Ancestral Mutation in Telomerase Causes Defects in Repeat Addition Processivity and Manifests As Familial Pulmonary Fibrosis

The telomerase reverse transcriptase synthesizes new telomeres onto chromosome ends by copying from a short template within its integral RNA component. During telomere synthesis, telomerase adds multiple short DNA repeats successively, a property known as repeat addition processivity. However, the consequences of defects in processivity on telomere length maintenance are not fully known. Germline mutations in telomerase cause haploinsufficiency in syndromes of telomere shortening, which most commonly manifest in the age-related disease idiopathic pulmonary fibrosis. We identified two pulmonary fibrosis families that share two non-synonymous substitutions in the catalytic domain of the telomerase reverse transcriptase gene hTERT: V791I and V867M. The two variants fell on the same hTERT allele and were associated with telomere shortening. Genealogy suggested that the pedigrees shared a single ancestor from the nineteenth century, and genetic studies confirmed the two families had a common founder. Functional studies indicated that, although the double mutant did not dramatically affect first repeat addition, hTERT V791I-V867M showed severe defects in telomere repeat addition processivity in vitro. Our data identify an ancestral mutation in telomerase with a novel loss-of-function mechanism. They indicate that telomere repeat addition processivity is a critical determinant of telomere length and telomere-mediated disease

Large-scale evaluation of outcomes after a genetic diagnosis in children with severe developmental disorders

Purpose We sought to evaluate outcomes for clinical management after a genetic diagnosis from the Deciphering Developmental Disorders study. Methods Individuals in the Deciphering Developmental Disorders study who had a pathogenic/likely pathogenic genotype in the DECIPHER database were selected for inclusion (n = 5010). Clinical notes from regional clinical genetics services notes were reviewed to assess predefined clinical outcomes relating to interventions, prenatal choices, and information provision. Results Outcomes were recorded for 4237 diagnosed probands (85% of those eligible) from all 24 recruiting centers across the United Kingdom and Ireland. Clinical management was reported to have changed in 28% of affected individuals. Where individual-level interventions were recorded, additional diagnostic or screening tests were started in 903 (21%) probands through referral to a range of different clinical specialties, and stopped or avoided in a further 26 (0.6%). Disease-specific treatment was started in 85 (2%) probands, including seizure-control medications and dietary supplements, and contra-indicated medications were stopped or avoided in a further 20 (0.5%). The option of prenatal/preimplantation genetic testing was discussed with 1204 (28%) families, despite the relatively advanced age of the parents at the time of diagnosis. Importantly, condition-specific information or literature was given to 3214 (76%) families, and 880 (21%) were involved in family support groups. In the most common condition (KBG syndrome; 79 [2%] probands), clinical interventions only partially reflected the temporal development of phenotypes, highlighting the importance of consensus management guidelines and patient support groups. Conclusion Our results underscore the importance of achieving a clinico-molecular diagnosis to ensure timely onward referral of patients, enabling appropriate care and anticipatory surveillance, and for accessing relevant patient support groups

Disease-related cortical thinning in presymptomatic granulin mutation carriers

Mutations in the granulin gene (GRN) cause familial frontotemporal dementia. Understanding the structural brain changes in presymptomatic GRN carriers would enforce the use of neuroimaging biomarkers for early diagnosis and monitoring. We studied 100 presymptomatic GRN mutation carriers and 94 noncarriers from the Genetic Frontotemporal dementia initiative (GENFI), with MRI structural images. We analyzed 3T MRI structural images using the FreeSurfer pipeline to calculate the whole brain cortical thickness (CTh) for each subject. We also perform a vertex-wise general linear model to assess differences between groups in the relationship between CTh and diverse covariables as gender, age, the estimated years to onset and education. We also explored differences according to TMEM106B genotype, a possible disease modifier. Whole brain CTh did not differ between carriers and noncarriers. Both groups showed age-related cortical thinning. The group-by-age interaction analysis showed that this age-related cortical thinning was significantly greater in GRN carriers in the left superior frontal cortex. TMEM106B did not significantly influence the age-related cortical thinning. Our results validate and expand previous findings suggesting a

Social cognition impairment in genetic frontotemporal dementia within the GENFI cohort

