Living with a blood cancer in later life: The complex challenges and related support needs of adults aged 75 and older.

OBJECTIVES: This study investigated the challenges and support needs of adults aged 75 and older during and after treatment for a blood cancer to aid targeted supportive resource development. METHODS: Adults aged 75 and older with a blood cancer participated in in-depth, semi-structured interviews about challenges and unmet support needs. Participants recruited through The Leukemia & Lymphoma Society were (1) in treatment or previously in treatment for a blood cancer at age 75 or older and (2) living in the United States or its territories. A thematic analysis was conducted with findings compared between 2 groups: (1) chronic -living with a chronic blood cancer; (2) acute -living with an acute blood cancer or both an acute and chronic blood cancer. RESULTS: Participants (n = 50) ranged from 75 to 91 years old. Both groups described similar experiences and identified 5 challenges and support needs: (1) socioemotional impact, (2) activities of daily living and instrumental activities of daily living (ADLs/iADLs), (3) uncertainty management, (4) treatment-related stressors, and (5) COVID-19-related strain. Properties for these themes illustrate challenges and support needs, with some differences between groups. For instance, those living with a chronic blood cancer highlighted financial strain with treatment-related stressors, while those with an acute blood cancer focused more on iADLs. SIGNIFICANCE OF RESULTS: Findings inform an agenda for targeted resource development for older adults with a blood cancer nearing the end of the life span. Results demonstrate the need for supportive services and family communication interventions to help patients manage iADLs and navigate socioemotional needs and challenges.

Communicating risk to promote colorectal cancer screening: a multi-method study to test tailored versus targeted message strategies.

Colorectal cancer (CRC) screening rates are suboptimal, partly due to poor communication about CRC risk. More effective methods are needed to educate patients, but little research has examined best practices for communicating CRC risk. This multi-method study tests whether tailoring CRC risk information increases screening intentions. Participants (N = 738) were randomized with a 2:2:1 allocation to tailored, targeted, and control message conditions. The primary outcome was intention to screen for CRC (yes/no). Additional variables include perceived message relevance, perceived susceptibility to CRC, and free-text comments evaluating the intervention. A chi-square test determined differences in the proportion of participants who intended to complete CRC screening by condition. A logistic-based path analysis explored mediation. Free-text comments were analyzed using advanced topic modeling analysis. CRC screening intentions were highest in the tailored intervention and significantly greater than control (P = 0.006). The tailored message condition significantly increased message relevance compared with control (P = 0.027) and targeted conditions (P = 0.002). The tailored condition also increased susceptibility (P < 0.001) compared with control, which mediated the relationship between the tailored condition and intention to screen (b = 0.04, SE = 0.02, 95% confidence interval = 0.02, 0.09). The qualitative data reflect similar trends. The theoretical mechanisms and practical implications of tailoring health education materials about CRC risk are discussed.

Structure and function of Norrin in assembly and activation of a Frizzled 4-Lrp5/6 complex.

Norrin is a cysteine-rich growth factor that is required for angiogenesis in the eye, ear, brain, and female reproductive organs. It functions as an atypical Wnt ligand by specifically binding to the Frizzled 4 (Fz4) receptor. Here we report the crystal structure of Norrin, which reveals a unique dimeric structure with each monomer adopting a conserved cystine knot fold. Functional studies demonstrate that the novel Norrin dimer interface is required for Fz4 activation. Furthermore, we demonstrate that Norrin contains separate binding sites for Fz4 and for the Wnt ligand coreceptor Lrp5 (low-density lipoprotein-related protein 5) or Lrp6. Instead of inducing Fz4 dimerization, Norrin induces the formation of a ternary complex with Fz4 and Lrp5/6 by binding to their respective extracellular domains. These results provide crucial insights into the assembly and activation of the Norrin-Fz4-Lrp5/6 signaling complex.

Perspectives of preschool children in England with speech and language needs in the development of evidence-based activities.

