Impact of mental health in persons living with rare disease: Findings from the AMCP Market Insights Program.

Within the framework of its Market Insights Program, AMCP convened a panel of experts representing diverse stakeholders to identify alterations to plan design and/or coverage options geared toward improving the diagnosis and treatment of mental health conditions among persons living with rare diseases (PLWRD). PLWRD face unique mental health challenges because of the misunderstood nature of their conditions, potential misdiagnosis, and limited treatment options. Economic burdens arise from increased medical needs, reliance on caregivers, and work disruptions. The interplay of these factors, along with health insurance coverage, creates a distinctive mental health landscape for PLWRD and a need to prioritize mental health support for this patient population. This article aims to (1) summarize expert perspectives on health care system challenges and areas of agreement concerning the management of mental health conditions and (2) advance payers' understanding of their role in supporting mental health care for patients with rare diseases. Addressing mental health needs of PLWRD presents multifaceted challenges. Managed care organizations play a pivotal role in supporting mental health care for PLWRD through their quality improvement initiatives and policies for coverage and reimbursement, which can impact both the rare disease treatment and mental health services PLWRD receive.

Optimizing the management of inherited blood disorders in a changing market: Findings from the AMCP Market Insights Program.

In this market insights program, AMCP brought together a panel of experts representing various stakeholders: national and regional health plans, integrated health care systems, employer benefits groups, clinical experts, the Centers for Disease Control and Prevention, and patient advocacy organizations. The objectives were to gain insights into the current and evolving treatments in hemophilia, sickle cell disease, and ß-thalassemia; measure the effects of recently approved therapies on clinicians, payers, and patients; recognize emerging trends within the stop-loss market; address potential issues and obstacles related to monitoring and reporting outcomes; and identify concerns associated with both existing and emerging contracting and reimbursement models. This article aims to summarize expert perspectives on health care system challenges and strategies concerning the management of inherited blood disorders and to advance managed care professionals' understanding of their role in supporting care for these patients. The experts emphasized that when shaping coverage policies, a patient-centered approach is crucial, focusing on preserving organ function to maintain eligibility for future gene therapies among individuals with inherited blood disorders. These strategies, including benefit design modifications, specialized provider networks, and centralized mechanisms like registries, are vital for evaluating effectiveness, facilitating decision-making, and managing costs and risks associated with new and emerging treatment options for inherited blood disorders.

Plasma extracellular vesicles and cell-free mitochondrial DNA are associated with cognitive dysfunction in treated older adults with HIV.

Extracellular vesicles (EVs) are nanoparticles with a role in intercellular communication. Cell-free mitochondrial DNA (cf-mtDNA) has been associated with cognitive dysfunction in people with HIV (PWH). We conducted a nested case-control study to test the hypothesis that plasma EVs are associated with cf-mtDNA and cognitive dysfunction in older PWH. A machine learning-based model identified total EVs, including select EV subpopulations, as well as urine cf-mtDNA and 4-meter walk time carry power to predict the neurocognitive impairment. These features resulted in an AUC-ROC of 0.845 + / - 0.109 (0.615, 1.00).

Patient-centered pharmacovigilance: priority actions from the inherited bleeding disorders community.

