The presence or absence of midsagittal tissue bridges and walking: a retrospective cohort study in spinal cord injury.

STUDY DESIGN: Cohort study. Retrospective analysis of T2-weighted magnetic resonance images (MRIs) and clinical documentation. OBJECTIVES: To evaluate the relationship between the presence/absence and widths of midsagittal tissue bridges and walking ability among veterans with cervical, predominantly chronic SCI. SETTING: University research and hospital setting. METHODS: T2-weighted midsagittal MRIs of 22 United States veterans with cervical spinal cord injuries were examined. The presence/absence of midsagittal tissue bridges were determined, and the widths of present ventral and dorsal tissue bridges were measured. Midsagittal tissue bridge characteristics were related to each participant's ability to walk based off examination of clinical documentation. RESULTS: Fourteen of the analyzed participant images revealed the presence of midsagittal tissue bridges. Ten of those individuals (71%) possessed overground walking ability. The 8 individuals with no apparent tissue bridges were all unable to walk. There was a significant correlation between walking and widths of ventral midsagittal tissue bridges (r = 0.69, 95%CI: 0.52, 0.92, p < 0.001), as well as dorsal midsagittal tissue bridges (r = 0.44, 95%CI: 0.15, 0.73, p = 0.039). CONCLUSION: The evaluation of midsagittal tissue bridges may be useful in various rehabilitation settings to help inform patients' plan of care, allocation of neuromodulatory resources, and appropriate stratification into research cohorts.

Needs of an uninsured equity-deserving minority patient cohort with physical disabilities during the first wave of the COVID-19 pandemic.

Background: Patients with disabilities and those from diverse equity-deserving backgrounds have been disproportionately affected by the SARS COV-2 ("COVID-19") pandemic. Objective: To describe the significant needs and social determinants of health that affected a group of uninsured patients (from equity-deserving groups) with rehabilitation diagnoses during the early months of the COVID-19 pandemic. Design: Retrospective cohort study utilizing a telephone-based needs assessment from April to October, 2020. Setting: Free interdisciplinary rehabilitation clinic serving patients with physical disabilities from equity-deserving minority backgrounds. Participants: 51 uninsured, diverse patients with spinal cord injuries, brain injuries, amputations, strokes, and other diagnoses requiring interdisciplinary rehabilitation care. Methods: Using a non-structured approach, telephone-based needs assessments were collected monthly. Reported needs were summarized into themes and the frequencies of each theme were recorded. Results: From the total number of concerns, medical issues were reported with the highest frequency (46%), followed by equipment needs (30%) and mental health concerns (30%). Other frequently mentioned needs centered around themes of rent, employment, and supplies. Rent and employment were more frequently cited in earlier months, and equipment problems were more frequently cited in later months. A minority of patients reported they had no needs, some of whom had acquired insurance. Conclusions: Our objective was to describe the needs of a racially and ethnically diverse set of uninsured individuals with physical disabilities seen at a specialized interdisciplinary rehabilitation pro bono clinic during the early months of COVID-19. Medical issues, equipment needs, and mental health concerns were the top three needs. To optimally serve them, care providers must be aware of current and future needs for their underserved patients, especially if future lockdowns occur.

Biopsychosocial sequelae and recovery trajectories from whiplash injury following a motor vehicle collision.

BACKGROUND CONTEXT: Five out of 10 injured in a motor vehicle collision (MVC) will develop persistent pain and disability. It is unclear if prolonged symptoms are related to peritraumatic pain/disability, psychological distress, muscle fat, lower extremity weakness. PURPOSE: To test if widespread muscle fat infiltration (MFI) was (1) unique to those with poor recovery, (2) present in the peritraumatic stage, (3) related to known risk factors. STUDY DESIGN/SETTING: A cohort study, single-center academic hospital. PATIENT SAMPLES: A total of 97 men and women (age 18-65) presenting to an urban academic emergency medicine department following MVC, but not requiring inpatient hospitalization. PRIMARY OUTCOME MEASURE: Neck disability at 12-months. METHODS: Participants underwent magnetic resonance imaging (MRI) to quantify neck and lower extremity MFI, completed questionnaires on pain/disability and psychological distress (< 1-week, 2-weeks, 3-, and 12-months) and underwent maximum volitional torque testing of their lower extremities (2-weeks, 3-, and 12-months). Percentage score on the Neck Disability Index at 12-months was used for a model of (1) Recovered (0%-8%), (2) Mild (10%-28%), and (3) Moderate/Severe (≥ 30%). This model was adjusted for BMI and age. RESULTS: Significant differences for neck MFI were revealed, with the Recovered group having significantly lower neck MFI than the Mild and Moderate/Severe groups at all time points. The Mild group had significantly more leg MFI at 12-months (p=.02) than the Recovered group. There were no other significant differences at any other time point. Lower extremity torques revealed no group differences. The Traumatic Injury Distress Scale (TIDS) and MFI of the neck at 1-week postinjury significantly predicted NDI score at 12-months. CONCLUSIONS: Higher neck MFI and distress may represent a risk factor though it is unclear whether this is a pre-existing phenotype or result of the trauma. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02157038.

