Retention and weight outcomes after transitioning an intensive behavioral weight management program from an in-person to a virtual format.

Background: Virtual care offers many potential advantages over traditional in-person care for people with chronic diseases including obesity. Before the COVID-19 pandemic, virtual care was not broadly implemented because of regulatory, legal, and reimbursement barriers. Objective: To evaluate the impact of the transition from an entirely in-person format to a virtual format during the COVID-19 pandemic on retention and weight reduction in a 2-year, structured, intensive behavioral weight management program for people with moderate to severe obesity. Methods: Retrospective cohort study of 1313 program participants stratified according to the phase of the program during which the transition to virtual visits occurred. Results: Age, sex, and baseline weight were independent predictors of program retention. Transition to virtual visits was associated with greater 2-year program retention. Retention but not mode of program delivery was associated with reduction in weight at 2-year. Conclusions: Transition from in-person to virtual program delivery improved retention and by doing so, indirectly improved weight loss at 2 years. Telemedicine has the potential to overcome many of the limitations associated with traditional in-person weight loss interventions. Clinical Trial Registration: This research was reviewed and approved by the University of Michigan Institutional Review Board and registered on ClinicalTrials.gov (NCT02043457). All participants provided written informed consent.

Barriers and facilitators of naloxone and safe injection facility interventions to reduce opioid drug-related deaths: A qualitative analysis.

BACKGROUND: Opioid drug-related deaths continue to be a significant public health concern in the Republic of Ireland (ROI) and Northern Ireland (NI). While both regions have implemented naloxone to reduce drug related deaths, there remains a gap in the implementation of a supervised injection facility (SIF). This study aimed to identify barriers and facilitators to implementing naloxone and a SIF to reduce opioid drug-related deaths in ROI and NI. METHODS: Semi-structured interviews (n=23) were conducted in ROI and NI with experts by experience (n=8), staff from low threshold services (n=9), and individuals involved in policy making (n= 6). Data were analyzed using coding reliability Thematic Analysis and were informed by the Risk Environmental Framework. RESULTS: The findings illustrated that stigma within the media, health centers, and the community was a significant barrier to naloxone distribution and SIF implementation. Policing and community intimidation were reported to hinder naloxone carriage in both the ROI and NI, while threats of paramilitary violence towards people who use drugs were unique to NI. Municipal government delays and policy maker apathy were reported to hinder SIF implementation in the ROI. Participants suggested peer-to-peer naloxone delivery and amending legislation to facilitate non-prescription naloxone would increase naloxone uptake. Participants recommended using webinars, Town Halls, and a Citizens' Assembly as tools to advocate for SIF implementation. CONCLUSION: Local and regional stigma reduction campaigns are needed in conjunction with policy changes to advance naloxone and a SIF. Tailoring stigma campaigns to incorporate the lived experience of people who use drugs, their family members, and the general community can aid in educating the public and change negative perceptions. This study highlights the need for ongoing efforts to reduce stigma and increase accessibility to evidence-based interventions to address opioid drug-related deaths in the ROI, NI, and internationally.

17⍺-Estradiol Protects against HIV-1 Tat-Induced Endolysosome Dysfunction and Dendritic Impairments in Neurons.

HIV-1 Tat continues to play an important role in the development of HIV-associated neurocognitive disorders (HAND), which persist in 15-55% of people living with HIV even with virological control. In the brain, Tat is present on neurons, where Tat exerts direct neuronal damaging effects by, at least in part, disrupting endolysosome functions, a pathological feature present in HAND. In this study, we determined the protective effects of 17α-estradiol (17αE2), the predominant form of estrogen in the brain, against Tat-induced endolysosome dysfunction and dendritic impairment in primary cultured hippocampal neurons. We demonstrated that pre-treatment with 17αE2 protected against Tat-induced endolysosome dysfunction and reduction in dendritic spine density. Estrogen receptor alpha (ERα) knockdown impairs the ability of 17αE2 to protect against Tat-induced endolysosome dysfunction and reduction in dendritic spine density. Furthermore, over-expressing an ERα mutant that fails to localize on endolysosomes impairs 17αE2's protective effects against Tat-induced endolysosome dysfunction and reduction in dendritic spine density. Our findings demonstrate that 17αE2 protects against Tat-induced neuronal injury via a novel ERα-mediated and endolysosome-dependent pathway, and such a finding might lead to the development of novel adjunct therapeutics against HAND.