Pharmacovigilance, the science and practice of monitoring the effects of medicinals and their safety, is the responsibility of all stakeholders involved in the development, manufacture, regulation, distribution, prescription, and use of drugs and devices. The patient is the stakeholder most impacted by and the greatest source of information on safety issues. It is rare, however, for the patient to take a central role and exert leadership in the design and execution of pharmacovigilance. Patient organizations in the inherited bleeding disorders community are among the most established and empowered, particularly in the rare disorders. In this review, two of the largest bleeding disorders patient organizations, Hemophilia Federation of America (HFA) and National Hemophilia Foundation (NHF), offer insights into the priority actions required of all stakeholders to improve pharmacovigilance. The recent and ongoing increase in incidents raising safety concerns and a therapeutic landscape on the cusp of unprecedented expansion heighten the urgency of a recommitment to the primacy of patient safety and well-being in drug development and distribution. Plain Language Summary: Patients at the center of product safety Every medical device and therapeutic product has potential benefits and harms. The pharmaceutical and biomedical companies that develop them must demonstrate that they are effective, and the safety risks are limited or manageable, for regulators to approve them for use and sale. After the product has been approved and people are using it in their daily lives, it is important to continue to collect information about any negative side effects or adverse events; this is called pharmacovigilance. Regulators, like the United States (US) Food and Drug Administration, the companies that sell and distribute the products, and healthcare professionals who prescribe them are all required to participate in collecting, reporting, analyzing, and communicating this information. The people with the most firsthand knowledge of the benefits and harms of the drug or device are the patients who use them. They have an important responsibility to learn how to recognize adverse events, how to report them, and to stay informed of any news about the product from the other partners in the pharmacovigilance network. Those partners have a crucial responsibility to provide clear, easy-to-understand information to patients about any new safety concerns that come to light. The community of people with inherited bleeding disorders has recently encountered problems with poor communication of product safety issues, prompting two large US patient organizations, National Hemophilia Foundation and Hemophilia Federation of America, to hold a Safety Summit with all the pharmacovigilance network partners. Together they developed recommendations to improve the collection and communication of information about product safety so that patients can make well-informed, timely decisions about their use of drugs and devices. This article presents these recommendations in the context of how pharmacovigilance is supposed to work and some of the challenges encountered by the community.

Plasma Cell-Free Mitochondrial DNA as a Marker of Geriatric Syndromes in Older Adults With HIV.

BACKGROUND: Older people with HIV experience more comorbidities and geriatric syndromes than their HIV-negative peers, perhaps due to residual inflammation despite suppressive antiretroviral therapy. Cell-free mitochondrial DNA (cfmtDNA) released during necrosis-mediated cell death potentially acts as both mediator and marker of inflammatory dysregulation. Thus, we evaluated plasma cfmtDNA as a potential biomarker of geriatric syndromes. METHODS: Participants underwent the Montreal Cognitive Assessment (MoCA), frailty testing, and measurement of plasma cfmtDNA by qPCR and inflammatory markers including C-reactive protein, interleukin-6 (IL-6), interferon gamma, and tumor necrosis factor alpha in this cross-sectional study. RESULTS: Across 155 participants, the median age was 60 years (Q1, Q3: 56, 64), one-third were female, and 92% had HIV-1 viral load <200 copies/mL. The median MoCA score was 24 (21, 27). The plasma cfmtDNA level was higher in those with cognitive impairment (MoCA <23) ( P = 0.02 by the t test) and remained significantly associated with cognitive impairment in a multivariable logistic regression model controlling for age, sex, race, CD4 T-cell nadir, HIV-1 viremia, and depression. Two-thirds of participants met the criteria for a prefrail or frail state; higher plasma cfmtDNA was associated with slow walk and exhaustion but not overall frailty state. Cognitive dysfunction was not associated with C-reactive protein, IL-6, interferon gamma, or tumor necrosis factor alpha, and frailty state was only associated with IL-6. CONCLUSIONS: Plasma cfmtDNA may have a role as a novel biomarker of cognitive dysfunction and key components of frailty. Longitudinal investigation of cfmtDNA is warranted to assess its utility as a biomarker of geriatric syndromes in older people with HIV.

Integrated Hemophilia Patient Care via a National Network of Care Centers in the United States: A Model for Rare Coagulation Disorders.

Rare, chronic diseases such as hemophilia and other congenital coagulation disorders require coordinated delivery of services for optimal outcomes. Hemophilia Treatment Centers (HTCs) are specialized, multidisciplinary health-care centers providing team-based care to meet the physical, psychosocial, and emotional needs of people with hemophilia (PWH) and may serve as a model for other rare coagulation disorders. Health-care purchasers, as well as the general medical community, may not appreciate the breadth and quality of services provided by HTCs. They exemplify the acculturalization and actualization of integrated care by providing comprehensive diagnostic and treatment services that reduce morbidity, mortality, avoidable emergency room visits, hospitalizations, and overall costs, while promoting a longer lifespan and improved patient functioning and outcomes. This is accomplished by a team-based approach relying upon a shared decision-making model to effectively prevent complications and manage symptoms in PWH, who are dependent on high-cost treatments. This article provides a concise yet comprehensive description of the core components of an HTC and the regional and national networks in the United States, which together achieve their incomparable value for all stakeholders.

