management of mental health conditions; and the impersonal approach to a sensitive topic. CONCLUSIONS: We proposed 13 strategies for implementing population-level portal-based screening for people with HIV. Before implementation, clinics can conduct local assessments of clinicians and clinic staff; engage clinicians and clinic staff with various roles and expertise to support the implementation; highlight advantages, relevance, and evidence for population-level portal-based mental health screening; make screening frequency adaptable based on patient history and symptoms; use user-centered design methods to refine results that are displayed and communicated in the electronic health record; make screening tools available for patients to use on demand in the portal; and create protocols for positive depression and anxiety screeners, including those indicating imminent risk. During implementation, clinics should communicate with clinicians and clinic staff and provide training on protocols; provide technical support and demonstrations for patients on how to use the portal; use multiple screening methods for broad reach; use patient-centered communication in portal messages; provide clinical decision support tools, training, and mentorship to help clinicians manage mental health concerns; and implement integrated behavioral health and increase mental health referral partnerships.