Caregivers' perspectives of community acceptance before and after surgical treatment for their child's disability.

In Tanzania, about 600 000 youth between 5 and 24 years old have a disability. Individuals with disabilities face numerous obstacles due to social stigma. The aim of this formative evaluation is to assess how caregivers of children with correctable disabilities (e.g., cleft lip/palate, club foot, and burn scar contractures) in Tanzania perceive their community's acceptance of their child before and after surgical treatment. Semi-structured interviews were conducted with 80 caregivers of children with disabilities treated at Kafika House in Arusha, Tanzania. The constant comparative method identified themes regarding the caregivers' feelings on their child's functional abilities and experiences of stigma in their community. Caregiver perceptions of stigma before and after surgical treatment were categorized and quantified as 'positive', 'neutral' and 'negative'. Thematic analysis of the 80 interviews resulted in five major themes: (1) stigma and acceptance (pre-treatment) and (2) post-treatment; (3) functional abilities (pre-treatment) and (4) post-treatment; and (5) emotional impact (pre- and post-treatment). These themes indicate caregivers and their children experience a range of emotional impacts before and after treatment, more severe stigma before treatment, and overall better social, emotional and functional status after treatment. Frequency analysis of caregiver experiences indicated that stigma experienced by children and their families decreased from 75% before surgical treatment to 2.5% after surgery. Surgical intervention and rehabilitation of physical disabilities mitigated experiences of social stigma for both children and their caregivers. Findings support the need for expanded treatment of correctable disabilities, larger investments in community-based rehabilitation programmes and further interventions to support stigmatized parents and their children.

Nursing and Medical Students' Responses About End-of-Life Communication Reveal Educational Opportunities for Spiritual Care.

BACKGROUND: The need for improved spiritual care education is a national directive, prompting many nursing and medical education programs to respond with spiritual curriculum. This article reports on research that tested an educational intervention to enhance nursing and medical students' understanding of end-of-life communication with families. METHOD: This mixed-methods study included three reflection questions to ascertain students' attitudes about their own death and dying. RESULTS: Many of the students' responses were spiritual in nature. Findings revealed two important misconceptions about death and one educational strategy that can be used to help students identify potential sources of spiritual discomfort in clinical situations. CONCLUSION: The findings offer a glimpse into the attitudes and beliefs of nursing and medical students that could influence how they view and deliver spiritual care, contributing to the evidence base for spiritual care education and curriculum. [J Nurs Educ. 2023;62(11):601-605.].

Decreasing Missed Appointments at a Community Health Center: A Community Collaborative Project.

Introduction: Missed appointments are a problem for health care systems, causing lost revenue and concern for poor health outcomes. This is particularly true at Community Health Centers (CHCs), where clients may already face substantial barriers to optimal care and outcomes. Identified solutions to this problem are limited, and often focus on reminder calls and messages to clients. Methods: This project utilized a unique academic/CHC collaboration to investigate and initiate solutions to their high missed appointment rates. Client phone calls to determine clinic specific needs, monthly team meetings to brainstorm and choose initiatives, engaging stake holders, and phased implementation were the tools used to address the high missed appointment rates within the limitations of the clinic resources available. Results: Within one quarter, missed appointment rates at the clinic dropped by 6%-17% for different appointment types. Conclusion: While the project was interrupted due to the pandemic, early outcomes were promising and the model may be helpful to other CHCs with similar concerns.

Community-based intervention to reduce stigma for children with disabilities in Lusaka, Zambia: a pilot.