Urine Cell-Free Mitochondrial DNA as a Marker of Weight Loss and Body Composition in Older Adults With HIV.

BACKGROUND: Older adults with HIV (OAH) experience more comorbidities and geriatric syndromes than their HIV-negative peers, perhaps because of chronic inflammation. Cell-free mitochondrial DNA (cfmtDNA) released from cells undergoing necrosis-mediated cell death potentially acts as both a mediator and marker of inflammatory dysregulation. We hypothesized that urinary cfmtDNA would be associated with frailty, body composition, and fall history in OAH. METHODS: OAH completed frailty testing, a psychosocial survey, body composition assessment, and measurement of urine cfmtDNA and urine albumin:creatinine in this cross-sectional study. Urine cfmtDNA was measured by quantative polymerase chain reaction and normalized to urinary creatinine. RESULTS: Across 150 participants, the mean age was 61 years (SD 6 years), half identified as Black, one-third were women, and 93% had HIV-1 viral load <200 copies/mL. Two-thirds met criteria for a prefrail or frail state. Those with unintentional weight loss had higher urine cfmtDNA concentrations (P = 0.03). Higher urine cfmtDNA was inversely associated with the skeletal muscle index (ß = -0.19, P < 0.01) and fat mass index (ß = -0.08, P = 0.02) in separate multiple linear regression models adjusted for age, sex, and presence of moderate-severe albuminuria. CONCLUSIONS: In this cross-sectional study of OAH, higher levels of urine cfmtDNA were more common in subjects with less robust physical condition, including unintentional weight loss and less height-scaled body mass of fat and muscle. These findings suggest urine cfmtDNA may reflect pathophysiologic aging processes in OAH, predisposing them to geriatric syndromes. Longitudinal investigation of urine cfmtDNA as a biomarker of geriatric syndromes is warranted.

Association of plasma mitochondrial DNA with COPD severity and progression in the SPIROMICS cohort.

BACKGROUND: There is a lack of mechanism-driven, clinically relevant biomarkers in chronic obstructive pulmonary disease (COPD). Mitochondrial dysfunction, a proposed disease mechanism in COPD, is associated with the release of mitochondrial DNA (mtDNA), but plasma cell-free mtDNA has not been previously examined prospectively for associations with clinical COPD measures. METHODS: P-mtDNA, defined as copy number of mitochondrially-encoded NADH dehydrogenase-1 (MT-ND1) gene, was measured by real-time quantitative PCR in 700 plasma samples from participants enrolled in the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) cohort. Associations between p-mtDNA and clinical disease parameters were examined, adjusting for age, sex, smoking status, and for informative loss to follow-up. RESULTS: P-mtDNA levels were higher in participants with mild or moderate COPD, compared to smokers without airflow obstruction, and to participants with severe COPD. Baseline increased p-mtDNA levels were associated with better CAT scores in female smokers without airflow obstruction and female participants with mild or moderate COPD on 1-year follow-up, but worse 6MWD in females with severe COPD. Higher p-mtDNA levels were associated with better 6MWD in male participants with severe COPD. These associations were no longer significant after adjusting for informative loss to follow-up. CONCLUSION: In this study, p-mtDNA levels associated with baseline COPD status but not future changes in clinical COPD measures after accounting for informative loss to follow-up. To better characterize mitochondrial dysfunction as a potential COPD endotype, these results should be confirmed and validated in future studies. TRIAL REGISTRATION:  ClinicalTrials.gov NCT01969344 (SPIROMICS).

Optimizing language for effective communication of gene therapy concepts with hemophilia patients: a qualitative study.