BACKGROUND: The existing evidence is limited in terms of perspectives of preschool children with speech and language needs and their views on activities used to support their needs. This paper discusses a stream of work from the interdisciplinary research programme known as "Child Talk," based in England, UK. The overall purpose of this work stream was to gain the perspectives of preschool children aged 2 to 5 years and 11 months, with speech and language needs, to use in the development of an evidence-based framework of activities. METHODS: Twenty-four preschool children with a variety of needs from diverse backgrounds took part. An observational methodology was used to capture children's experiences. Children were filmed during a series of sessions, with innovative head-mounted cameras worn by the children and supported by researcher field notes. Framework analysis was used to analyse the data based on the body movement, vocalization, and visual attention of the children during these sessions. RESULTS AND CONCLUSIONS: Results included that children expressed enjoyment and engagement in the activities. The children expressed themselves and demonstrated their focus "multimodally" through combinations of body language, vocalization, and visual attention. These modalities were present across all contexts and children. It highlights the importance of encouraging participation in preschool children and consequently this innovative piece of work has national and international importance.

Speech therapy for children with dysarthria acquired before three years of age.

BACKGROUND: Children with motor impairments often have the motor speech disorder dysarthria, a condition which effects the tone, strength and co-ordination of any or all of the muscles used for speech. Resulting speech difficulties can range from mild, with slightly slurred articulation and breathy voice, to profound, with an inability to produce any recognisable words. Children with dysarthria are often prescribed communication aids to supplement their natural forms of communication. However, there is variation in practice regarding the provision of therapy focusing on voice and speech production. Descriptive studies have suggested that therapy may improve speech, but its effectiveness has not been evaluated. OBJECTIVES: To assess whether any speech and language therapy intervention aimed at improving the speech of children with dysarthria is more effective in increasing children's speech intelligibility or communicative participation than no intervention at all , and to compare the efficacy of individual types of speech language therapy in improving the speech intelligibility or communicative participation of children with dysarthria. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2015 , Issue 7 ), MEDLINE, EMBASE, CINAHL , LLBA, ERIC, PsychInfo, Web of Science, Scopus, UK National Research Register and Dissertation Abstracts up to July 2015, handsearched relevant journals published between 1980 and July 2015, and searched proceedings of relevant conferences between 1996 to 2015. We placed no restrictions on the language or setting of the studies. A previous version of this review considered studies published up to April 2009. In this update we searched for studies published from April 2009 to July 2015. SELECTION CRITERIA: We considered randomised controlled trials and studies using quasi-experimental designs in which children were allocated to groups using non-random methods. DATA COLLECTION AND ANALYSIS: One author (LP) conducted searches of all databases, journals and conference reports. All searches included a reliability check in which a second review author independently checked a random sample comprising 15% of all identified reports. We planned that two review authors would independently assess the quality and extract data from eligible studies. MAIN RESULTS: No randomised controlled trials or group studies were identified. AUTHORS' CONCLUSIONS: This review found no evidence from randomised trials of the effectiveness of speech and language therapy interventions to improve the speech of children with early acquired dysarthria. Rigorous, fully powered randomised controlled trials are needed to investigate if the positive changes in children's speech observed in phase I and phase II studies are generalisable to the population of children with early acquired dysarthria served by speech and language therapy services. Research should examine change in children's speech production and intelligibility. It must also investigate children's participation in social and educational activities, and their quality of life, as well as the cost and acceptability of interventions.

Comparing Wise Pattern to Non-Wise Pattern Skin Sparing Mastectomy: A Critical Evaluation of Patient Demographics and Surgical Outcomes.