PURPOSE: This pilot intervention aims to reduce stigma towards children with disabilities living in family-based care. MATERIALS AND METHODS: Kusamala + is a pre-post evaluation of a pilot community-based intervention in two low-income compounds in Lusaka, Zambia. Door-to-door canvassing and community referrals were used to identify and enroll children with disabilities. Parents/guardians and community members completed surveys regarding stigma and support. Health professionals supervised, trained, and provided ongoing support for 2-3 community caregivers (CCGs). CCG's provided home-based education, referrals, playgroups, and social support for 20-25 families each. Community events were held at health facilities, churches and community spaces to reduce community-level stigma towards children with disabilities. RESULTS: Staff identified 632 children with disabilities. Staff completed over 4500 home visits, 288 children joined playgroups, made 775 referrals, and over 23,000 attended community sensitization events. Longitudinal data was available for 129 families with a child with a disability. Over one year, families and community members reported less perceived rejection by family and peers but less agreement that children with disabilities should be treated the same as other children. CONCLUSION: Kusamala + was a feasible, acceptable and broad reach with limited program impact. Future work will incorporate lessons learned with a focus on sustainability and scalability.Implications for rehabilitationChildren with disability are often hidden and isolated in low- and middle-income countries (LMIC), particularly in low-resource communities.Stigma towards children with disabilities continues in LMIC and further reduces that child's ability to engage fully in social and civic life.Community- and home-based programming is a feasible and acceptable approach to engaging with community and families with a child with a disability.The identification and referral of additional children with disabilities to physiotherapy and other government services can provide additional strain on already limited resources.Once a pilot program is deemed acceptable and feasible, any further design planning must include considerations for sustainability and scalability.System strengthening is a key component of sustainability and scalability to ensure success in planning, implementation, monitoring and evaluation.

Using community-based interventions to reduce public stigma of children with disabilities: A feasibility study.

BACKGROUND: Public stigma, or negative community-held beliefs, about children with disabilities (CWDs) often leads to negative outcomes for CWD and their families. This study considers the effectiveness of four community-level interventions to reduce public stigma in two Lusaka, Zambia communities. METHODS: This feasibility study describes four community-based interventions to provide education to consider whether perceptions of attitudes and stigma towards CWD changed after implementing four educational interventions. RESULTS: Results revealed that these interventions were achievable. Preliminary multiple regression analyses indicated a significant impact of attending an event on the attitude scale, while no effect on the stigma scale. Presence at multiple anti-stigma events exhibited no effect for the stigma scale, while the attitude scale showed significance. DISCUSSION: This study builds on the limited research available in low-income countries to reduce public stigma towards CWD, with the hope of enhance quality of life for CWD and their families.

Development and evaluation of an interprofessional community health course in Zambia.

Persistent global health inequities and workforce shortage require innovative strategies to prepare professionals for teamwork in a global context. Over two years, students (n = 33) from education, nursing, occupational therapy, public health, and physical therapy participated in a course in Zambia that emphasized interprofessional collaborative practice (IPP), cultural fluency, and understanding ecological approaches to health. Faculty measured the learning outcomes of the course using the Interprofessional Education Collaborative (IPEC) Competency Self-Assessment Tool (pre and posttest), and a focus group to gain a deeper understanding of the student experience and course effectiveness. The Beliefs, Events and Values Inventory (BEVI) was used post trip to determine feasibility of distribution and response of the tool via e-mail. These preliminary results suggested that students developed skills and knowledge related to IPP, cultural fluency, and ecological approaches to health. Specifically, students acknowledged growth in their ability to communicate more effectively with other health professions, and ability to evaluate personal assumptions and biases toward health, healthcare, and cultural practices. The method of developing this course could be a model for other institutions wanting to grow IPP experiences for their students.

The Impact of Level of Physical Therapist Assistant Involvement on Patient Outcomes Following Stroke.

OBJECTIVE: This study investigates if higher utilization of physical therapist assistants adversely affects patient outcomes in the acute rehabilitation setting for patients following a cerebrovascular accident (CVA). METHODS: Participants were admitted to 1 of 5 inpatient rehabilitation facilities following a CVA from 2008 to 2010. High physical therapist assistant use was defined as ≥20% of the physical therapist visits being provided by the physical therapist assistant for an episode of care. Multivariable regression techniques examined differences in functional outcome, discharge location, and length of stay between high and low physical therapist assistant use groups. Propensity scoring methods supplemented findings of the regression analyses. RESULTS: Of the 1561 participants, 496 (32%) had high physical therapist assistant involvement. Baseline participant characteristics such as age, sex, baseline motor function, and comorbidities did not differ between high and low physical therapist assistant use groups. After adjusting for patient characteristics, rehabilitation facility, and year, higher physical therapist assistant use did not adversely affect functional outcome or length of stay. Fewer conclusions can be drawn regarding discharge location, although there was no significant difference in discharge location between groups with high and low physical therapist assistant utilization. Propensity scoring methods supported the findings of the regression analyses. CONCLUSIONS: Higher physical therapist assistant involvement in the rehabilitation of patients following CVA did not adversely affect functional outcome, increase length of stay, or reduce the likelihood of discharge to home from an inpatient rehabilitation facility. IMPACT: The results demonstrate the value of the physical therapist assistant in the provision of physical therapy for patients with stroke in the inpatient rehabilitation setting. Higher involvement of the physical therapist assistant may provide cost savings while maintaining patient outcomes for this setting and population.

