Mouse mandibular-derived osteoclast progenitors have differences in intrinsic properties compared with femoral-derived progenitors.

Craniofacial osteoclasts are essential for site-specific processes such as alveolar bone resorption, tooth eruption, and orthodontic tooth movement. Much of the current understanding of osteoclast development and function comes from studies using long bone-derived cells. Minimal investigation has been done to explore skeletal site differences. The overall goal of this study was to determine if mandibular- and femoral-derived osteoclasts represent distinct populations. To test this hypothesis, bone marrow cells were initially analyzed from the mandible and femur of 2-month-old mice. It was shown that mandibular-derived osteoclasts have enhanced size (mm2) compared with femoral-derived osteoclasts. Since bone marrow macrophages are a heterogenous population, we additionally selected for monocytes and demonstrated that mandibular-derived monocytes also form osteoclasts with increased size compared with femoral-derived monocytes. Osteoclast precursor populations from both skeletal sites were analyzed by flow cytometry. A newly described Ly6CHigh+ population as well as the Ly6Cint population was increased in the mandibular-derived cells. The difference in differentiation potential between monocyte cultures suggests that the increase in the Ly6CHigh+ population may explain the enhanced differentiation potential in mandibular-derived cells. Monocyte genes such as Pu.1, C/ebp-a, and Prdm1 are increased in expression in mandibular-derived monocytes compared with femoral-derived monocytes. As expected with enhanced differentiation, osteoclast genes including Nfatc1, Dc-stamp, Ctsk, and Rank are upregulated in mandibular-derived osteoclast precursors. Future studies will determine how changes in the environment of the mandible lead to changes in percentages of osteoclast progenitors and their differentiation potential.

Synchronous retreat of Thwaites and Pine Island glaciers in response to external forcings in the presatellite era.

Today, relatively warm Circumpolar Deep Water is melting Thwaites Glacier at the base of its ice shelf and at the grounding zone, contributing to significant ice retreat. Accelerating ice loss has been observed since the 1970s; however, it is unclear when this phase of significant melting initiated. We analyzed the marine sedimentary record to reconstruct Thwaites Glacier's history from the early Holocene to present. Marine geophysical surveys were carried out along the floating ice-shelf margin to identify core locations from various geomorphic settings. We use sedimentological data and physical properties to define sedimentary facies at seven core sites. Glaciomarine sediment deposits reveal that the grounded ice in the Amundsen Sea Embayment had already retreated to within ~45 km of the modern grounding zone prior to ca. 9,400 y ago. Sediments deposited within the past 100+ y record abrupt changes in environmental conditions. On seafloor highs, these shifts document ice-shelf thinning initiating at least as early as the 1940s. Sediments recovered from deep basins reflect a transition from ice proximal to slightly more distal conditions, suggesting ongoing grounding-zone retreat since the 1950s. The timing of ice-shelf unpinning from the seafloor for Thwaites Glacier coincides with similar records from neighboring Pine Island Glacier. Our work provides robust new evidence that glacier retreat in the Amundsen Sea was initiated in the mid-twentieth century, likely associated with climate variability.

Exophiala dermatitidis fungal infective endocarditis on prosthetic mitral valve.

Fungal infective endocarditis, although rare, carries a high mortality risk. We present a case of successful multidisciplinary management of Exophiala dermatitidis infective endocarditis in an immunocompetent male with a bio-prosthetic mitral valve. This case highlights the clinical presentation and provides valuable treatment insights into this rare fungal entity. Prompt consideration of fungal pathogens in predisposed patients, expedited detection through non-culture-based tests, and a combined surgical and prolonged antifungal approach are pivotal.

A systematic review of the international evidence on the effectiveness of COVID-19 mitigation measures in communal rough sleeping accommodation.