BACKGROUND: For communities of people living with hemophilia and other genetic conditions, gene therapy could represent a paradigm shift in treatment strategies. As investigational therapeutic modalities such as gene therapy become more widely used and discussed, there is a critical need for all stakeholders to communicate using a lexicon that is intelligible, accurate, consistent, and representative of novel treatments. In doing so, expectations can be more carefully managed and potential risks, benefits, and limitations better understood. In recognition of this need, a first-ever study of gene therapy lexicon was conducted using established methods of market research and linguistic analysis. METHODS: Ninety-four participants representing hematologists, nurses, caregivers, and people with hemophilia A, in six countries (US, UK, Spain, Germany, France, Italy) took part in a series of in-depth interviews, face-to-face focus groups, an advisory board meeting, and online group interviews to develop, refine, and test verbal, written, and pictorial language concepts through a three-phase iterative process. Sessions were conducted in local languages using detailed discussion guides. Feedback from participants was captured using real-time instant-response dial testing to measure moment-by-moment emotional responses to language stimuli. Semiquantitative analysis of the responses informed selection of preferred language concepts for final testing, and qualitative discussion explored preference rationale. Participants also completed polling and forced rank and choice written exercises. RESULTS: Study feedback showed that the hemophilia community has preferences around consistent lexicon to describe hemophilia and its management. Expert linguistic analysis of feedback from the three phases enabled agreement of a consensus lexicon of vocabulary and an optimized summary narrative for talking about gene therapy amongst people affected by hemophilia A. Preferences were largely consistent across audiences and countries, although some country-specific recommendations were made. A representative summary phrase was agreed: "Gene therapy is being studied in clinical trials with the aim to allow the body to produce factor VIII protein on its own". CONCLUSIONS: The use of preferred language across different stakeholders increases understanding and comfort during discussions of novel and complex therapeutic modalities such as gene therapy. Consistent use of community-informed lexicon minimizes miscommunication and facilitates informed decision-making regarding potential future treatment opportunities.

Elevated cardiac risk score by Atherosclerotic Cardiovascular Disease calculation is associated with albuminuria in older people living with HIV.

: Globally, the proportion of older people living with HIV (PLWH) is growing and the burden of noncommunicable diseases, including cardiac and renal disease, is increasing. There are few studies of renal disease and cardiac risk in older PLWH. This study investigates the relationship between albuminuria and cardiac risk as estimated by the Atherosclerotic Cardiovascular Disease 10-year risk calculator. We report that albuminuria is associated with a higher Atherosclerotic Cardiovascular Disease risk score in both diabetic and nondiabetic older PLWH.

Association of urine mitochondrial DNA with clinical measures of COPD in the SPIROMICS cohort.

BACKGROUNDMitochondrial dysfunction, a proposed mechanism of chronic obstructive pulmonary disease (COPD) pathogenesis, is associated with the leakage of mitochondrial DNA (mtDNA), which may be detected extracellularly in various bodily fluids. Despite evidence for the increased prevalence of chronic kidney disease in COPD subjects and for mitochondrial dysfunction in the kidneys of murine COPD models, whether urine mtDNA (u-mtDNA) associates with measures of disease severity in COPD is unknown.METHODSCell-free u-mtDNA, defined as copy number of mitochondrially encoded NADH dehydrogenase-1 (MTND1) gene, was measured by quantitative PCR and normalized to urine creatinine in cell-free urine samples from participants in the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) cohort. Urine albumin/creatinine ratios (UACR) were measured in the same samples. Associations between u-mtDNA, UACR, and clinical disease parameters - including FEV1 % predicted, clinical measures of exercise tolerance, respiratory symptom burden, and chest CT measures of lung structure - were examined.RESULTSU-mtDNA and UACR levels were measured in never smokers (n = 64), smokers without airflow obstruction (n = 109), participants with mild/moderate COPD (n = 142), and participants with severe COPD (n = 168). U-mtDNA was associated with increased respiratory symptom burden, especially among smokers without COPD. Significant sex differences in u-mtDNA levels were observed, with females having higher u-mtDNA levels across all study subgroups. U-mtDNA associated with worse spirometry and CT emphysema in males only and with worse respiratory symptoms in females only. Similar associations were not found with UACR.CONCLUSIONU-mtDNA levels may help to identify distinct clinical phenotypes and underlying pathobiological differences in males versus females with COPD.TRIAL REGISTRATIONThis study has been registered at ClinicalTrials.gov ( NCT01969344).FUNDINGUS NIH, National Heart, Lung and Blood Institute, supplemented by contributions made through the Foundation for the NIH and the COPD Foundation from AstraZeneca/MedImmune, Bayer, Bellerophon Therapeutics, Boehringer-Ingelheim Pharmaceuticals Inc., Chiesi Farmaceutici S.p.A., Forest Research Institute Inc., GlaxoSmithKline, Grifols Therapeutics Inc., Ikaria Inc., Novartis Pharmaceuticals Corporation, Nycomed GmbH, ProterixBio, Regeneron Pharmaceuticals Inc., Sanofi, Sunovion, Takeda Pharmaceutical Company, and Theravance Biopharma and Mylan.