BACKGROUND: Multiple skin-sparing incisions are utilized in immediate post-mastectomy breast reconstruction; however, the Wise pattern incision (WPI) may have superior cosmetic outcomes for large ptotic breasts compared to non-Wise pattern incisions (NWPI). We evaluated patient demographics and surgical outcomes with WPI versus NWPI. METHODS: An electronic medical record search was performed for patients at a single academic institution from 2019 to 2022 with ICD-10-CM diagnosis code "Z42.1: encounter for breast reconstruction following mastectomy." Retrospective chart review evaluated patient demographics, intraoperative factors, postoperative complications, and surgical cost. RESULTS: 288 patients were included; 58 had WPI and 230 had NWPI. Median BMI differed between WPI (30.5) and NWPI (26.4) (P < 0.001). 57% of WPI had preoperative grade 3 ptosis versus 23% of NWPI (P < 0.001). No difference was found in median operative times (WPI: 219 minutes, NWPI: 194 minutes, P = 0.38). Overall rates of postoperative complications differed between WPI (62%) and NWPI (45%) on univariate, but not multivariate, analysis. Median total surgery charge was higher for WPI (WPI: $36,223, NWPI: $31,185, P < 0.001), while implant cost was higher for NWPI (WPI: $2,700, NPWI: $8,040, P < 0.001). CONCLUSIONS: There was no significant difference in operative time, overall complication rate, or charge between incision types once adjusted for confounding factors. The higher complication rate in the WPI group was likely driven by higher BMI, a known risk factor for surgical complications regardless of approach. Surgeons can consider WPI as a noninferior option for patients with higher BMI and ptosis.

Youth mental health care use during the COVID-19 pandemic in Alberta, Canada: an interrupted time series, population-based study.

BACKGROUND: During the COVID-19 pandemic, youth had rising mental health needs and changes in service accessibility. Our study investigated changes in use of mental health care services for Canadian youth in Alberta before and during the COVID-19 pandemic. We also investigated how youth utilization patterns differed for subgroups based on social factors (i.e., age, gender, socioeconomic status, and geography) previously associated with health care access. METHODS: We used cross-sectional population-based data from Alberta, Canada to understand youth (15-24 year) mental health care use from 2018/19 to 2021/22. We performed interrupted time series design, segmented regression modeling on type of mental health care use (i.e., general physician, psychiatrist, emergency room, and hospitalization) and diagnosis-related use. We also investigated the characteristics of youth who utilized mental health care services and stratified diagnosis-related use patterns by youth subgroups. RESULTS: The proportion of youth using mental health care significantly increased from 15.6% in 2018/19 to 18.8% in 2021/22. Mental health care use showed an immediate drop in April 2020 when the COVID-19 pandemic was declared and public health protections were instituted, followed by a steady rise during the next 2 years. An increase was significant for general physician and psychiatrist visits. Most individual diagnoses included in this study showed significant increasing trends during the pandemic (i.e., anxiety, adjustment, ADHD, schizophrenia, and self-harm), with substance use showing an overall decrease. Mortality rates greatly increased for youth being seen for mental health reasons from 71 per 100,000 youth in 2018/19 to 163 per 100,000 in 2021/22. In addition, there were clear shifts over time in the characteristics of youth using mental health care services. Specifically, there was increased utilization for women/girls compared to men/boys and for youth from wealthier neighborhoods. Increases over time in the utilization of services for self-harm were limited to younger youth (15-16 year). CONCLUSIONS: The study provides evidence of shifts in mental health care use during the COVID-19 pandemic. Findings can be used to plan for ongoing mental health needs of youth, future pandemic responses, and other public health emergencies.

Persons living with dementia and caregivers' communication preferences for receiving a dementia diagnosis.