BACKGROUND: Accommodations with shared washing facilities increase the risks of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection for people experiencing rough sleeping and evidence on what interventions are effective in reducing these risks needs to be understood. METHODS: Systematic review, search date 6 December 2022 with methods published a priori. Electronic searches were conducted in MEDLINE, PubMed, Cochrane Library, CINAHL and the World Health Organization (WHO) COVID-19 Database and supplemented with grey literature searches, hand searches of reference lists and publication lists of known experts. Observational, interventional and modelling studies were included; screening, data extraction and risk of bias assessment were done in duplicate and narrative analyses were conducted. RESULTS: Fourteen studies from five countries (USA, England, France, Singapore and Canada) were included. Ten studies were surveillance reports, one was an uncontrolled pilot intervention, and three were modelling studies. Only two studies were longitudinal. All studies described the effectiveness of different individual or packages of mitigation measures. CONCLUSIONS: Despite a weak evidence base, the research suggests that combined mitigation measures can help to reduce SARS-CoV-2 transmission but are unlikely to prevent outbreaks entirely. Evidence suggests that community prevalence may modify the effectiveness of mitigation measures. More longitudinal research is needed. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42021292803.

A 14-day pulse of PLX5622 modifies α-synucleinopathy in preformed fibril-infused aged mice of both sexes.

Reactive microglia are observed with aging and in Lewy body disorders, including within the olfactory bulb of men with Parkinson's disease. However, the functional impact of microglia in these disorders is still debated. Resetting these reactive cells by a brief dietary pulse of the colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 may hold therapeutic potential against Lewy-related pathologies. To our knowledge, withdrawal of PLX5622 after short-term exposure has not been tested in the preformed α-synuclein fibril (PFF) model, including in aged mice of both sexes. Compared to aged female mice, we report that aged males on the control diet showed higher numbers of phosphorylated α-synuclein+ inclusions in the limbic rhinencephalon after PFFs were injected in the posterior olfactory bulb. However, aged females displayed larger inclusion sizes compared to males. Short-term (14-day) dietary exposure to PLX5622 followed by control chow reduced inclusion numbers and levels of insoluble α-synuclein in aged males-but not females-and unexpectedly raised inclusion sizes in both sexes. Transient delivery of PLX5622 also improved spatial reference memory in PFF-infused aged mice, as evidenced by an increase in novel arm entries in a Y-maze. Superior memory was positively correlated with inclusion sizes but negatively correlated with inclusion numbers. Although we caution that PLX5622 delivery must be tested further in models of α-synucleinopathy, our data suggest that larger-sized-but fewer-α-synucleinopathic structures are associated with better neurological outcomes in PFF-infused aged mice.

Cysteine depletion sensitizes prostate cancer cells to agents that enhance DNA damage and to immune checkpoint inhibition.

BACKGROUND: Prostate Cancer (PCa) represents one of the most commonly diagnosed neoplasms in men and is associated with significant morbidity and mortality. Therapy resistance and significant side effects of current treatment strategies indicate the need for more effective agents to treat both androgen-dependent and androgen-independent PCa. In earlier studies, we demonstrated that depletion of L-cysteine/cystine with an engineered human enzyme, Cyst(e)inase, increased intracellular ROS levels and inhibited PCa growth in vitro and in vivo. The current study was conducted to further explore the mechanisms and potential combinatorial approaches with Cyst(e)inase for treatment of PCa. METHODS: DNA single strand breaks and clustered oxidative DNA damage were evaluated by alkaline comet assay and pulsed field gel electrophoresis, respectively. Neutral comet assay and immunofluorescence staining was used to measure DNA double strand breaks. Cell survival and reactive oxygen species level were measured by crystal violet assay and DCFDA staining, respectively. Western blot was used to determine protein expression. FACS analyses were preformed for immune cell phenotyping. Allograft and xenograft tumor models were used for assessing effects on tumor growth. RESULTS: PCa cells treated with Cyst(e)inase lead to DNA single and double strand breaks resulted from clustered oxidative DNA damage (SSBs and DSBs). Cyst(e)inase in combination with Auranofin, a thioredoxin reductase inhibitor, further increased intracellular ROS and DNA DSBs and synergistically inhibited PCa cell growth in vitro and in vivo. A combination of Cyst(e)inase with a PARP inhibitor (Olaparib) also increased DNA DSBs and synergistically inhibited PCa cell growth in vitro and in vivo without additional ROS induction. Knockdown of BRCA2 in PCa cells increased DSBs and enhanced sensitivity to Cyst(e)inase. Finally, Cyst(e)inase treatment altered tumor immune infiltrates and PD-L1 expression and sensitized PCa cells to anti-PD-L1 treatment. CONCLUSIONS: The current results demonstrate the importance of oxidative DNA damage either alone or in combination for Cyst(e)inase-induced anticancer activity. Furthermore, cysteine/cystine depletion alters the tumor immune landscape favoring enhanced immune checkpoint inhibition targeting PD-L1. Thus, combinatorial approaches with Cyst(e)inase could lead to novel therapeutic strategies for PCa.