A key symptom of frontotemporal dementia (FTD) is difficulty interacting socially with others. Social cognition problems in FTD include impaired emotion processing and theory of mind difficulties, and whilst these have been studied extensively in sporadic FTD, few studies have investigated them in familial FTD. Facial Emotion Recognition (FER) and Faux Pas (FP) recognition tests were used to study social cognition within the Genetic Frontotemporal Dementia Initiative (GENFI), a large familial FTD cohort of C9orf72, GRN, and MAPT mutation carriers. 627 participants undertook at least one of the tasks, and were separated into mutation-negative healthy controls, presymptomatic mutation carriers (split into early and late groups) and symptomatic mutation carriers. Groups were compared using a linear regression model with bootstrapping, adjusting for age, sex, education, and for the FP recognition test, language. Neural correlates of social cognition deficits were explored using a voxel-based morphometry (VBM) study. All three of the symptomatic genetic groups were impaired on both tasks with no significant difference between them. However, prior to onset, only the late presymptomatic C9orf72 mutation carriers on the FER test were impaired compared to the control group, with a subanalysis showing differences particularly in fear and sadness. The VBM analysis revealed that impaired social cognition was mainly associated with a left hemisphere predominant network of regions involving particularly the striatum, orbitofrontal cortex and insula, and to a lesser extent the inferomedial temporal lobe and other areas of the frontal lobe. In conclusion, theory of mind and emotion processing abilities are impaired in familial FTD, with early changes occurring prior to symptom onset in C9orf72 presymptomatic mutation carriers. Future work should investigate how performance changes over time, in order to gain a clearer insight into social cognitive impairment over the course of the disease

Effect of the COVID-19 pandemic on emergency department utilization of computed tomography scans of appendicitis and diverticulitis

Abstract Purpose Investigating the effect of the COVID-19 lockdown on adult patient visits, computed tomography (CT) abdominal scans, and presentations of appendicitis and diverticulitis, to emergency departments (ED) in St. John’s NL. Methods A retrospective quantitative analysis was applied, using ED visits and Canadian Triage and Acuity Scale (CTAS) scores. mPower (Nuance Communications, UK) identified CT abdominal scan reports, which were categorized into (1) normal/other, (2) appendicitis, or (3) diverticulitis. Time intervals included pre-lockdown (January–February), lockdown (March–June), and post-lockdown (July–August). Data from 2018 to 2019 (January–August) were used to generate expected patient volumes for 2020, and pre- and post-lockdown were included to control for other variables outside the lockdown. Results Chi-squared goodness of fit tested for deviations from predicted means for 2018–2019. Compared to expectations, daily ED visits from January to August 2020 showed a significant (p &lt; 0.001) decrease in patient volumes independent of gender, age, and CTAS scores. During and post-lockdown, CT abdominal scans did not drop in proportion to patient volume. Appendicitis presentations remained indifferent to lockdown, while diverticulitis presentations appeared to wane, with no difference in combined complicated cases in comparison to what was expected. Conclusion During lockdown, significantly fewer patients presented to the ED. The proportion of ordered CT abdominal scans increased significantly per person seen, without change in CTAS scores. Considering combined pathology cases increased during the lockdown, ED physicians were warranted in increasing abdominal imaging as patients did not avoid the ED. This may have resulted from a change in clinical practice where the uncertainty of COVID-19 increased CT scan usage. </jats:sec

Oral Tablet Formulations with Lactoferrin, a Cohesive Biomacromolecule

Background/Objectives: The aim of our research was to understand how excipients, unit operations, and process parameters impact processability and resulting properties, performance, and stability of tablets containing bovine lactoferrin, a cohesive biomacromolecule. Methods: Microcrystalline cellulose (MCC), croscarmellose (xCMC), lactose (LAC), hydroxypropyl methylcellulose (HPMC), and sodium stearyl fumarate (SSF) were used to produce various tablet formulations containing lactoferrin across a concentration range of 5 to 45%, targeting immediate- or controlled release performance. Tablets were made either by direct compression or via dry granulation followed by tableting. In addition to release performance, tablet attributes were characterized for tensile strength, friability, weight uniformity, and content uniformity. Results: Acceptable tablet tensile strength, friability, and performance were obtained for lactoferrin concentrations ranging from 15 to 45%, using a variety of excipients and manufacturing approaches. In several cases, dry granulation improved content uniformity. Excipient choice and tablet compression force impacted drug release, particularly when MCC alone was used as dry binder for immediate release. Dry granulation impacted tablet tensile properties, but did not significantly impact release performance. Lactoferrin&ndash;excipient compatibility was demonstrated for up to 2 years in ambient laboratory conditions. Conclusions: The study demonstrates that robust tablets can be produced using excipients and processes amenable to scale-up for industrial production. Consistent, stable, and suitably performing tablets were successfully produced using a variety of excipients, processing approaches, and across a broad concentration range with this cohesive biomacromolecule active pharmaceutical ingredient (API). Both immediate- and controlled release performance modes were possible