Optimized Sleep After Brain Injury (OSABI): A Pilot Study of a Sleep Hygiene Intervention for Individuals With Moderate to Severe Traumatic Brain Injury.

Background. Disrupted sleep is common after traumatic brain injury (TBI) particularly in the inpatient rehabilitation setting where it may affect participation in therapy and outcomes. Treatment of sleep disruption in this setting is varied and largely unexamined. Objective. To study the feasibility of instituting a sleep hygiene intervention on a rehabilitation unit. Methods. Twenty-two individuals admitted to a brain injury unit were enrolled and allocated, using minimization, to either a sleep hygiene protocol (SHP) or standard of care (SOC). All participants wore actigraphs, underwent serial cognitive testing, and had light monitors placed in their hospital rooms for 4 weeks. Additionally, participants in the SHP received 30 minutes of blue-light therapy each morning, had restricted caffeine intake after noon, and were limited to 30-minute naps during the day. SHP participants had their lights out time set according to preinjury sleep time preference. Both groups were treated with the same restricted formulary of centrally acting medications. Results. Of 258 patients screened, 27 met all study inclusion criteria of whom 22 were enrolled. Nine participants in each group who had at least 21 days of treatment were retained for analysis. The protocol was rated favorably by participants, families, and staff. Actigraph sleep metrics improved in both groups during the 4-week intervention; however, only in the SHP was the change significant. Conclusions. Sleep hygiene is a feasible, nonpharmacologic intervention to treat disrupted sleep in a TBI inpatient rehabilitation setting. A larger study is warranted to examine treatment efficacy. ClinicalTrials.gov Identifier: NCT02838082.

Considerations and adaptions to the modulated arc total body irradiation technique: dosimetry description.

Total body irradiation (TBI) is a complex treatment technique, which has been slow to transition to a three-dimensional (3D) planning approach. There is limited literature available providing a detailed description on methods to plan TBI on a 3D planning system. 3D planning using the modulated arc TBI (MATBI) technique is a complex process involving a significant number of quality assurance processes and scripts, due to more than 40 treatment beams and two patient positions. This article will focus on the workflow and technical planning aspects of our institution's MATBI technique and identify reasons for modifications made to the developing institution's original MATBI approach. Included is a description of specific simulation equipment, detailed explanation of the four-stage computing process including the role of scripting to standardise and streamline what is otherwise a complex number of steps. The information provided is specific to one centre's approach but shows the fundamental planning process and demonstrates a streamlined method, which can be adapted to other planning systems. Overall, the ability to accurately represent the TBI technique in 3D on a planning system will be shown.

Disrupted sleep predicts next day agitation following moderate to severe brain injury.

Objective: Disrupted sleep is common during acute recovery from traumatic brain injury (TBI) and has been linked to daytime agitation. This study investigated the relationship among nighttime sleep efficiency (SE), total sleep time (TST), wakefulness after sleep onset (WASO), and number of wake bouts (NWB) as measured by actigraphy to observer ratings of agitation for patients with TBI who were undergoing inpatient rehabilitation. Methods: This is a retrospective, observational study of a convenience sample of 65 individuals admitted to TBI inpatient rehabilitation who were monitored with actigraphy and the Agitated Behaviour Scale (ABS) for the first 72 h. Each patient's average SE, TST, WASO, and NWB for the 72-h period was calculated using actigraphy for the rest interval from 2100 to 0700. Daily ABS scores were obtained for each day following the nighttime sleep period. Results: Patients were not significantly different on age, gender, etiology of injury, days post-injury, rehabilitation length of stay, or severity of injury as measured by length of posttraumatic amnesia (PTA). SE and TST were significantly lower for patients with agitation than for patients without agitation. Conclusions: This study suggests a relationship between disrupted sleep and agitation for patients with TBI who are undergoing inpatient rehabilitation.

