Variable neurologic phenotype in a GEFS+ family with a novel mutation in SCN1A

AbstractPurposeTo describe the spectrum of clinical disease in a mutliplex family with an autosomal dominant form of generalized epilepsy with febrile seizures plus (GEFS+) and determine its genetic etiology.MethodsMedical and family history was obtained on 11 clinically affected individuals and their relatives across three generations through medical chart review and home visits. A candidate gene approach including haplotype analysis and direct sequencing was used.ResultsAn epilepsy-associated haplotype was identified on 2q24. Direct sequencing of the entire SCN1A gene identified seven sequence variants. However, only one of these, c.1162 T>C, was not found in population controls. This transition in exon 8 of SCN1A predicts a substitution (Y388H) of a highly conserved tyrosine residue in the loop between transmembrane segments S5 and S6 of the sodium channel protein (Nav1.1). Clinical features in mutation carriers of this novel missense mutation were highly variable, ranging from febrile seizures to severe refractory epilepsy.ConclusionA novel missense mutation in the pore-forming region of the sodium channel gene SCN1A causes GEFS+ with a variable phenotype that includes mood and anxiety disorders, as well as ataxia, expanding the GEFS+ spectrum to include neuropsychiatric disease

The clinical and genetic epidemiology of pediatric idiopathic epilepsy in Newfoundland and Labrador

Background: Epilepsy is a common and very heterogeneous neurologic disorder which shows a predilection towards the pediatric population. Idiopathic epilepsy (IE) refers to cases with no known underlying etiology other than a presumed genetic predisposition. IE accounts for approximately half of all cases of epilepsy. Newfoundland and Labrador has a tertiary referral center for pediatric neurology patients where virtually all children living on the Avalon Peninsula are treated. The current study aims to determine the clinical and genetic epidemiologic characteristics in this population. Purpose: To describe the incidence, genetic and clinical epidemiology of pediatric IE in the province of Newfoundland and Labrador. Methods: All children < 15 years of age with IE were ascertained through the provincial pediatric neurology clinic at the Janeway Child Health Centre. Family history, medical history and blood samples were obtained from affected children and their family members. All blood samples were screened for mutations in the seven candidate genes (SCN1A, SCN2A, SCN1B, KCNQ2, GABRA1, GABRG2 and KCNQ3) of highest priority, based on previously reported phenotype-genotype relationships, by direct bidirectional Sanger DNA sequencing. Results: The mean annual incidence of IE for the population of children living on the Avalon region of Newfoundland from 2000 to 2004 was 107 per 100 000. This rate is approximately three-fold greater than comparable populations in other developed countries. Incidence was similar in males and females. Multiple different epilepsy phenotypes were identified between and amongst families. Of 117 families with IE eligible for study, 86 (74%) provided detailed pedigree data. Fifty-five families (64%) had a positive family history. Eight (9%) of these had family histories compatible with autosomal dominant (AD) inheritance and these families lived in five different geographic isolates. DNA was obtained from 79 individuals in 21 families. Seven genes previously associated with childhood epilepsy were sequenced and excluded in all but one family which had a pathogenic mutation in SCN1A. This gene encodes a sodium channel subunit and a novel missense mutation (c.1162T>C, p.Tyr388His) was identified in a multiplex family segregating a severe, clinically novel form of autosomal dominant generalized epilepsy with febrile seizures plus (GEFS+). The phenotype was consistent with GEFS+, with a variable phenotype that included mood and anxiety disorders, as well as ataxia – thereby expanding the phenotypic spectrum of GEFS+ to include neuropsychiatric disease. Conclusions: The incidence of IE in the Avalon Peninsula of Newfoundland is three times higher than comparison populations and the rate of familial disease is high throughout the province of Newfoundland and Labrador. The distribution of familial and AD IE in different geographic isolates, together with the clinical heterogeneity of disease, suggests substantial genetic heterogeneity. A novel SCN1A mutation and phenotype was identified

An Integrated Mind–Body Approach to Arthritis: A Pilot Study

Arthritis affects both the physical and psychological abilities of people in all walks of life. There are currently no recommended effective ‘disease-modifying’ remedies. Therapists and physicians are therefore exploring possible benefits from non-conventional therapeutic approaches. The purpose is to assess the changes in fitness and psychosocial outcomes of six doctor-referred patients as a result of participating in the I Can Move Again (ICMA) program. Six female participants diagnosed with arthritis were recruited from a local family practitioner. The subjects participated in a series of daily classes for 12 weeks including massage, mindfulness, bounce-back chairs, resistance chairs, aerobic and anaerobic training, rebounders, and whole body vibration platform Tai Chi. Demographic, psychosocial, and physical data were collected at the ICMA and at Y-Be-Fit (Provo, UT). Significant pre to post mean differences were found for sit-ups (F (1,8) =5.42 P =0.048), chair stand (F (1,10) =6.622 P =0.028), arm curl (F (1,10) =14.379 P =0.004), six-minute walk test distance (F (1,9)=19.188 P=0.002), and speed (F,(1,8) =13.984 P =0.006), and rotation right (F (1,10) =8.921 P =0.014) and left (F (1,10) =11.373 P =0.007), in 27 of the 61-item questionnaire. The preliminary data on the six subjects lacked sufficient statistical power to detect the significant differences that could exist, thus committing a Type II error, but it is important to note an overall, substantial trend in improvement in the patients’ physical outcomes and psychosocial perceptions associated with improvements in activities of daily living

