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Background Rare disease research is hampered in part by the fact that patients are geographically dispersed. Rare disease patient communities are recognized for their use of the internet to learn about their condition and find peer-to-peer support. As such, web-based technologies offer promise for overcoming geographic barriers in rare disease research for many. Qualitative focus groups (FGs) are a widely used methodology used to understand patients and parents/families ‘lived experience’ and unmet needs is important to improve care for rare diseases. It is unclear if web-enabled (virtual) FGs are comparable to traditional in-person approaches. We conducted in-person (n = 3) and virtual (n = 3) FGs with rare disease patients to determine if virtual FGs produce similar results in-person FGs. Results Three in-person (n = 33 participants) and three virtual (n = 25 participants) FGs were conducted examining attitudes and beliefs regarding genetic testing and family communication of risk. Participants included 30 males, 18 females, and 10 parents/guardians. Two independent investigators identified excerpts (meaningful sections of text) and coded themes/sub-themes using a codebook. Inter-coder agreement across identified excerpts (n = 530) in both FG formats was 844/875 (96.5%). Two additional investigators reviewed coded excerpts and did not identify additional themes/sub-themes—supporting data saturation across FG formats. Virtual FGs accounted for 303/530 (57.2%) of total excerpts and 957/1721 (55.7%) of all identified themes/sub-themes. Formats were similar in terms of overall number of excerpts (101 ± 7.8 vs. 75.7 ± 18.8, p  = 0.26) and themes/sub-themes (319 ± 6.1 vs. 254.7 ± 103.6, p  = 0.34) between virtual and in-person FGs. However, virtual FGs had significantly more coded excerpts specifically relating to sensitive/intimate topics including ‘attitudes and beliefs’ (n = 320 vs. n = 235, p  < 0.001), ‘information and support’ (n = 184 vs. n = 99, p  < 0.001), and ‘family communication’ (n = 208 vs. n = 114, p  < 0.001). Conclusions Virtual FGs yielded similar numbers of coded excerpts compared to traditional in-person FGs. Virtual FGs appear to support the relative anonymity of participants, resulting in richer discussion of highly sensitive, intimate topics. Findings support the validity and methodologic rigor of using web-enabled technologies for conducting FGs in rare diseases.

Background The Chronic Care Model (CCM) is a longstanding and widely adopted model guiding chronic illness management. Little is known about how CCM elements are implemented in rare disease care or how patients’ care experiences relate to health-related quality of life (HRQoL). We engaged patients living with systemic sclerosis (SSc) to assess current care according to the CCM from the patient perspective and their HRQoL. Methods We employed an explanatory sequential mixed methods design. First, we conducted a cross-sectional quantitative survey (n = 101) using the Patient Assessment of Chronic Illness Care (PACIC) and Systemic Sclerosis Quality of Life (SScQoL) questionnaires. Next, we used data from individual patient interviews (n = 4) and one patient focus group (n = 4) to further explore care experiences of people living with SSc with a focus on the PACIC dimensions. Results The mean overall PACIC score was 3.0/5.0 (95% CI 2.8–3.2, n = 100), indicating care was ‘never’ to ‘generally not’ aligned with the CCM. Lowest PACIC subscale scores related to ‘goal setting/tailoring’ (mean = 2.5, 95% CI 2.2–2.7) and ‘problem solving/contextual counselling’ (mean = 2.9, 95% CI 2.7–3.2). No significant correlations were identified between the mean PACIC and SScQoL scores. Interviews revealed patients frequently encounter major shortcomings in care including ‘experiencing organized care with limited participation’, ‘not knowing which strategies are effective or harmful’ and ‘feeling left alone with disease and psychosocial consequences’. Patients often responded to challenges by ‘dealing with the illness in tailored measure’, ‘taking over complex coordination of care’ and ‘relying on an accessible and trustworthy team’. Conclusions The low PACIC mean overall score is comparable to findings in patients with common chronic diseases. Key elements of the CCM have yet to be systematically implemented in Swiss SSc management. Identified gaps in care related to lack of shared decision-making, goal-setting and individual counselling-aspects that are essential for supporting patient self-management skills. Furthermore, there appears to be a lack of complex care coordination tailored to individual patient needs.