Objective: As the number of individuals diagnosed with dementia increases, so does the need to understand the preferences of persons living with dementia (PLWD) and caregivers for how clinicians can deliver a dementia diagnosis effectively, which can be a difficult process. This study describes the diagnostic communication preferences of PLWD and caregivers. Methods: We conducted semi-structured individual phone interviews with two groups: PLWD who were diagnosed in the past two years (n = 11) and family caregivers of PLWD (n = 19) living in Florida. PLWD and caregivers were not recruited/enrolled as dyads. Results: The groups' communication preferences were largely similar. Data were analyzed thematically into five themes: communicate the diagnosis clearly, meet information needs, discuss PLWD/caregiver resources, prepare for continued care, and communicate to establish and maintain relationships. Conclusion: Participants wanted clear communication, information, and support, but differed in some details (e.g. the language used to describe the diagnosis and the amount/type of desired information). Clinicians can apply general principles but will need to tailor them to individual preferences of PLWD and caregivers. Innovation: Limited research has elicited PLWD and caregivers' communication preferences for receiving dementia diagnoses, particularly through an individualized data collection method allowing for richer descriptions and deeper understanding.

Educating Hematology-Oncology Fellows About How to Communicate with Patients About Clinical Trials: A Needs Assessment.

Objectives: Only 5-8% of adults with cancer participate in cancer clinical trials (CCTs), with even lower rates among underrepresented groups. Improving oncologists' communication skills may enhance the frequency and quality of their discussions with patients about CCTs, consequently increasing participation. However, little is known about interest in or presence of CCT-related communication training during Hematology-Oncology (Hem-Onc) fellowships. This study aimed to describe, from the perspective of Hem-Onc fellowship program directors (PDs): (1) the current landscape of CCT education for Hem-Onc fellows; (2) the acceptability and feasibility of implementing a CCT communication skills workshop for Hem-Onc fellows. Methods: We used an explanatory sequential mixed-methods approach. PDs were surveyed and interviewed about their graduate medical education (GME) programs' current CCT curriculum, training challenges, fellows' CCT knowledge and CCT communication skills, and preferences for a CCT communication workshop. Results: PDs were surveyed (n = 40) and interviewed (n = 12). PDs reported that their institutions prioritize CCT accrual (M = 4.58, SD = .78; 1-5 scale, 5 = "Strongly Agree") and clinical research training (M = 4.20, SD = .85). CCT skills that programs least often addressed were how to (1) discuss CCTs with newly diagnosed patients, (2) talk to patients about CCTs when none are available, and (3) help patients find CCTs at other institutions. PDs were interested in a CCT communication workshop for fellows ("yes" = 67.5%, "maybe" = 32.5%) and said training would be feasible (M = 4.28, SD = .78) and useful (M = 4.47, SD = .78). Qualitative results described programs' current approaches to CCT education and insights about developing and implementing CCT communication training. Conclusions: There is a clear need to improve CCT communication skills training in Hem-Onc fellowship programs and to implement and scale such training to increase CCT participation, especially among diverse patient populations. Furthermore, Hem-Onc GME PDs view such training as feasible and useful.

Understanding the Impact of COVID-19 on Chronic Lymphocytic Leukemia (CLL) Caregiving and Related Resource Needs.

Chronic lymphocytic leukemia (CLL) caregivers play a central role in disease management-a role that has been heightened during the COVID-19 pandemic given the healthcare system's reliance on frontline family caregivers and CLL patients' increased risk of infection and mortality. Using a mixed-method design, we investigated the impact of the pandemic on CLL caregivers (Aim 1) and their perceived resource needs (Aim 2): 575 CLL caregivers responded to an online survey; 12 spousal CLL caregivers were interviewed. Two open-ended survey items were thematically analyzed and compared with interview findings. Aim 1 results showed that two years into the pandemic, CLL caregivers continue to struggle with coping with distress, living in isolation, and losing in-person care opportunities. Caregivers described experiencing increasing caregiving burden, realizing the vaccine may not work or didn't work for their loved one with CLL, feeling cautiously hopeful about EVUSHELD, and dealing with unsupportive/skeptical individuals. Aim 2 results indicate that CLL caregivers needed reliable, ongoing information about COVID-19 risk, information about and access to vaccination, safety/precautionary measures, and monoclonal infusions. Findings illustrate ongoing challenges facing CLL caregivers and provide an agenda to better support the caregivers of this vulnerable population during the COVID-19 pandemic.