A Newfoundland cohort of familial and sporadic idiopathic pulmonary fibrosis patients: clinical and genetic features

Background: Idiopathic pulmonary fibrosis (IPF) is an adult-onset Idiopathic Interstitial Pneumonia (IIP) usually diagnosed between age 50 to 70 years. Individuals with Familial Pulmonary Fibrosis (FPF) have at least one affected first or second-degree relative and account for 0.5-20% of cases. Methods: We ascertained and collected DNA samples from a large population-based cohort of IPF patients from Newfoundland, Canada. For each proband, a family history was documented and medical records were reviewed. Each proband was classified as familial (28 patients) or sporadic (50 patients) and all 78 probands were screened for variants in four highly penetrant, adult-onset PF genes (SFTPC, SFTPA2, TERT, TERC). Results: Seventy-eight IPF probands were enrolled of whom 28 (35.9%) had a positive family history. These 28 familial patients led to the recruitment of an additional 49 affected relatives (total of 77 FPF patients). By age 60 years, 42% of the familial cohort had been diagnosed with PF compared with only 16% of the sporadic patient collection (χ2 = 8.77, p = 0.003). Mean age of diagnosis in the familial group was significantly younger than the sporadic group (61.4 years vs. 66.6 yrs, p = 0.012) with a wider age range of diagnosis (19–92 years compared with 47–82 years). Thirty-three of 77 (42.8%) FPF patients had a tissue diagnosis and all but five had usual interstitial pneumonia histology. Compared with other published case series, the familial IIP histologies were more homogeneous. Three of 28 familial probands (10.7%) and none of the 50 sporadic probands had pathogenic variants in the four genes tested. All three familial probands had mutations in TERT. Other phenotypes associated with telomerase deficiency were present in these families including cirrhosis, bone marrow hypoplasia and premature graying. Telomere length assays were performed on mutation carriers from two families and confirmed telomere-related deficiency. Conclusion: The proportion of familial cases in our cohort is higher than any previously reported estimate and we suggest that this is due to the fact that Newfoundland cohort is ethnically homogeneous and drawn from a founder population. In our patient collection, diagnosis with IPF prior to age 45 years predicted familial disease. In two of the three TERT mutation families, the pedigree appearance is consistent with genetic anticipation. In the other 25 FPF families negative for mutations in known PF genes, we did not identify other telomerase associated medical problems (bone marrow dysfunction, cirrhosis) and we hypothesize that there are novel PF genes segregating in our population

Evaluating Understandings of State and Federal Pandemic Policies: The Situation of Refugees from the Congo Wars in Tampa, Florida

This article addresses underlying inequities for resettling refugees that have been exposed by COVID-19, including language barriers and access to public health information, food, health care, housing, and employment. It also speaks to theoretical concerns about the role of structural forces in creating increased health risks for vulnerable populations. Fieldwork that began in May 2020 investigated the extent to which refugees in Tampa understand and can operationalize the state and federal pandemic policies that have been put in place in the wake of the spread of COVID-19. The issues include understanding of COVID-19 and how it is transmitted, ability and willingness to practice distancing, access to food assistance, ability to help children with remote learning, and workplace disruptions, including the need to file for unemployment. Our method speaks to community-based approaches to anthropological fieldwork in pandemic situations, while demonstrating that critical language skills and in-depth cultural knowledge are essential for evaluating public health pandemic messaging and helping vulnerable populations

Front-line Hospice Staff Perceptions of Barriers and Opportunities to Discussing Advance Care Planning With Hospice Patients and Their Families

ObjectivesTo understand the facilitators and barriers to hospice staff engagement of patients and surrogates in advance care planning (ACP) conversations.DesignQualitative study conducted with purposive sampling and semistructured interviews using ATLAS.ti software to assist with template analysis.Settings and participantsParticipants included 51 hospice professionals (31 clinicians, 13 leaders, and 7 quality improvement administrators) from 4 geographically distinct nonprofit US hospices serving more than 2700 people.MeasuresInterview domains were derived from the implementation science framework of Capability, Opportunity, Motivation, and Behavior (COM-B), with additional questions soliciting recommendations for behavior change. Differences in themes were reconciled by consensus. The facilitator, barrier, and recommendation themes were organized within the COM-B framework.ResultsCapability was facilitated by interdisciplinary teamwork and specified clinical staff roles and inhibited by lack of self-perceived skill in engaging in ACP conversations. Opportunities for ACP occurred during admission to hospice, acute changes, or deterioration in patient condition. Opportunity-related environmental barriers included time constraints such as short patient stay in hospice and workload expectations that prevented clinicians from spending more time with patients and families. Motivation to discuss ACP was facilitated by the employee's goal of providing personalized, patient-centered care. Implicit assumptions about patients' and families' preferences reduced staff's motivation to engage in ACP. Hospice staff made recommendations to improve ACP discussions, including training and modeling practice sessions, earlier introduction of ACP concepts by clinicians in prehospice settings, and increasing workforce diversity to reflect the patient populations the organizations want to reach and cultural competency.Conclusions and implicationsEven hospice staff can be uncomfortable discussing death and dying. Yet staff were able to identify what worked well. Solutions to increase behavior of ACP engagement included staff training and modeling practice sessions, introducing ACP prior to hospice, and increasing workforce diversity to improve cultural competency