How do naloxone-based interventions work to reduce overdose deaths: a realist review.

BACKGROUND: Naloxone-based interventions as part of health systems can reverse an opioid overdose. Previous systematic reviews have identified the effectiveness of naloxone; however, the role of context and mechanisms for its use has not been explored. This realist systematic review aims to identify a theory of how naloxone works based on the contexts and mechanisms that contribute to the success of the intervention for improved outcomes. METHODS: Pre-registered at PROSPERO, this realist review followed RAMESES standards of reporting. Keywords included 'naloxone' and ' opioid overdose'. All study designs were included. Data extraction using 55 relevant outputs based on realist logic produced evidence of two middle-range theories: Naloxone Bystander Intervention Theory and Skills Transfer Theory. RESULTS: Harm reduction and/or low threshold contexts provide a non-judgemental approach which support in-group norms of helping and empower the social identity of the trained and untrained bystander. This context also creates the conditions necessary for skills transfer and diffusion of the intervention into social networks. Stigma and negative attitudes held by first responders and stakeholders involved in the implementation process, such as police or GPs, can prohibit the bystander response by inducing fear in responding. This interferes with skills transfer, naloxone use and carriage of naloxone kits. CONCLUSIONS: The findings provide theoretically informed guidance regarding the harm reduction contexts that are essential for the successful implementation of naloxone-based interventions. Peer-to-peer models of training are helpful as it reinforces social identity and successful skills transfer between bystanders. Health systems may want to assess the prevalence of, and take steps to reduce opioid-related stigma with key stakeholders in contexts using a low threshold training approach to build an environment  to support positive naloxone outcomes. TRIAL REGISTRATION: PROSPERO 2019 CRD42019141003.

Endolysosome Localization of ERα Is Involved in the Protective Effect of 17α-Estradiol against HIV-1 gp120-Induced Neuronal Injury.

Neurotoxic HIV-1 viral proteins contribute to the development of HIV-associated neurocognitive disorder (HAND), the prevalence of which remains high (30-50%) with no effective treatment available. Estrogen is a known neuroprotective agent; however, the diverse mechanisms of estrogen action on the different types of estrogen receptors is not completely understood. In this study, we determined the extent to which and mechanisms by which 17α-estradiol (17αE2), a natural less-feminizing estrogen, offers neuroprotection against HIV-1 gp120-induced neuronal injury. Endolysosomes are important for neuronal function, and endolysosomal dysfunction contributes to HAND and other neurodegenerative disorders. In hippocampal neurons, estrogen receptor α (ERα) is localized to endolysosomes and 17αE2 acidifies endolysosomes. ERα knockdown or overexpressing an ERα mutant that is deficient in endolysosome localization prevents 17αE2-induced endolysosome acidification. Furthermore, 17αE2-induced increases in dendritic spine density depend on endolysosome localization of ERα. Pretreatment with 17αE2 protected against HIV-1 gp120-induced endolysosome deacidification and reductions in dendritic spines; such protective effects depended on endolysosome localization of ERα. In male HIV-1 transgenic rats, we show that 17αE2 treatment prevents the development of enlarged endolysosomes and reduction in dendritic spines. Our findings demonstrate a novel endolysosome-dependent pathway that governs the ERα-mediated neuroprotective actions of 17αE2, findings that might lead to the development of novel therapeutic strategies against HAND.SIGNIFICANCE STATEMENT Extranuclear presence of membrane-bound estrogen receptors (ERs) underlie the enhancing effect of estrogen on cognition and synaptic function. The estrogen receptor subtype ERα is present on endolysosomes and plays a critical role in the enhancing effects of 17αE2 on endolysosomes and dendritic spines. These findings provide novel insight into the neuroprotective actions of estrogen. Furthermore, 17αE2 protected against HIV-1 gp120-induced endolysosome dysfunction and reductions in dendritic spines, and these protective effects of 17αE2 were mediated via endolysosome localization of ERα. Such findings provide a rationale for developing 17αE2 as a therapeutic strategy against HIV-associated neurocognitive disorders.

SARS-CoV-2 S1 Protein Induces Endolysosome Dysfunction and Neuritic Dystrophy.