Can virtual human clinicians help close the gap in colorectal cancer screening for rural adults in the United States? The influence of rural identity on perceptions of virtual human clinicians.

Rural adults experience disparities in colorectal cancer screening, a trend even more distinct among rural Black adults. Healthcare disruptions caused by COVID-19 exacerbated inequities, heightening attention on virtual communication strategies to increase screening. Yet little is known about how rural adults perceive virtual human clinicians (VHCs). Given that identifying as rural influences perceived source credibility often through appearance judgments, the goal of this pilot was to explore how to develop VHCs that individuals highly identified with rurality find attractive. Between November 2018 and April 2019, we tested a culturally tailored, VHC-led telehealth intervention delivering evidence-based colorectal cancer prevention education with White and Black adults (N = 2079) in the United States recruited through an online panel who were non-adherent to screening guidelines and between 50 and 73 years of age. Participants were randomized on three factors (VHC race-matching, VHC gender-matching, Intervention type). Ordinal logistic regression models examined VHC appearance ratings. Participants with a high rural identity (AOR = 1.12, CI = [1.02, 1.23], p =.02) rated the VHCs more attractive. High rural belonging influenced VHC attractiveness for Black participants (AOR = 1.22, CI = [1.03, 1.44], p =.02). Also, Black participants interacting with a Black VHC and reporting high rural self-concept rated the VHC as more attractive (AOR = 2.22, CI = [1.27, 3.91], p =.01). Findings suggest adults for whom rural identity is important have more positive impressions of VHC attractiveness. For patients with strong rural identities, enhancing VHC appearance is critical to tailoring colorectal cancer prevention interventions.

Dimeric arrangement of the parathyroid hormone receptor and a structural mechanism for ligand-induced dissociation.

The parathyroid hormone receptor (PTH1R) is a class B G protein-coupled receptor that is activated by parathyroid hormone (PTH) and PTH-related protein (PTHrP). Little is known about the oligomeric state of the receptor and its regulation by hormone. The crystal structure of the ligand-free PTH1R extracellular domain (ECD) reveals an unexpected dimer in which the C-terminal segment of both ECD protomers forms an alpha-helix that mimics PTH/PTHrP by occupying the peptide binding groove of the opposing protomer. ECD-mediated oligomerization of intact PTH1R was confirmed in living cells by bioluminescence and fluorescence resonance energy transfer experiments. As predicted by the structure, PTH binding disrupted receptor oligomerization. A receptor rendered monomeric by mutations in the ECD retained wild-type PTH binding and cAMP signaling ability. Our results are consistent with the hypothesis that PTH1R forms constitutive dimers that are dissociated by ligand binding and that monomeric PTH1R is capable of activating G protein.

Structural basis for parathyroid hormone-related protein binding to the parathyroid hormone receptor and design of conformation-selective peptides.

Parathyroid hormone (PTH) and PTH-related protein (PTHrP) are two related peptides that control calcium/phosphate homeostasis and bone development, respectively, through activation of the PTH/PTHrP receptor (PTH1R), a class B G protein-coupled receptor. Both peptides hold clinical interest for their capacities to stimulate bone formation. PTH and PTHrP display different selectivity for two distinct PTH1R conformations, but how their binding to the receptor differs is unclear. The high resolution crystal structure of PTHrP bound to the extracellular domain (ECD) of PTH1R reveals that PTHrP binds as an amphipathic alpha-helix to the same hydrophobic groove in the ECD as occupied by PTH, but in contrast to a straight, continuous PTH helix, the PTHrP helix is gently curved and C-terminally "unwound." The receptor accommodates the altered binding modes by shifting the side chain conformations of two residues within the binding groove: Leu-41 and Ile-115, the former acting as a rotamer toggle switch to accommodate PTH/PTHrP sequence divergence, and the latter adapting to the PTHrP curvature. Binding studies performed with PTH/PTHrP hybrid ligands having reciprocal exchanges of residues involved in different contacts confirmed functional consequences for the altered interactions and enabled the design of altered PTH and PTHrP peptides that adopt the ECD-binding mode of the opposite peptide. Hybrid peptides that bound the ECD poorly were selective for the G protein-coupled PTH1R conformation. These results establish a molecular model for better understanding of how two biologically distinct ligands can act through a single receptor and provide a template for designing better PTH/PTHrP therapeutics.