Barriers to reducing preoperative testing for low-risk surgical procedures: A qualitative assessment guided by the Theoretical Domains Framework

Introduction While numerous guidelines do not recommend preoperative tests for low risk patients undergoing low risk surgeries, they are often routinely performed. Canadian data suggests preoperative tests (e.g. ECGs and chest x-rays) preceded 17.9%-35.5% of low-risk procedures. Translating guidelines into clinical practice can be challenging and it is important to understand what is driving behaviour when developing interventions to change it. Aim Thus, we completed a theory-based investigation of the perceived barriers and enablers to reducing unnecessary preoperative tests for low-risk surgical procedures in Newfoundland, Canada. Method We used snowball sampling to recruit surgeons, anaesthesiologists, or preoperative clinic nurses. Interviews were conducted by two researchers using an interview guide with 31 questions based on the theoretical domains framework. Data was transcribed and coded into the 14 theoretical domains and then themes were identified for each domain. Results We interviewed 17 surgeons, anaesthesiologists, or preoperative clinic nurses with 1 to 34 years’ experience. Overall, while respondents agreed with the guidelines they described several factors, across seven relevant theoretical domains, that influence whether tests are ordered. The most common included uncertainty about who is responsible for test ordering, inability to access patient records or to consult/communicate with colleagues about ordering decisions and worry about surgery delays/cancellation if tests are not ordered. Other factors included workplace norms that conflicted with guidelines and concerns about missing something serious or litigation. In terms of enablers, respondents believed that clear institutional guidelines including who is responsible for test ordering and information about the risk of missing something serious, supported by improved communication between those involved in the ordering process and periodic evaluation will reduce any unnecessary preoperative testing. Conclusion These findings suggest that both health system and health provider factors need to be addressed in an intervention to reduce pre-operative testing

The Impact of School-based Intervention on Healthy Behaviors for 6th Grade Students

The prevalence of obesity in children has been steadily rising, with 18.1% of 12 year-old children obese in 2007-2008. Multiple school-based programs and interventions are currently being utilized to address the increasing obesity rates. The purpose of this class project was to develop and implement an educational program for 6th grade children addressing appropriate beverage intake, snacking behaviors, and physical activity. Two 6th grade classes (approximately 50 students total) at Bursley Elementary in Jenison, MI are the target population. We will provide the students with nutrition education based on developed materials during designated class periods. The effectiveness of the intervention will be measured using pre- and post-assessments. Increasing the awareness of the importance of healthy behaviors among these 6th grade students may encourage them to develop healthier lifestyles

"It's Case by Case, and It's a Struggle": A Qualitative Study of Hospice Practices, Perspectives, and Ethical Dilemmas When Caring for Hospice Enrollees with Full-Code Status or Intensive Treatment Preferences.

Objective: Characterize hospice staff practices and perspectives on discussing end-of-life care preferences with patients/families, including those desiring intensive treatment and/or full code. Background: Patients in the United States can elect hospice while remaining full code or seeking intensive interventions, for example, blood transfusions, or chemotherapy. These preferences conflict with professional norms, hospice philosophy, and Medicare hospice payment policies. Little is known about how hospice staff manage patient/family preferences for full-code status and intensive treatments. Methods: We recruited employees of four nonprofit US hospices with varying clinical and hospice experience for semi-structured, in-depth interviews. Open-ended questions explored participants' practices and perceptions of discussing end-of-life care preferences in hospice, with specific probes about intensive treatment or remaining full code. Interdisciplinary researchers coded and analyzed data using the constant comparative method. Results: Participants included 25% executive leaders, 14% quality improvement administrative staff, 61% clinicians (23 nurses, 21 social workers, 7 physicians, and 2 chaplains). Participants reported challenges in engaging patients/families about end-of-life care preferences. Preferences for intensive treatment or full-code status presented an ethical dilemma for some participants. Participants described strategies to navigate such preferences, including educating about treatment options, and expressed diverse reactions, including accepting or attempting to shift enrollee preferences. Discussion: This study illuminates a rarely studied aspect of hospice care: how hospice staff engage with enrollees choosing full code and/or intensive treatments. Such patient preferences can produce ethical dilemmas for hospice staff. Enhanced communication training and guidelines, updated organizational and federal policies, and ethics consult services may mitigate these dilemmas