Objective measures of sleep and wakefulness in patients with moderate to severe brain injury on an inpatient rehabilitation unit. Pearls and pitfalls of actigraph monitoring.

BACKGROUND: As awareness of disrupted sleep in patients with traumatic brain injury (TBI) increases so does interest in finding objective measures of sleep. As a result, many clinicians are turning to actigraphs to monitor sleep in patients with altered consciousness. Actigraphs are accelerometers which have been used in sleep research for over four decades. OBJECTIVE: The purpose of the present study was to determine the best method for scoring actigraphs in a TBI population and to describe the benefits and pitfalls of using actigraphs with patients on a brain injury rehabilitation unit. METHODS: A retrospective chart review of 43 patients compared three different ways of scoring night time rest periods: autoscoring, manual scoring, and set interval scoring for the sleep parameters of sleep efficiency, wakefulness after sleep onset, and total sleep time. Nursing compliance with using the event marker on the device to set rest period was also analyzed. RESULTS: The autoscoring method of determining the rest interval showed an inflation of sleep efficiency. For each sleep parameter compared, the strongest correlations were observed between the manual and set interval scoring methods. Compliance using event markers to set rest interval was low (16.7%). CONCLUSIONS: Set interval scoring is the most efficient method to determine the rest interval in TBI patients. The use of event markers was an unreliable method to determine rest period.

Modification of a modulated arc total body irradiation technique: Implementation and first clinical experience for paediatric patients.

INTRODUCTION: To implement the modulated arc total body irradiation (MATBI) technique within the existing infrastructure of a radiation oncology department. The technique needed to treat paediatric patients of all ages, some of whom would require general anaesthesia (GA). METHODS: The MATBI technique required minor modifications to be incorporated within existing departmental infrastructure. Ancillary equipment essential to the technique were identified and in some cases custom designed to meet health and safety criteria. GA equipment was also considered. To evaluate the effectiveness of the implemented technique, an audit of the cases clinically treated was conducted. RESULTS: A motorised treatment couch was designed to allow the patient to be positioned in stabilisation equipment at a height, then lowered to the floor to accommodate source-to-skin-distances from 180 cm to 198 cm to treat the fixed 40 cm × 40 cm field size. Treatment couch design also facilitated positioning of the bespoke two-part spoiler. While organ at risk dose is limited using a beam weight optimisation technique, the dose is further reduced using compensators placed close to the patient's skin on a 3D printed custom-made support bridge. A digital radiography system is used to verify compensator position. Fifteen patients have been treated to date for various diseases using a variety of dose fractionations ranging from 2 Gy in a single fraction to 12 Gy in 6 fractions. Five patients have required GA due to age or behavioural issues. CONCLUSION: The modified MATBI technique and the equipment required for treatment delivery has been found to be well tolerated by all patients.

Targeted genetic analysis in a large cohort of familial and sporadic cases of aneurysm or dissection of the thoracic aorta.

PURPOSE: Thoracic aortic aneurysm/aortic dissection (TAAD) is a disorder with highly variable age of onset and phenotype. We sought to determine the prevalence of pathogenic variants in TAAD-associated genes in a mixed cohort of sporadic and familial TAAD patients and identify relevant genotype-phenotype relationships. METHODS: We used a targeted polymerase chain reaction and next-generation sequencing-based panel for genetic analysis of 15 TAAD-associated genes in 1,025 unrelated TAAD cases. RESULTS: We identified 49 pathogenic or likely pathogenic (P/LP) variants in 47 cases (4.9% of those successfully sequenced). Almost half of the variants were in nonsyndromic cases with no known family history of aortic disease. Twenty-five variants were within FBN1 and two patients were found to harbor two P/LP variants. Presence of a related syndrome, younger age at presentation, family history of aortic disease, and involvement of the ascending aorta increased the risk of carrying a P/LP variant. CONCLUSION: Given the poor prognosis of TAAD that is undiagnosed prior to acute rupture or dissection, genetic analysis of both familial and sporadic cases of TAAD will lead to new diagnoses, more informed management, and possibly reduced mortality through earlier, preclinical diagnosis in genetically determined cases and their family members.