Internet delivery of intensive speech and language therapy for children with cerebral palsy: a pilot randomised controlled trial.

OBJECTIVES: To test the feasibility of recruitment, retention, outcome measures and internet delivery of dysarthria therapy for young people with cerebral palsy in a randomised controlled trial. DESIGN: Mixed methods. Single blind pilot randomised controlled trial, with control offered Skype therapy at end of study. Qualitative study of the acceptability of therapy delivery via Skype. SETTING: Nine speech and language therapy departments in northern England recruited participants to the study. Skype therapy was provided in a university setting. PARTICIPANTS: Twenty-two children (14 M, 8 F) with dysarthria and cerebral palsy (mean age 8.8 years (SD 3.2)) agreed to take part. Participants were randomised to dysarthria therapy via Skype (n=11) or treatment as usual (n=11). INTERVENTIONS: Children received either usual speech therapy from their local therapist for 6 weeks or dysarthria therapy via Skype from a research therapist. Usual therapy sessions varied in frequency, duration and content. Skype dysarthria therapy focused on breath control and phonation to produce clear speech at a steady rate, and comprised three 40 min sessions per week for 6 weeks. PRIMARY AND SECONDARY OUTCOME MEASURES: Feasibility and acceptability of the trial design, intervention and outcome measures. RESULTS: Departments recruited two to three participants. All participants agreed to random allocation. None withdrew from the study. Recordings of children's speech were made at all time points and rated by listeners. Families allocated to Skype dysarthria therapy judged internet delivery of the therapy to be acceptable. All families reported that the study design was acceptable. Treatment integrity checks suggested that the phrases practised in one therapy exercise should be reduced in length. CONCLUSIONS: A delayed treatment design, in which dysarthria therapy is offered at the end of the study to families allocated to treatment as usual, is acceptable. A randomised controlled trial of internet delivered dysarthria therapy is feasible.

Molecular recognition of corticotropin-releasing factor by its G-protein-coupled receptor CRFR1.

The bimolecular interaction between corticotropin-releasing factor (CRF), a neuropeptide, and its type 1 receptor (CRFR1), a class B G-protein-coupled receptor (GPCR), is crucial for activation of the hypothalamic-pituitary-adrenal axis in response to stress, and has been a target of intense drug design for the treatment of anxiety, depression, and related disorders. As a class B GPCR, CRFR1 contains an N-terminal extracellular domain (ECD) that provides the primary ligand binding determinants. Here we present three crystal structures of the human CRFR1 ECD, one in a ligand-free form and two in distinct CRF-bound states. The CRFR1 ECD adopts the alpha-beta-betaalpha fold observed for other class B GPCR ECDs, but the N-terminal alpha-helix is significantly shorter and does not contact CRF. CRF adopts a continuous alpha-helix that docks in a hydrophobic surface of the ECD that is distinct from the peptide-binding site of other class B GPCRs, thereby providing a basis for the specificity of ligand recognition between CRFR1 and other class B GPCRs. The binding of CRF is accompanied by clamp-like conformational changes of two loops of the receptor that anchor the CRF C terminus, including the C-terminal amide group. These structural studies provide a molecular framework for understanding peptide binding and specificity by the CRF receptors as well as a template for designing potent and selective CRFR1 antagonists for therapeutic applications.