Between the genetic extremes of rare monogenic and common polygenic diseases lie diverse oligogenic disorders involving mutations in more than one locus in each affected individual. Elucidating the principles of oligogenic inheritance and mechanisms of genetic interactions could help unravel the newly appreciated role of rare sequence variants in polygenic disorders. With few exceptions, however, the precise genetic architecture of oligogenic diseases remains unknown. Isolated gonadotropin-releasing hormone (GnRH) deficiency caused by defective secretion or action of hypothalamic GnRH is a rare genetic disease that manifests as sexual immaturity and infertility. Recent reports of patients who harbor pathogenic rare variants in more than one gene have challenged the long-held view that the disorder is strictly monogenic, yet the frequency and extent of oligogenicity in isolated GnRH deficiency have not been investigated. By systematically defining genetic variants in large cohorts of well-phenotyped patients (n = 397), family members, and unaffected subjects (n = 179) for the majority of known disease genes, this study suggests a significant role of oligogenicity in this disease. Remarkably, oligogenicity in isolated GnRH deficiency was as frequent as homozygosity/compound heterozygosity at a single locus (2.5%). Among the 22% of patients with detectable rare protein-altering variants, the likelihood of oligogenicity was 11.3%. No oligogenicity was detected among controls (P < 0.05), even though deleterious variants were present. Viewing isolated GnRH deficiency as an oligogenic condition has implications for understanding the pathogenesis of its reproductive and nonreproductive phenotypes; deciphering the etiology of common GnRH-related disorders; and modeling the genetic architecture of other oligogenic and multifactorial diseases.

Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic form of isolated gonadotropin‐releasing hormone (GnRH) deficiency caused by mutations in > 30 genes. Fibroblast growth factor receptor 1 ( FGFR1 ) is the most frequently mutated gene in CHH and is implicated in GnRH neuron development and maintenance. We note that a CHH FGFR1 mutation (p.L342S) decreases signaling of the metabolic regulator FGF21 by impairing the association of FGFR1 with β‐Klotho (KLB), the obligate co‐receptor for FGF21. We thus hypothesized that the metabolic FGF21/KLB/FGFR1 pathway is involved in CHH. Genetic screening of 334 CHH patients identified seven heterozygous loss‐of‐function KLB mutations in 13 patients (4%). Most patients with KLB mutations (9/13) exhibited metabolic defects. In mice, lack of Klb led to delayed puberty, altered estrous cyclicity, and subfertility due to a hypothalamic defect associated with inability of GnRH neurons to release GnRH in response to FGF21. Peripheral FGF21 administration could indeed reach GnRH neurons through circumventricular organs in the hypothalamus. We conclude that FGF21/KLB/FGFR1 signaling plays an essential role in GnRH biology, potentially linking metabolism with reproduction. Synopsis Defects in FGF21/KLB/FGFR1 signaling contribute to GnRH deficiency in both humans and mice. This signaling pathway is a novel link between metabolism and reproduction. Heterozygous loss‐of‐function mutations in KLB are found in patients with congenital hypogonadotropic hypogonadism. Klb ‐deficient mice delayed sexual maturation and impaired fertility with decreased gonadotropins due to a hypothalamic defect. Klb is expressed in the postnatal hypothalamus including GnRH neurons. FGF21 reaches GnRH neurons via fenestrated capillaries in the hypothalamus in vivo and enhances GnRH release in median eminence explants in vitro . Graphical Abstract Defects in FGF21/KLB/FGFR1 signaling contribute to GnRH deficiency in both humans and mice. This signaling pathway is a novel link between metabolism and reproduction.

Background Rare disease patients are geographically dispersed, posing challenges to research. Some researchers have partnered with patient organizations and used web-based approaches to overcome geographic recruitment barriers. Critics of such methods claim that samples are homogenous and do not represent the broader patient population—as patients recruited from patient organizations are thought to have high levels of needs. We applied latent class mixture modeling (LCMM) to define patient clusters based on underlying characteristics. We used previously collected data from a cohort of patients with congenital hypogonadotropic hypogonadism who were recruited online in collaboration with a patient organization. Patient demographics, clinical information, Revised Illness Perception Questionnaire (IPQ-R) scores and Zung self-rating depression Scale (SDS) were used as variables for LCMM analysis. Specifically, we aimed to test the classic critique that patients recruited online in collaboration with a patient organization are a homogenous group with high needs. We hypothesized that distinct classes (clinical profiles) of patients could be identified—thereby demonstrating the validity of online recruitment and supporting transferability of findings. Results In total, 154 patients with CHH were included. The LCMM analysis identified three distinct subgroups (Class I: n = 84 [54.5%], Class II: n = 41 [26.6%], Class III: n = 29 [18.8%]) that differed significantly in terms of age, education, disease consequences, emotional consequences, illness coherence and depression symptoms (all p  < 0.001) as well as age at diagnosis ( p  = 0.045). Classes depict a continuum of psychosocial impact ranging from severe to relatively modest. Additional analyses revealed later diagnosis (Class I: 19.2 ± 6.7 years [95% CI 17.8–20.7]) is significantly associated with worse psychological adaptation and coping as assessed by disease consequences, emotional responses, making sense of one’s illness and SDS depressive symptoms (all p  < 0.001). Conclusions We identify three distinct classes of patients who were recruited online in collaboration with a patient organization. Findings refute prior critiques of patient partnership and web-based recruitment for rare disease research. This is the first empirical data suggesting negative psychosocial sequelae of later diagnosis (“diagnostic odyssey”) often observed in CHH.