Positive Outcomes of Optimizing Student-Preceptor Continuity in a Traditional Block Clerkship.

PROBLEM: Student-preceptor discontinuity during 3rd-year clerkships limits the quality and quantity of supervision, teaching, and feedback. Although longitudinal integrative clerkships increase continuity and are associated with improved student and preceptor experience, they require schoolwide curricular reform. Alternative innovations enhancing student-preceptor relationships within the constraints of a traditional block clerkship may demonstrate similar benefits. INTERVENTION: We piloted a continuity-enhanced general pediatric ambulatory schedule during 2 consecutive clerkship blocks in 2013. Students in the continuity-enhanced model (n = 29) were assigned 1-3 primary clinic preceptors, whereas those in the traditional model (n = 30) worked with 5-8. Data were gathered from student assessments and anonymous student and preceptor surveys. We used t and Fisher's exact tests to compare the two groups and performed thematic analysis of free-text survey comments. CONTEXT: Our school utilizes a block clerkship model with approximately 30 students rotating through the pediatric clerkship every 8 weeks. During the 3-week ambulatory portion, students spend 8 half days in the general pediatric ambulatory clinic. At the conclusion of each clinic, attendings completed brief student evaluation cards. Traditionally, student and attending schedules were created independently, resulting in transient supervisory relationships and dissatisfaction with clinical engagement, feedback, and evaluation. OUTCOME: Seventy-three percent (43/59) of the students completed the survey. Ten general ambulatory attendings collectively completed 87.5% (35/40) of the monthly surveys. Continuity students received significantly more narrative evaluation comments (10.6 vs. 5.8, p <. 001) from general ambulatory clinic attendings and were more likely to have at least one general ambulatory clinic attending endorse being able to provide meaningful feedback and evaluation (n = 29, 100% vs. n = 20, 66.7%, p <. 001). Continuity students were also more likely to endorse being able to ask at least one of these attendings for a letter of recommendation (71.4% vs. 9.1%, p <. 001) and to have at least one general ambulatory clinic attending endorse being able to provide a meaningful letter of recommendation if asked (62.1% vs. 3.3%, p <. 001). Students (88.4%) and attendings (85.7%) preferred the continuity-enhanced schedule. The most frequent theme of both student and attending free-text survey remarks were relationships and assessment. LESSONS LEARNED: Intentional scheduling of clerkship students to enhance preceptor continuity resulted in significant positive outcomes echoing the relationship-based educational benefits of longitudinal clerkships, particularly in regards to student assessment and feedback. Clerkship directors and other medical educators should consider implementing small changes within block clerkships to maximize student-preceptor continuity.

Targeted next-generation sequencing makes new molecular diagnoses and expands genotype-phenotype relationship in Ehlers-Danlos syndrome.

PURPOSE: Ehlers-Danlos syndrome (EDS) comprises a group of overlapping hereditary disorders of connective tissue with significant morbidity and mortality, including major vascular complications. We sought to identify the diagnostic utility of a next-generation sequencing (NGS) panel in a mixed EDS cohort. METHODS: We developed and applied PCR-based NGS assays for targeted, unbiased sequencing of 12 collagen and aortopathy genes to a cohort of 177 unrelated EDS patients. Variants were scored blind to previous genetic testing and then compared with results of previous Sanger sequencing. RESULTS: Twenty-eight pathogenic variants in COL5A1/2, COL3A1, FBN1, and COL1A1 and four likely pathogenic variants in COL1A1, TGFBR1/2, and SMAD3 were identified by the NGS assays. These included all previously detected single-nucleotide and other short pathogenic variants in these genes, and seven newly detected pathogenic or likely pathogenic variants leading to clinically significant diagnostic revisions. Twenty-two variants of uncertain significance were identified, seven of which were in aortopathy genes and required clinical follow-up. CONCLUSION: Unbiased NGS-based sequencing made new molecular diagnoses outside the expected EDS genotype-phenotype relationship and identified previously undetected clinically actionable variants in aortopathy susceptibility genes. These data may be of value in guiding future clinical pathways for genetic diagnosis in EDS.Genet Med 18 11, 1119-1127.