Mitophagy-dependent macrophage reprogramming protects against kidney fibrosis.

Mitophagy, by maintaining mitochondrial quality control, plays a key role in maintaining kidney function and is impaired in pathologic states. Macrophages are well known for their pathogenic role in kidney fibrosis. Here, we report that PINK1/Parkin-mediated mitophagy in macrophages is compromised in experimental and human kidney fibrosis. We demonstrate downregulation of mitophagy regulators mitofusin-2 (MFN2) and Parkin downstream of PINK1 in kidney fibrosis. Loss of either Pink1 or Prkn promoted renal extracellular matrix accumulation and frequency of profibrotic/M2 macrophages. Pink1-/- or Prkn-/- BM-derived macrophages (BMDMs) showed enhanced expression of rictor. Mitochondria from TGF-ß1-treated Pink1-/- BMDMs exhibited increased superoxide levels, along with reduced respiration and ATP production. In addition, mitophagy in macrophages involves PINK1-mediated phosphorylation of downstream MFN2, MFN2-facilitated recruitment of Parkin to damaged mitochondria, and macrophage-specific deletion of Mfn2 aggravates kidney fibrosis. Moreover, mitophagy regulators were downregulated in human CKD kidney and TGF-ß1-treated human renal macrophages, whereas Mdivi1 treatment suppressed mitophagy mediators and promoted fibrotic response. Taken together, our study is the first to our knowledge to demonstrate that macrophage mitophagy plays a protective role against kidney fibrosis via regulating the PINK1/MFN2/Parkin-mediated pathway.

Management of US men, women, and children with hemophilia and methods and demographics of the Bridging Hemophilia B Experiences, Results and Opportunities into Solutions (B-HERO-S) study.

The Bridging Hemophilia B Experiences, Results and Opportunities Into Solutions (B-HERO-S) initiative was launched in an effort to address specific gaps in the understanding of the psychosocial impact of mild-moderate-severe hemophilia B. The original Hemophilia Experiences, Results and Opportunities (HERO) qualitative study evaluated the needs of people with hemophilia A or B in multiple countries; however, a majority of participants had the more common moderate-severe hemophilia A. The B-HERO-S study was designed in collaboration with the hemophilia community to evaluate the needs of adults with hemophilia B and caregivers of children with hemophilia B, including affected women and caregivers of girls with hemophilia. The report presented here describes participant demographics and comorbidities, as well as treatment regimens and access to treatment. Bleeding symptoms were reported by 27% of mothers of children with hemophilia B who participated. Women were more likely than men to self-report arthritis and depression/anxiety as comorbidities associated with hemophilia B. More adults and children with hemophilia B were on routine treatment than on on-demand treatment, and a high percentage of adults with moderate hemophilia B received routine treatment (86%). Many adults with hemophilia B (78%) and caregivers (69%) expressed concern about access to factor in the next 5 years, and of adults with hemophilia B, women more commonly experienced issues with access to factor in the past than did men (72% vs 44%). The findings of the B-HERO-S study reveal potential unmet needs of some patients with mild-moderate hemophilia B, and the results may be leveraged to inform patient outreach by hemophilia treatment centers and education initiatives.

Treatment outcomes, quality of life, and impact of hemophilia on young adults (aged 18-30 years) with hemophilia.

The Hemophilia Experiences, Results and Opportunities (HERO) initiative assessed psychosocial issues reported by people with moderate to severe hemophilia and was led by a multidisciplinary international advisory board. This analysis reports data from young adult respondents (aged 18-30 years), including both US and overall global (including US respondents) results, and investigates treatment outcomes, quality of life, and impacts of hemophilia on relationships. More young adults in HERO received prophylaxis than on-demand treatment, although a majority reported not using factor products exactly as prescribed, and 50% of global respondents and 26% of US respondents reported issues with access to factor replacement therapy in the previous 5 years. Many young adults with hemophilia reported comorbidities, including bone/skeletal arthritis, chronic pain, and viral infections, and nearly half of young adults reported anxiety/depression. Most reported pain interference with daily activities in the past 4 weeks, although a majority reported participating in lower-risk activities and approximately half in intermediate-risk activities. Most young adults were very or quite satisfied with the support of partners/spouses, family, and friends, although roughly one-third reported that hemophilia affected their ability to develop close relationships with a partner. A majority of young adults reported that hemophilia has had a negative impact on employment, and 62% of global respondents and 78% of US respondents were employed at least part-time. Together these data highlight the psychosocial issues experienced by young adults with hemophilia and suggest that increased focus on these issues may improve comprehensive care during the transition to adulthood.