This study aims to determine clusters of access to healthcare among adults with rare diseases in Switzerland, identify associated individual characteristics of access, and impact on health-related quality of life (HRQoL). Swiss adults ( = 341) diagnosed with a rare disease completed an online survey including the Perception of Access to Healthcare Questionnaire (PAHQ) and Short Form Health Survey (SF-12). We employed partition around medoids algorithm to identify patient clusters based on the PAHQ. Various sociodemographic/disease-related factors and HRQoL were assessed. We identified two patient clusters: higher ( = 227) and lower access ( = 114). Significantly associated with lower access were an unstable disease course ( < 0.05), increased number of misdiagnoses ( < 0.05), and diseases affecting the nervous system ( < 0.01). Membership in the lower access cluster was significantly associated with worse HRQoL ( < 0.05). Findings highlight the need for comprehensive assessment of healthcare access in adults with rare diseases and identifies potential targets for tailored interventions.

Purpose The purpose of this study was to explore the acceptance of a novel role, the advanced practice nurse in lung cancer (APNLC), from the perspective of patients and healthcare professionals in a country lacking a regulatory oversight for advanced practice nursing (APN) roles. Methods and Design This study utilized a qualitative methodology using focus groups and semistructured interviews. Participants were purposively sampled in a Swiss academic medical center. Two focus groups were conducted: the first included nurses (n = 5) and the social worker, while the second targeted physicians (n = 6). The APNLC and patients (n = 4) were interviewed using semistructured interviews. Data were analyzed using thematic content analysis. Findings Three main themes were identified: APNLC role identification, APNLC role‐specific contributions, and APNLC flexible service. Physicians and patients clearly recognized the APNLC role, noting contributions to continuity of care, psychosocial support, and enabling symptom self‐management. Nurses perceived the APNLC role as overlapping with the oncology nurse role. Flexibility in providing care was seen as the strength of the APNLC role, yet this also posed organizational challenges. Conclusions The new role appears to be well accepted by patients and physicians, yet barriers posed by nursing colleagues remain challenging. Clinical Relevance Based on existing literature and the present findings, we propose a model to guide future implementation and enhance acceptance of the APNLC role. This model comprises three actions: (a) formalizing nursing role expectations, (b) providing appropriate support and resources, and (c) promoting a national plan for APN regulation.

Background The American College of Obstetricians and Gynecologists recommends prenatal genetic testing (PGT) be offered to all pregnant persons regardless of known risk factors. However, significant racial/ethnic differences exist regarding acceptance of PGT contributing to disparities. Latinas (Latinx), one of the fastest growing ethnic groups in the United States, have low PGT acceptance rates. This systematic scoping review aimed to provide a landscape of existing literature on Latinx individuals’ knowledge of, preferences for, and experiences with prenatal and preconception genetic testing. Synthesizing the current state of the science may inform development of culturally tailored interventions to support high-quality PGT decisions (e.g., informed, aligned with a pregnant persons’ values). Methods We conducted a structured, systematic literature search of published articles and gray literature in electronic databases (PubMed, PsycINFO, CINAHL, Medline, Embase, Eric, Social Services Abstracts, and PsycArticles). Articles in English published prior to March 2021 were retrieved relating to genetics, pregnancy, and Latina women. Articles underwent title, abstract and full-text review by independent investigators to assess inclusion and exclusion criteria. Risk of bias was evaluated by two investigators. Iterative thematic analysis was employed to group study findings into themes to identify possible targets for interventions. Results The search generated 5511 unique articles. After title screening, 335 underwent abstract review and subsequently 61 full-text review. Twenty-eight studies met inclusion criteria and 7 additional studies were included after reviewing reference lists. Three overarching themes emerged: genetic knowledge/literacy (26/35, 74%), provider (mis)communication/patient satisfaction (21/35, 60%), and cross-cultural beliefs (12/35, 34%). Studies indicate discordant patient-provider language (n = 5), miscommunication (n = 4), and lack of concordant decision-making (n = 4) pose barriers to high-quality PGT decisions. Immigration status (n = 1) and religious beliefs (n = 5) are additional factors influencing PGT decisions. Conclusions Identified studies suggest that cultural and linguistic factors affect Latinx PGT decision-making. Latinx individual’s comprehension and recall of PGT information is enhanced by culturally and linguistically concordant providers—suggesting that culturally-informed interventions may enhance PGT acceptability and support high-quality decisions. Future directions to surmount PGT disparities may include community health workers and cultural brokers to empower Latinx people to make informed decisions aligned with their values and preferences. Plain language summary Significant racial, ethnic, and language disparities exist in prenatal genetic testing (PGT). Latina (Latinx) people, one of the fastest growing ethnic groups in the United States, have low acceptance rates of PGT. This scoping review provides a systematic search of the literature to better understand Latinx individuals’ knowledge of, preferences for, and experiences with PGT. Eight electronic data bases were systematically searched and identified articles underwent title, abstract, full text, and reference review. Iterative thematic analysis was conducted to group article findings into themes. Thirty-five studies met inclusion criteria and three overarching themes were identified: genetic knowledge/literacy, provider (mis)communication/patient satisfaction, and cross-cultural beliefs. Findings indicate that discordant patient-provider decision making and language and patient provider miscommunication pose barriers to high-quality PGT decisions. Latinx individuals’ understanding and recall of PGT information is improved when delivered in a culturally and linguistically concordant manner. This suggests culturally-informed interventions, including the use of community health workers or cultural brokers, may enhance PGT acceptability and support high quality pregnancy decisions.