Tracking the genomic evolution of esophageal adenocarcinoma through neoadjuvant chemotherapy.

UNLABELLED: Esophageal adenocarcinomas are associated with a dismal prognosis. Deciphering the evolutionary history of this disease may shed light on therapeutically tractable targets and reveal dynamic mutational processes during the disease course and following neoadjuvant chemotherapy (NAC). We exome sequenced 40 tumor regions from 8 patients with operable esophageal adenocarcinomas, before and after platinum-containing NAC. This revealed the evolutionary genomic landscape of esophageal adenocarcinomas with the presence of heterogeneous driver mutations, parallel evolution, early genome-doubling events, and an association between high intratumor heterogeneity and poor response to NAC. Multiregion sequencing demonstrated a significant reduction in thymine to guanine mutations within a CpTpT context when comparing early and late mutational processes and the presence of a platinum signature with enrichment of cytosine to adenine mutations within a CpC context following NAC. Esophageal adenocarcinomas are characterized by early chromosomal instability leading to amplifications containing targetable oncogenes persisting through chemotherapy, providing a rationale for future therapeutic approaches. SIGNIFICANCE: This work illustrates dynamic mutational processes occurring during esophageal adenocarcinoma evolution and following selective pressures of platinum exposure, emphasizing the iatrogenic impact of therapy on cancer evolution. Identification of amplifications encoding targetable oncogenes maintained through NAC suggests the presence of stable vulnerabilities, unimpeded by cytotoxics, suitable for therapeutic intervention.

Assessment of cone beam CT registration for prostate radiation therapy: fiducial marker and soft tissue methods.

INTRODUCTION: This investigation aimed to assess the consistency and accuracy of radiation therapists (RTs) performing cone beam computed tomography (CBCT) alignment to fiducial markers (FMs) (CBCTFM ) and the soft tissue prostate (CBCTST ). METHODS: Six patients receiving prostate radiation therapy underwent daily CBCTs. Manual alignment of CBCTFM and CBCTST was performed by three RTs. Inter-observer agreement was assessed using a modified Bland-Altman analysis for each alignment method. Clinically acceptable 95% limits of agreement with the mean (LoAmean ) were defined as ±2.0 mm for CBCTFM and ±3.0 mm for CBCTST . Differences between CBCTST alignment and the observer-averaged CBCTFM (AvCBCTFM ) alignment were analysed. Clinically acceptable 95% LoA were defined as ±3.0 mm for the comparison of CBCTST and AvCBCTFM . RESULTS: CBCTFM and CBCTST alignments were performed for 185 images. The CBCTFM 95% LoAmean were within ±2.0 mm in all planes. CBCTST 95% LoAmean were within ±3.0 mm in all planes. Comparison of CBCTST with AvCBCTFM resulted in 95% LoA of -4.9 to 2.6, -1.6 to 2.5 and -4.7 to 1.9 mm in the superior-inferior, left-right and anterior-posterior planes, respectively. CONCLUSIONS: Significant differences were found between soft tissue alignment and the predicted FM position. FMs are useful in reducing inter-observer variability compared with soft tissue alignment. Consideration needs to be given to margin design when using soft tissue matching due to increased inter-observer variability. This study highlights some of the complexities of soft tissue guidance for prostate radiation therapy.

Development of synchronous VHL syndrome tumors reveals contingencies and constraints to tumor evolution.