SARS-CoV-2 is the viral cause of the COVID-19 pandemic. Increasingly, significant neurological disorders have been associated with COVID-19. However, the pathogenesis of these neurological disorders remains unclear especially because only low or undetectable levels of SARS-CoV-2 have been reported in human brain specimens. Because SARS-CoV-2 S1 protein can be released from viral membranes, can cross the blood-brain barrier, and is present in brain cells including neurons, we tested the hypothesis that SARS-CoV-2 S1 protein can directly induce neuronal injury. Incubation of primary human cortical neurons with SARS-CoV-2 S1 protein resulted in accumulation of the S1 protein in endolysosomes as well as endolysosome de-acidification. Further, SARS-CoV-2 S1 protein induced aberrant endolysosome morphology and neuritic varicosities. Our findings suggest that SARS-CoV-2 S1 protein directly induces neuritic dystrophy, which could contribute to the high incidence of neurological disorders associated with COVID-19.

Antiretroviral Drugs Promote Amyloidogenesis by De-Acidifying Endolysosomes.

Antiretroviral therapeutics (ART) have effectively increased the long-term survival of HIV-1 infected individuals. However, the prevalence of HIV-1 associated neurocognitive disorders (HAND) has increased and so too have clinical manifestations and pathological features of Alzheimer's disease (AD) in people living with HIV-1/AIDS. Although underlying mechanisms are not clear, chronic exposure to ART drugs has been implicated in the development of AD-like symptoms and pathology. ART drugs are categorized according to their mechanism of action in controlling HIV-1 levels. All ART drugs are organic compounds that can be classified as being either weak acids or weak bases, and these physicochemical properties may be of central importance to ART drug-induced AD-like pathology because weak bases accumulate in endolysosomes, weak bases can de-acidify endolysosomes where amyloidogenesis occurs, and endolysosome de-acidification increases amyloid beta (Aß) protein production and decreases Aß degradation. Here, we investigated the effects of ART drugs on endolysosome pH and Aß levels in rat primary cultured neurons. ART drugs that de-acidified endolysosomes increased Aß levels, whereas those that acidified endolysosomes decreased Aß levels. Acidification of endolysosomes with the mucolipin transient receptor potential (TRPML) channel agonist ML-SA1 blocked ART drug-induced increases in Aß levels. Further, ART drug-induced endolysosome de-acidification increased endolysosome sizes; effects that were blocked by ML-SA1-induced endolysosome acidification. These results suggest that ART drug-induced endolysosome de-acidification plays an important role in ART drug-induced amyloidogenesis and that endolysosome acidification might attenuate AD-like pathology in HIV-1 positive people taking ART drugs that de-acidify endolysosomes. Graphical Abstract.

Two-pore channels regulate Tat endolysosome escape and Tat-mediated HIV-1 LTR transactivation.

HIV-1 Tat is essential for HIV-1 replication and appears to play an important role in the pathogenesis of HIV-associated neurological complications. Secreted from infected or transfected cells, Tat has the extraordinary ability to cross the plasma membrane. In the brain, Tat can be taken up by CNS cells via receptor-mediated endocytosis. Following endocytosis and its internalization into endolysosomes, Tat must be released in order for it to activate the HIV-1 LTR promoter and facilitate HIV-1 viral replication in the nucleus. However, the underlying mechanisms whereby Tat escapes endolysosomes remain unclear. Because Tat disrupts intracellular calcium homeostasis, we investigated the involvement of calcium in Tat endolysosome escape and subsequent LTR transactivation. We demonstrated that chelating endolysosome calcium with high-affinity rhodamine-dextran or chelating cytosolic calcium with BAPTA-AM attenuated Tat endolysosome escape and LTR transactivation. Significantly, we demonstrated that pharmacologically blocking and knocking down the endolysosome-resident two-pore channels (TPCs) attenuated Tat endolysosome escape and LTR transactivation. This calcium-mediated effect appears to be selective for TPCs because knocking down TRPML1 calcium channels was without effect. Our findings suggest that calcium released from TPCs is involved in Tat endolysosome escape and subsequent LTR transactivation. TPCs might represent a novel therapeutic target against HIV-1 infection and HIV-associated neurological complications.

BK channels regulate extracellular Tat-mediated HIV-1 LTR transactivation.