Critical appraisal in rapid systematic reviews of COVID-19 studies: implementation of the Quality Criteria Checklist (QCC).

In this letter, we briefly describe how we selected and implemented the quality criteria checklist (QCC) as a critical appraisal tool in rapid systematic reviews conducted to inform public health advice, guidance and policy during the COVID-19 pandemic. As these rapid reviews usually included a range of study designs, it was key to identify a single tool that would allow for reliable critical appraisal across most experimental and observational study designs and applicable to a range of topics. After carefully considering a number of existing tools, the QCC was selected as it had good interrater agreement between three reviewers (Fleiss kappa coefficient 0.639) and was found to be easy and fast to apply once familiar with the tool. The QCC consists of 10 questions, with sub-questions to specify how it should be applied to a specific study design. Four of these questions are considered as critical (on selection bias, group comparability, intervention/exposure assessment and outcome assessment) and the rating of a study (high, moderate or low methodological quality) depends on the responses to these four critical questions. Our results suggest that the QCC is an appropriate critical appraisal tool to assess experimental and observational studies within COVID-19 rapid reviews. This study was done at pace during the COVID-19 pandemic; further reliability analyses should be conducted, and more research is needed to validate the QCC across a range of public health topics.

RANK signaling in osteoclast precursors results in a more permissive epigenetic landscape and sexually divergent patterns of gene expression.

Background: Sex is an important risk factor in the development of osteoporosis and other bone loss disorders, with women often demonstrating greater susceptibility than men. While variation in sex steroids, such as estradiol, accounts for much of the risk, there are likely additional non-endocrine factors at transcriptional and epigenetic levels that result in a higher rate of bone loss in women. Identification of these factors could improve risk assessment and therapies to preserve and improve bone health. Methods: Osteoclast precursors were isolated male and female C57Bl/6 mice and cultured with either MCSF alone or MCSF and RANKL. Following the culture period RNA was isolated for RNA sequencing and DNA was isolated for tagmentation and ATAC sequencing. RNA-Seq and ATAC-seq were evaluated via pathway analysis to identify sex- and RANKL-differential transcription and chromatin accessibility. Results: Osteoclasts demonstrated significant alterations in gene expression compared to macrophages with both shared and differential pathways between the sexes. Transcriptional pathways differentially regulated between male and female cells were associated with immunological functions with evidence of greater sensitivity in male macrophages and female osteoclasts. ATAC-Seq revealed a large increase in chromatin accessibility following RANKL treatment with few alterations attributable to sex. Comparison of RNA-Seq and ATAC-seq data revealed few common pathways suggesting that many of the transcriptional changes of osteoclastogenesis occur independently of chromatin remodeling.

End-user understanding of qualitative comparative analysis used within evidence synthesis: A mixed-methods study.

BACKGROUND: Enhanced uptake of systematic reviews that use qualitative comparative analyses (QCA) requires knowing how end-users interpret such findings. The study purpose was to identify effective approaches to communicating results from a QCA within a systematic review. METHODS: Sequential exploratory mixed methods design; thematic analysis of interviews with 11 end-users followed by a randomized experiment with 254 participants that provided QCA results for a hypothetical review presented through three formats (text, table, and figure). A survey administered after the experiment assessed subjective and objective comprehension of QCA results. RESULTS: Interview themes included use of jargon; appropriate use of appendices, tables, figures; and integration of QCA results within the systematic review. In the experiment, we observed a significant difference (p = 0.035) in subjective comprehension across the three presentation formats. Participants randomized to the figure and text formats scored higher compared to the table. No significant differences were observed for objective comprehension overall (p = 0.11). However, for parameter interpretation (a unique component of QCA results), scores among participants that received the figure format were significantly higher than scores for participants who received the text (p = 0.001) or table (p = 0.004). No significant differences (p = 0.09) were observed in objective comprehension for configuration interpretation. CONCLUSIONS: End-users of systematic reviews saw value in the use of QCA, but unfamiliar methods and terminology were barriers to full understanding of the findings. When presenting results, a figure format appears to be superior to text or table formats based on measures of subjective comprehension and some measures of objective comprehension.