BACKGROUND: Genomic analysis of multi-focal renal cell carcinomas from an individual with a germline VHL mutation offers a unique opportunity to study tumor evolution. RESULTS: We perform whole exome sequencing on four clear cell renal cell carcinomas removed from both kidneys of a patient with a germline VHL mutation. We report that tumors arising in this context are clonally independent and harbour distinct secondary events exemplified by loss of chromosome 3p, despite an identical genetic background and tissue microenvironment. We propose that divergent mutational and copy number anomalies are contingent upon the nature of 3p loss of heterozygosity occurring early in tumorigenesis. However, despite distinct 3p events, genomic, proteomic and immunohistochemical analyses reveal evidence for convergence upon the PI3K-AKT-mTOR signaling pathway. Four germline tumors in this young patient, and in a second, older patient with VHL syndrome demonstrate minimal intra-tumor heterogeneity and mutational burden, and evaluable tumors appear to follow a linear evolutionary route, compared to tumors from patients with sporadic clear cell renal cell carcinoma. CONCLUSIONS: In tumors developing from a germline VHL mutation, the evolutionary principles of contingency and convergence in tumor development are complementary. In this small set of patients with early stage VHL-associated tumors, there is reduced mutation burden and limited evidence of intra-tumor heterogeneity.

Targeted genetic testing for familial hypercholesterolaemia using next generation sequencing: a population-based study.

BACKGROUND: Familial hypercholesterolaemia (FH) is a common Mendelian condition which, untreated, results in premature coronary heart disease. An estimated 88% of FH cases are undiagnosed in the UK. We previously validated a method for FH mutation detection in a lipid clinic population using next generation sequencing (NGS), but this did not address the challenge of identifying index cases in primary care where most undiagnosed patients receive healthcare. Here, we evaluate the targeted use of NGS as a potential route to diagnosis of FH in a primary care population subset selected for hypercholesterolaemia. METHODS: We used microfluidics-based PCR amplification coupled with NGS and multiplex ligation-dependent probe amplification (MLPA) to detect mutations in LDLR, APOB and PCSK9 in three phenotypic groups within the Generation Scotland: Scottish Family Health Study including 193 individuals with high total cholesterol, 232 with moderately high total cholesterol despite cholesterol-lowering therapy, and 192 normocholesterolaemic controls. RESULTS: Pathogenic mutations were found in 2.1% of hypercholesterolaemic individuals, in 2.2% of subjects on cholesterol-lowering therapy and in 42% of their available first-degree relatives. In addition, variants of uncertain clinical significance (VUCS) were detected in 1.4% of the hypercholesterolaemic and cholesterol-lowering therapy groups. No pathogenic variants or VUCS were detected in controls. CONCLUSIONS: We demonstrated that population-based genetic testing using these protocols is able to deliver definitive molecular diagnoses of FH in individuals with high cholesterol or on cholesterol-lowering therapy. The lower cost and labour associated with NGS-based testing may increase the attractiveness of a population-based approach to FH detection compared to genetic testing with conventional sequencing. This could provide one route to increasing the present low percentage of FH cases with a genetic diagnosis.

Interobserver variability of radiation therapists aligning to fiducial markers for prostate radiation therapy.

INTRODUCTION: As the use of fiducial markers (FMs) for the localisation of the prostate during external beam radiation therapy (EBRT) has become part of routine practice, radiation therapists (RTs) have become increasingly responsible for online image interpretation. The aim of this investigation was to quantify the limits of agreement (LoA) between RTs when localising to FMs with orthogonal kilovoltage (kV) imaging. METHODS: Six patients receiving prostate EBRT utilising FMs were included in this study. Treatment localisation was performed using kV imaging prior to each fraction. Online stereoscopic assessment of FMs, performed by the treating RTs, was compared with the offline assessment by three RTs. Observer agreement was determined by pairwise Bland-Altman analysis. RESULTS: Stereoscopic analysis of 225 image pairs was performed online at the time of treatment, and offline by three RT observers. Eighteen pairwise Bland-Altman analyses were completed to assess the level of agreement between observers. Localisation by RTs was found to be within clinically acceptable 95% LoAs. CONCLUSIONS: Small differences between RTs, in both the online and offline setting, were found to be within clinically acceptable limits. RTs were able to make consistent and reliable judgements when matching FMs on planar kV imaging.