Procedure for obtaining a urine sample from a urostomy, ileal conduit, and colon conduit: a best practice guideline for clinicians.

The purpose of this document was to define the correct technique for obtaining a urine sample from a urostomy, ileal, or colon conduit. While healthcare providers do not commonly encounter patients with a urostomy, knowledge of the correct procedure to obtain a urine specimen is essential. Urine samples obtained incorrectly from a urostomy can lead to inaccurate cultures, resulting in an improper diagnosis and treatment, which can endanger the life of a patient. This column presents patient preparation, the procedure to obtain a specimen with and without a catheter, and aftercare of the patient and specimen. This best practice guideline has been developed by a panel of certified ostomy nurses serving on the Wound, Ostomy and Continence Nurses (WOCN) Society's Clinical Practice Ostomy Committee. The guideline has undergone content validation through a consensus-building process by the WOCN Society, which was managed by the Center for Clinical Investigation.

ORAI1-mediated calcium influx in lactation and in breast cancer.

The entry of calcium into the mammary epithelial cell from the maternal plasma (i.e., calcium influx mechanisms) during lactation is poorly understood. As alterations in calcium channels and pumps are a key feature of some cancers, including breast cancer, understanding these calcium influx pathways may have significance beyond mammary biology. We show that the store-operated calcium influx protein, Orai1, is increased during lactation whereas the Orai1 activator Stim1, but not Stim2, is downregulated. Stim2 siRNA reduced basal calcium levels in a lactation model. Our results suggest that calcium influx is remodeled in mammary epithelial cells during lactation, with calcium influx increased through Orai1, activated by Stim2. Breast cancer cell lines had increased levels of ORAI1. ORAI1 siRNA in breast cancer cells reduced store-operated calcium entry and remodeled the calcium influx associated with invasive stimuli. Analysis of microarray data from 295 breast cancers showed that the transcriptional breast cancer subtype with the poorest prognosis (basal) was associated with an altered relationship between the ORAI1 regulators STIM1 and STIM2, and that women with breast cancers with STIM1(high)/STIM2(low) tumors had a significantly poorer prognosis. Our studies show that during lactation there is a remodeling in the nature of calcium influx and that alteration in the ORAI1 influx pathway may be a feature of some breast cancers, particularly those with the poorest prognosis. Our studies suggest that this pathway may be a novel therapeutic target for breast cancer treatment in these women.

Pharmacist-led, interdisciplinary model for delivery of supportive care in the ambulatory cancer clinic setting.

PURPOSE: To describe a pharmacist-led, interdisciplinary method of care delivery begun at the University of North Carolina. We describe the characteristics of the population seen and the role of the individual members of the interdisciplinary team, and provide an early analysis of the program's impact on symptom improvement. METHODS: A supportive care consultation service was begun at the University of North Carolina Hospitals to serve adult outpatients with cancer undergoing treatment or follow-up. Patients data were entered into an institutional review board-approved database to permit detailed assessments over time. Patient demographics were analyzed using descriptive statistics, medications used and changes made were noted, and symptom scores from a previously described instrument were captured and compared over time. RESULTS: Patients were seen from all adult oncology services, including gynecologic, radiation, medical, and surgical. The characteristics of the population seen were similar to those of the hospital population as a whole. Most of the patients were seen for pain management, and many required a medication change. Symptom scores improved by the second visit, and the improvement was maintained. CONCLUSION: We are able to demonstrate that the use of a pharmacist-led, interdisciplinary team produced an improvement in symptom scores comparable to what has been seen in the inpatient palliative care service within our institution. Projected shortages of oncology providers may be mitigated by pharmacists working in collaborative practices, with prescriptive authority, in the ambulatory oncology setting.