CXCR4 and CXCR7 signaling promotes tumor progression and obesity-associated epithelial-mesenchymal transition in prostate cancer cells.

Obesity is associated with increased prostate cancer (PCa) progression and higher mortality, however, the mechanism(s) remain still unclear. Here, we investigated signaling by the ASC-secreted chemokine CXCL12 in a mouse allograft model of PCa and in HiMyc mice in the context of diet-induced obesity. Treatment of mice with CXCR4 antagonist inhibited CXCL12-induced signaling pathways, tumor growth and EMT in HMVP2 allograft tumors. Similar results were obtained following prostate epithelium-specific deletion of CXCR4 in HiMyc mice. We also show that CXCR4 signaling regulates expression of JMJD2A histone demethylase and histone methylation which is modulated by AMD3100. Importantly, treatment with a CXCR7 antagonist also inhibited allograft tumor growth and EMT. The current results demonstrate that both CXCR4 and CXCR7 play an important role in cancer progression and establish CXCL12 signaling pathways, activated in obesity, as potential targets for PCa intervention. In addition, other factors secreted by ASCs, may also contribute to cancer aggressiveness in obesity.

α-synucleinopathy exerts sex-dimorphic effects on the multipurpose DNA repair/redox protein APE1 in mice and humans.

Lewy body disorders are characterized by oxidative damage to DNA and inclusions rich in aggregated forms of α-synuclein. Among other roles, apurinic/apyrimidinic endonuclease 1 (APE1) repairs oxidative DNA damage, and APE1 polymorphisms have been linked to cases of Lewy body disorders. However, the link between APE1 and α-synuclein is unexplored. We report that knockdown or inhibition of APE1 amplified inclusion formation in primary hippocampal cultures challenged with preformed α-synuclein fibrils. Fibril infusions into the mouse olfactory bulb/anterior olfactory nucleus (OB/AON) elicited a modest decrease in APE1 expression in the brains of male mice but an increase in females. Similarly, men with Lewy body disorders displayed lower APE1 expression in the OB and amygdala compared to women. Preformed fibril infusions of the mouse OB/AON induced more robust base excision repair of DNA lesions in females than males. No fibril-mediated loss of APE1 expression was observed in male mice when the antioxidant N-acetylcysteine was added to their diet. These findings reveal a potential sex-biased link between α-synucleinopathy and APE1 in mice and humans. Further studies are warranted to determine how this multifunctional protein modifies α-synuclein inclusions and, conversely, how α-synucleinopathy and biological sex interact to modify APE1.

Long distance airborne transmission of SARS-CoV-2: rapid systematic review.

OBJECTIVES: To evaluate the potential for long distance airborne transmission of SARS-CoV-2 in indoor community settings and to investigate factors that might influence transmission. DESIGN: Rapid systematic review and narrative synthesis. DATA SOURCES: Medline, Embase, medRxiv, Arxiv, and WHO COVID-19 Research Database for studies published from 27 July 2020 to 19 January 2022; existing relevant rapid systematic review for studies published from 1 January 2020 to 27 July 2020; and citation analysis in Web of Science and Cocites. ELIGIBILITY CRITERIA FOR STUDY SELECTION: Observational studies reporting on transmission events in indoor community (non-healthcare) settings in which long distance airborne transmission of SARS-CoV-2 was the most likely route. Studies such as those of household transmission where the main transmission route was likely to be close contact or fomite transmission were excluded. DATA EXTRACTION AND SYNTHESIS: Data extraction was done by one reviewer and independently checked by a second reviewer. Primary outcomes were SARS-CoV-2 infections through long distance airborne transmission (>2 m) and any modifying factors. Methodological quality of included studies was rated using the quality criteria checklist, and certainty of primary outcomes was determined using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework. Narrative synthesis was themed by setting. RESULTS: 22 reports relating to 18 studies were identified (methodological quality was high in three, medium in five, and low in 10); all the studies were outbreak investigations. Long distance airborne transmission was likely to have occurred for some or all transmission events in 16 studies and was unclear in two studies (GRADE: very low certainty). In the 16 studies, one or more factors plausibly increased the likelihood of long distance airborne transmission, particularly insufficient air replacement (very low certainty), directional air flow (very low certainty), and activities associated with increased emission of aerosols, such as singing or speaking loudly (very low certainty). In 13 studies, the primary cases were reported as being asymptomatic, presymptomatic, or around symptom onset at the time of transmission. Although some of the included studies were well conducted outbreak investigations, they remain at risk of bias owing to study design and do not always provide the level of detail needed to fully assess transmission routes. CONCLUSION: This rapid systematic review found evidence suggesting that long distance airborne transmission of SARS-CoV-2 might occur in indoor settings such as restaurants, workplaces, and venues for choirs, and identified factors such as insufficient air replacement that probably contributed to transmission. These results strengthen the need for mitigation measures in indoor settings, particularly the use of adequate ventilation. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42021236762.