HIV-1 Tat is essential for HIV-1 replication and plays an important role in latent HIV-1 infection, HIV-1 associated neurological complication, and other HIV-1 comorbidities. Secreted from HIV-1 infected or transfected cells, Tat can be up-taken into cells by receptor-mediated endocytosis and internalized into endolysosomes. To reach nucleus where it can facilitate HIV-1 viral replication, exogenous Tat has to escape the degradation by endolysosomes. Because of findings that endolysosome de-acidification with, for example, the weak-base anti-malarial drug chloroquine prevents exogenous Tat degradation and enhances the amount of Tat available to activate HIV-1 LTR, we hypothesize that acidifying endolysosomes may enhance Tat degradation in endolysosomes and restrict LTR transactivation. Here, we determined the involvement of endolysosome-resident transient receptor potential mucolipin 1 channel (TRPML1) and the big conductance Ca2+-activated potassium (BK) channel in regulating endolysosome pH, as well as Tat-mediated HIV-1 LTR transactivation in U87MG cells stably integrated with HIV-1 LTR luciferase reporter. Activating TRPML1 channels with ML-SA1 acidified endolysosomes and restricted Tat-mediated HIV-1 LTR transactivation. These effects of ML-SA1 appeared to be mediated through activation of BK channels, because the effects of ML-SA1 on Tat-mediated HIV-1 LTR transactivation were blocked using pharmacological inhibitors or shRNA knock-down of BK channels. On the other hand, activating TRPML1 and BK channels enhanced cellular degradation of exogenous Tat. These results suggest that acidifying endolysosomes by activating TRPML1 or BK channels may provide therapeutic benefit against latent HIV-1 infection, HIV-1 associated neurocognitive disorders, and other HIV-1 comorbidities.

HIV-1 gp120 Promotes Lysosomal Exocytosis in Human Schwann Cells.

Human immunodeficiency virus type 1 (HIV-1) associated neuropathy is the most common neurological complication of HIV-1, with debilitating pain affecting the quality of life. HIV-1 gp120 plays an important role in the pathogenesis of HIV neuropathy via direct neurotoxic effects or indirect pro-inflammatory responses. Studies have shown that gp120-induced release of mediators from Schwann cells induce CCR5-dependent DRG neurotoxicity, however, CCR5 antagonists failed to improve pain in HIV- infected individuals. Thus, there is an urgent need for a better understanding of neuropathic pain pathogenesis and developing effective therapeutic strategies. Because lysosomal exocytosis in Schwann cells is an indispensable process for regulating myelination and demyelination, we determined the extent to which gp120 affected lysosomal exocytosis in human Schwann cells. We demonstrated that gp120 promoted the movement of lysosomes toward plasma membranes, induced lysosomal exocytosis, and increased the release of ATP into the extracellular media. Mechanistically, we demonstrated lysosome de-acidification, and activation of P2X4 and VNUT to underlie gp120-induced lysosome exocytosis. Functionally, we demonstrated that gp120-induced lysosome exocytosis and release of ATP from Schwann cells leads to increases in intracellular calcium and generation of cytosolic reactive oxygen species in DRG neurons. Our results suggest that gp120-induced lysosome exocytosis and release of ATP from Schwann cells and DRG neurons contribute to the pathogenesis of HIV-1 associated neuropathy.

Temporal progression of Alzheimer's disease in brains and intestines of transgenic mice.

The amyloid beta (Aß) peptide is associated with the neurodegenerative and inflammatory changes in brains affected by Alzheimer's disease (AD). We hypothesized that the enteric nervous system also produces Aß in an intestinal component of disease. To test this idea, we compared C57BL/6 wild-type (WT) male and female mice to two models of Alzheimer's disease, amyloid precursor protein (APP)/presenilin 1 (PS1) mice and amyloid precursor protein NL-G-F (AppNL-G-F) mice, at 3, 6, and 12 months of age. Brain Aß plaque deposition in AppNL-G-F mice preceded that in the APP/PS1 mice, observable by 3 months. Three-month-old female AppNL-G-F mice had decreased intestinal motility compared with WT and APP/PS1 mice. However, 3-month-old female APP/PS1 mice demonstrated increased intestinal permeability compared with WT and AppNL-G-F mice. Both sexes of APP/PS1 and AppNL-G-F mice demonstrated increased colon lipocalin 2 mRNA and insoluble Aß 1-42 levels at 3 months. These data demonstrate an unrecognized enteric aspect of disease in 2 different mouse models correlating with the earliest brain changes.