Type 1 diabetes mellitus (T1DM) in children and adolescents is associated with significant cardiovascular morbidity and mortality. Early detection of vascular dysfunction is key to patient management yet current assessment techniques are invasive and not suitable for pediatric patient populations. A novel approach using isometric handgrip exercise during magnetic resonance imaging (IHE-MRI) has recently been developed to evaluate coronary endothelial function non-invasively in adults. This project aimed to assess endothelium-dependent coronary arterial response to IHE-MRI in children with T1DM and in age matched healthy controls. Healthy volunteers and children with T1DM (>5 years) were recruited. IHE-MRI cross-sectional coronary artery area measurements were recorded at rest and under stress. Carotid intima media thickness (CIMT) and aortic pulse wave velocity (PWV) were assessed for comparison. Student's t-tests were used to compare results between groups. Seven children with T1DM (3 female, median 14.8 years, mean 14.8 ± 1.9 years) and 16 healthy controls (7 female, median 14.8 years, mean 14.2 ± 2.4 years) participated. A significant increase in stress-induced cross-sectional coronary area was measured in controls (5.4 mm2 at rest to 6.39 mm2 under stress, 18.8 ± 10.7%, p = 0.0004). In contrast, mean area change in patients with T1DM was not significant (7.17 mm2 at rest to 7.59 mm2 under stress, 10.5% ± 28.1%, p = n.s.). There was no significant difference in the results for neither PWV nor CIMT between patients and controls, (5.3±1.5 m/s vs.4.8±0.7 m/s and 0.4±0.03mm vs.0.46 mm ± 0.03 respectively, both p = n.s.). Our pilot study demonstrates the feasibility of using a totally non-invasive IHE-MRI technique in children and adolescents with and without T1DM. Preliminary results suggest a blunted endothelium-dependent coronary vasomotor function in children with T1DM (>5 years). Better knowledge and new methodologies may improve surveillance and care for T1DM patients to reduce cardiovascular morbidity and mortality.

OBJECTIVE:-- The goal of this study was to examine the relationship between serum testosterone levels and insulin sensitivity and mitochondrial function in men. RESEARCH DESIGN AND METHODS--A total of 60 men (mean age 60.5 ± 1.2 years) had a detailed hormonal and metabolic evaluation. Insulin sensitivity was measured using a hyperinsulinemic-euglycemic clamp. Mitochondrial function was assessed by measuring maximal aerobic capacity (VO[subscript 2max]) and expression of oxidative phosphorylation genes in skeletal muscle. RESULTS:--A total of 45% of subjects had normal glucose tolerance, 20% had impaired glucose tolerance, and 35% had type 2 diabetes. Testosterone levels were positively correlated with insulin sensitivity (r = 0.4, P < 0.005). Subjects with hypogonadal testosterone levels (n = 10) had a BMI >25 kg/m² and a threefold higher prevalence of the metabolic syndrome than their eugonadal counterparts (n = 50); this relationship held true after adjusting for age and sex hormone-binding globulin but not BMI. Testosterone levels also correlated with VO[subscript 2max] (r = 0.43, P < 0.05) and oxidative phosphorylation gene expression (r = 0.57, P < 0.0001). CONCLUSIONS:--These data indicate that low serum testosterone levels are associated with an adverse metabolic profile and suggest a novel unifying mechanism for the previously independent observations that low testosterone levels and impaired mitochondrial function promote insulin resistance in men.