Venoarterial Extracorporeal Membrane Oxygenation to Facilitate Transcutaneous Mitral Valve Replacement in Critical Mitral Stenosis.

Biological mitral valve restenosis after replacement in rheumatic heart disease is a rare complication. This case illustrates venoarterial extracorporeal membrane oxygenation to facilitate transcatheter mitral valve replacement in a patient with suprasystemic pulmonary pressure and cardiogenic shock with multiorgan failure secondary to critical mitral stenosis of a bioprosthetic valve.(Level of Difficulty: Advanced.).

Internal and External Motivations and Risk Perception toward COVID-19 Vaccination in Adolescents in the U.S.

The COVID-19 vaccine is widely available to adolescents in the U.S.; however, vaccine hesitancy poses a threat to full coverage. The literature shows that perceived risks and the presence or lack of motivators are determinants for vaccination decisions, yet research evidence from minors is scant. This study adopted the Protection Motivation framework to identify differences in these facilitators and compare the influence of internal and external motivators among American adolescents in COVID-19 vaccine uptake. A nationwide online survey analyzed 13−17-year-old teenagers' COVID-19 beliefs as well as present or potential reasons for accepting the vaccine. Of the 439 participants, 21.18% were not and did not plan to get vaccinated. Another 52.39% had at least one dosage, of which over three-quarters were internally motivated (whereas those unvaccinated were more likely to be externally motivated, X2 = 4.117, p = 0.042). In unvaccinated individuals, older adolescents reported slightly more internal motivators than younger adolescents (t = −2.023, p = 0.046). Internal motivation was associated with higher risk perception (r2 = 0.06651, p = 0.001), but risk perception had a stronger relationship with vaccination status (r2 = 0.1816, p < 0.001), with vaccinated individuals showing higher risk perception than those unvaccinated (mean difference = 0.42 on a scale of 1−4; t = −3.603, p < 0.001); the risk perception difference was even greater between hesitant and non-hesitant participants (mean difference = 0.63; t = −0.892, p < 0.001). The relationship was moderated by perceived knowledge, where the difference in risk perception between vaccination status was only significant for those with low perceived knowledge (f = 10.59, p = 0.001). Increasing awareness of disease risks and stressing internal motivators may be key to improving uptake in young people. Future research could delve deeper into risk perception formation of adolescents and why and how it differs across populations.

Aureochromes maintain polyunsaturated fatty acid content in Nannochloropsis oceanica.

Nannochloropsis oceanica, like other stramenopile microalgae, is rich in long-chain polyunsaturated fatty acids (LC-PUFAs) such as eicosapentaenoic acid (EPA). We observed that fatty acid desaturases (FADs) involved in LC-PUFA biosynthesis were among the strongest blue light-induced genes in N. oceanica CCMP1779. Blue light was also necessary for maintaining LC-PUFA levels in CCMP1779 cells, and growth under red light led to a reduction in EPA content. Aureochromes are stramenopile-specific proteins that contain a light-oxygen-voltage (LOV)-sensing domain that associates with a flavin mononucleotide and is able to sense blue light. These proteins also contain a basic leucine zipper DNA-binding motif and can act as blue light-regulated transcription factors by associating with an E-box like motif, which we found enriched in the promoters of blue light-induced genes. We demonstrated that, in vitro, two CCMP1779 aureochromes were able to absorb blue light. Moreover, the loss or reduction of the expression of any of the three aureochrome genes led to a decrease in the blue light-specific induction of several FADs in CCMP1779. EPA content was also significantly reduced in NoAUREO2 and NoAUREO4 mutants. Taken together, our results indicate that aureochromes mediate blue light-dependent regulation of LC-PUFA content in N. oceanica CCMP1779 cells.