Impact of a Structured Weight Management Program on Worker Productivity.

OBJECTIVE: To determine the impact of an intensive behavioral weight management program on presenteeism and absenteeism in obese participants employed full-time. METHODS: Participants were recruited from the University of Michigan Weight Management program (WMP), a multidisciplinary lifestyle program targeting 15% body weight loss. Absenteeism and presenteeism were assessed using the World Health Organization Health and Work Performance Questionnaire (HPQ) at baseline and 6 months. RESULTS: One hundred forty-two participants, predominantly college-educated white-collar employees, were included in the study. After 6 months in the program, there was no significant change in absenteeism or presenteeism compared with baseline. There was a trend towards reduced absenteeism. CONCLUSIONS: Participation in an intensive weight management program did not adversely impact worker productive time. Conversely, our findings should be reassuring to employer groups and to employees with obesity concerned about time spent away from work.

Acidifying Endolysosomes Prevented Low-Density Lipoprotein-Induced Amyloidogenesis.

Cholesterol dyshomeostasis has been linked to the pathogenesis of sporadic Alzheimer's disease (AD). In furthering the understanding of mechanisms by which increased levels of circulating cholesterol augments the risk of developing sporadic AD, others and we have reported that low-density lipoprotein (LDL) enters brain parenchyma by disrupting the blood-brain barrier and that endolysosome de-acidification plays a role in LDL-induced amyloidogenesis in neurons. Here, we tested the hypothesis that endolysosome de-acidification was central to amyloid-ß (Aß) generation and that acidifying endolysosomes protects against LDL-induced increases in Aß levels in neurons. We demonstrated that LDL, but not HDL, de-acidified endolysosomes and increased intraneuronal and secreted levels of Aß. ML-SA1, an agonist of endolysosome-resident TRPML1 channels, acidified endolysosomes, and TRPML1 knockdown attenuated ML-SA1-induced endolysosome acidification. ML-SA1 blocked LDL-induced increases in intraneuronal and secreted levels of Aß as well as Aß accumulation in endolysosomes, prevented BACE1 accumulation in endolysosomes, and decreased BACE1 activity levels. LDL downregulated TRPML1 protein levels, and TRPML1 knockdown worsens LDL-induced increases in Aß. Our findings suggest that endolysosome acidification by activating TRPML1 may represent a protective strategy against sporadic AD.

A community-based randomized controlled trial of Mom Power parenting intervention for mothers with interpersonal trauma histories and their young children.

We conducted a study to evaluate the effectiveness of Mom Power, a multifamily parenting intervention to improve mental health and parenting among high-risk mothers with young children in a community-based randomized controlled trial (CB-RCT) design. Participants (N = 122) were high-risk mothers (e.g., interpersonal trauma histories, mental health problems, poverty) and their young children (age <6 years), randomized either to Mom Power, a parenting intervention (treatment condition), or weekly mailings of parenting information (control condition). In this study, the 13-session intervention was delivered by community clinicians trained to fidelity. Pre- and post-trial assessments included mothers' mental health symptoms, parenting stress and helplessness, and connection to care. Mom Power was delivered in the community with fidelity and had good uptake (>65%) despite the risk nature of the sample. Overall, we found improvements in mental health and parenting stress for Mom Power participants but not for controls; in contrast, control mothers increased in parent-child role reversal across the trial period. The benefits of Mom Power treatment (vs. control) were accentuated for mothers with interpersonal trauma histories. Results of this CB-RCT confirm the effectiveness of Mom Power for improving mental health and parenting outcomes for high-risk, trauma-exposed women with young children. ClinicalTrials.gov Identifier: NCT01554215.

Impact of weight loss on waist circumference and the components of the metabolic syndrome.