Respect, interaction, immediacy and the role community plays in registering an organ donation decision.

BACKGROUND: Registering a donation decision is fundamental to increasing the number of people who donate the organs and tissues essential for transplantation, but the number of registered organ donors is insufficient to meet this demand. Most people in Australia support organ donation, but only a third have registered their decision on the Australian Organ Donor Register (AODR). We addressed this paradox by investigating how feelings of community, engendered through an ethic of hospitality and care and a non-proselytizing dialogue about organ donation, facilitated the decision to register. METHODS: An Immediate Registration Opportunity was set up in a large public hospital in NSW, Australia. The public was approached and invited to engage in an open, respectful dialogic interaction that met people where their beliefs were and allowed their concerns and fears about donation to be discussed. This included a survey that measured positive and negative beliefs about organ donation, mood, atmosphere, and feelings of community coupled with an on-the-spot opportunity to register their donation decision. RESULTS: Over four days, we interacted with 357 participants; 75.5% (210) of eligible-to-register participants registered on the AODR. Generalized Structural Equation Modelling highlighted that as connection to community increased, so did the salience of positive beliefs about organ donation. Positive beliefs, in turn, were negatively correlated with negative beliefs about donation and, as the strength of negative beliefs decreased, the probability of registration on the AODR increased. Participants who registered on the AODR reported stronger connection to the broader community than participants who did not register. CONCLUSION: A respectful non-judgmental interaction that allows beliefs and concerns about organ donation to be discussed, coupled with an immediate opportunity to register, encouraged registration. Within this framework, feelings of belonging to a community were a key determinant that enabled many to make the decision to register.

Systems of Care in Cardiogenic Shock.

Outcomes for cardiogenic shock (CS) patients remain relatively poor despite significant advancements in primary percutaneous coronary interventions (PCI) and temporary circulatory support (TCS) technologies. Mortality from CS shows great disparities that seem to reflect large variations in access to care and physician practice patterns. Recent reports of different models to standardize care in CS have shown considerable potential at improving outcomes. The creation of regional, integrated, 3-tiered systems, would facilitate standardized interventions and equitable access to care. Multidisciplinary CS teams at Level I centers would direct care in a hub-and-spoke model through jointly developed protocols and real-time shared decision making. Levels II and III centers would provide early access to life-saving therapies and safe transfer to designated hub centers. In regions with large geographical distances, the implementation of telemedicine-cardiac intensive care unit (CICU) care can be an important resource for the creation of effective systems of care.

Patients' Characterization of Medication, Emotions, and Incongruent Perceptions around Adherence.

Medication nonadherence is prevalent among patients with chronic diseases. Previous research focused on patients' beliefs in medication or illness and applied risk-benefit analyses when reasoning their behavior. This qualitative study examined rheumatoid arthritis (RA) patients' perceptions and feelings toward medication in parallel with attitudes about their own adherence. We conducted four 90-min focus groups and seven 60-min interviews with a diverse sample of RA patients (n = 27). Discussions covered dilemmas encountered, emotions, and thought process concerning medication, and included application of projective techniques. Transcripts were analyzed in NVivo-12 using a thematic coding framework through multiple rounds of deduction and categorization. Three themes emerged, each with mixed sentiments. (1) Ambivalent feelings toward medication: participants experienced internal conflicts as their appreciation of drugs for relief contradicted worries about side effects or "toxicity" and desire to not identify as sick, portraying medications as "best friend" and "evil". (2) Struggles in taking medication: participants "hated" the burden of managing regimen and resented the reliance and embarrassment. (3) Attitudes and behavior around adherence: most participants self-reported high adherence yet also described frequently self-adjusting medications, displaying perception-action incongruency. Some expressed nervousness and resistance while others felt empowered when modifying dosage, which might have motivated or helped them self-justify nonadherence. Only a few who deviated from prescription discussed it with their clinicians though most participants expressed the desire to do so; open communication with providers reinforced a sense of confidence and control of their own health. Promoting personalized care with shared decision-making that empowers and supports patients in managing their long-term treatment could encourage adherence and improve overall health outcome.