OBJECTIVE: Central adiposity is a component of the metabolic syndrome (MetS). Little is known about the impact of medical weight loss and decreased waist circumference (WC) on the MetS. Our objective was to assess the impact of changes in WC on blood pressure, lipids and glycemia. RESEARCH DESIGN AND METHODS: We studied 430 obese patients enrolled in a 2-year, intensive, behavioral, weight management program. We report results for participants who completed 6-month and 2-year follow-up. RESULTS: Participants were 49±9 years of age (mean±SD), 56% were women and 85% were white. Baseline body mass index (BMI) was 41±6 kg/m2 and baseline WC was 120±14 cm. At 6 months, BMI decreased by 6±3 kg/m2 and WC by 14±9 cm. Relative change in WC was defined as the 6-month or 2-year WC minus the baseline WC divided by the baseline WC. Systolic blood pressure decreased by 8 mm Hg for the tertile of participants with the largest relative decrease in WC and by 2 mm Hg for those with the smallest relative decrease in WC (p=0.025). Similar patterns of improvement were observed in total cholesterol (-29 vs -12 mg/dL, p=0.017), low-density lipoprotein-cholesterol (-19 vs -4 mg/dL, p=0.033), and glycated hemoglobin (-1.2 vs -0.3%, p=0.006). At 2 years, BMI decreased by 5±4 kg/m2 and WC by 11±11 cm and similar patterns of improvements were seen in components of the MetS. At both 6 months and 2 years, larger relative decreases in WC were associated with greater improvements in lipids and glycemia independent of sex. CONCLUSIONS: In obese people, greater relative decreases in WC with medical weight loss are associated with greater improvements in components of the MetS independent of sex.

Factors associated with participant retention in a clinical, intensive, behavioral weight management program.

BACKGROUND: We sought to identify factors associated with participant retention in a 2-year, physician-lead, multidisciplinary, clinical weight management program that employs meal replacements to produce weight loss and intensive behavioral interventions and financial incentives for weight loss maintenance. We studied 270 participants enrolled in 2010 and 2011. Sociodemographic factors, health insurance, distance traveled, body mass index, comorbidities, health-related quality-of-life, and depression were explored as potential predictors of retention. RESULTS: Mean age was 49 ± 8 years and BMI was 41 ± 5 kg/m(2). Retention was excellent at 3 months (90%) and 6 months (83%). Attrition was greatest after participants were transitioned to regular foodstuffs and fell to 67% at 12 months and 51% at 2 years. Weight decreased by 15 ± 12 kg and BMI decreased by 5.1 ± 4.0 kg/m(2) in 2-year completers. Older age, lower baseline BMI, and financial incentives for program participation were independently associated with retention. Fewer depressive symptoms at baseline were associated with retention. CONCLUSIONS: This multidisciplinary, clinical, weight management program demonstrated high retention and excellent outcomes. Older age at baseline, less extreme obesity, and financial incentives were associated with program retention.

Mom Power: preliminary outcomes of a group intervention to improve mental health and parenting among high-risk mothers.

Maternal psychopathology and traumatic life experiences may adversely impact family functioning, the quality of the parent-child relationship and the attachment bond, placing the child's early social-emotional development at risk. Attachment-based parenting interventions may be particularly useful in decreasing negative outcomes for children exposed to risk contexts, yet high risk families frequently do not engage in programs to address mental health and/or parenting needs. This study evaluated the effects of Mom Power (MP), a 13-session parenting and self-care skills group program for high-risk mothers and their young children (age <6 years old), focused on enhancing mothers' mental health, parenting competence, and engagement in treatment. Mothers were referred from community health providers for a phase 1 trial to assess feasibility, acceptability, and pilot outcomes. At baseline, many reported several identified risk factors, including trauma exposure, psychopathology, poverty, and single parenthood. Ninety-nine mother-child pairs were initially recruited into the MP program with 68 women completing and providing pre- and post-self-report measures assessing demographics and trauma history (pre-assessment only), maternal mental health (depression and post-traumatic stress disorder (PTSD)), parenting, and intervention satisfaction. Results indicate that MP participation was associated with reduction in depression, PTSD, and caregiving helplessness. A dose response relationship was evident in that, despite baseline equivalence, women who attended ≥70 % of the 10 groups (completers; N = 68) improved on parenting and mental health outcomes, in contrast to non-completers (N = 12). Effects were most pronounced for women with a mental health diagnosis at baseline. The intervention was perceived as helpful and user-friendly. Results indicate that MP is feasible, acceptable, and holds promise for improving maternal mental health and parenting competence among high-risk dyads. Further research is warranted to evaluate the efficacy of MP using randomized controlled designs.