St Andrew's COVID-19 surgery safety (StACS) study: The Burns Centre experience.

BACKGROUND: The COVID-19 pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has the potential to significantly impact burns patients both directly through infective complications of an immunocompromised cohort, and indirectly through disruption of care pathways and resource limitations. The pandemic presents new challenges that must be overcome to maintain patient safety; in particular, the potential increased risks of surgical intervention, anaesthesia and ventilation. This study comprehensively reviews the measures implemented to adapt referral pathways and mitigate the risk posed by COVID-19 during the height of the pandemic, within a large Burns Centre. METHODS: A prospective cohort study was designed to assess patients treated at the Burns Centre during the UK COVID-19 pandemic peak (April-May 2020), following implementation of new safety measures. All patients were analysed for 30-day mortality. In addition, a prospective controlled cohort study was undertaken on all inpatients and a random sample of outpatients with telephone follow-up at 30 days. These patients were divided into three groups (operative inpatients, non-operative inpatients, outpatients). COVID-19 related data collected included test results, contact with proven cases, isolation status and symptoms. The implemented departmental service COVID-19 safety adaptations are described. RESULTS: Of 323 patients treated at the Burns Centre during the study period, no 30-day COVID-19 related deaths occurred (0/323). Of the 80 patients analysed in the prospective controlled cohort section of the study, 51 underwent COVID-19 testing, 3.9% (2/51) were positive. Both cases were in the operative group, however in comparison to the non-operative and outpatient groups, there was no significant increase in COVID-19 incidence in operative patients. CONCLUSIONS: We found no COVID-19 related mortality during the study period. With appropriate precautions, burns patients were not exposed to an increased COVID-19 risk. Similarly, burns patients undergoing operative management were not at a significantly increased risk of contracting COVID-19 in comparison to non-operative groups.

Self-reported Dysphagia and Pharyngeal Volume Following Whiplash Injury.

Difficulty swallowing has been reported following whiplash injury; however, the reasons remain poorly understood. A possible factor may be the observed changes in pharyngeal volume. The current exploratory study was designed to examine the prevalence of self-reported dysphagia after whiplash and the relationship with recovery status and change in pharyngeal volume. Data were available from a longitudinal study of adults with whiplash. Data included magnetic resonance imaging (MRI) of the cervical spine, the Dysphagia Handicap Index (DHI), and Neck Disability Index (NDI) collected over four timepoints (< 1 week, 2 weeks, 3 months, and 12 months post-injury). Initial cross-sectional analysis examined 60 patients with DHI data from at least one timepoint. A second, longitudinal analysis was conducted on 31 participants with MRI, NDI, and DHI data at both early (< 1-2 weeks) and late (3-12 months) timepoints. The pharynx was contoured on axial T2-weighted MRI slices using OsiriX image processing software and pharyngeal volume (mm3) was quantified. In the 60-patient cohort, prevalence of self-reported dysphagia (DHI ≥ 3) was observed in 50% of participants at least once in 12 months (M = 4.9, SD 8.16, range 0-40). In the longitudinal cohort (n = 31), mean total DHI significantly (p = 0.006) increased between early and late stages. There was no relationship (p = 1.0) between dysphagia and recovery status, per the NDI% score. Pharyngeal volume remained stable and there was no relationship between dysphagia and pharyngeal volume change (p = 1.0). This exploratory study supports the need for further work to understand the nature of dysphagia, extent of functional compromise, and the underlying pathophysiology post-whiplash.

Symptom-burden in people living with frailty and chronic kidney disease.

BACKGROUND: Frailty is independently associated with worse health-related quality of life (HRQOL) in chronic kidney disease (CKD). However, the relationship between frailty and symptom experience is not well described in people living with CKD. This study's aim was to evaluate the relationship between frailty and symptom-burden in CKD. METHODS: This study is a secondary analysis of a cross-sectional observational study, the QCKD study (ISRCTN87066351), in which participants completed physical activity, cardiopulmonary fitness, symptom-burden and HRQOL questionnaires. A modified version of the Frailty Phenotype, comprising 3 self-report components, was created to assess frailty status. Multiple linear regression was performed to assess the association between symptom-burden/HRQOL and frailty. Logistic regression was performed to assess the association between experiencing symptoms frequently and frailty. Principal Component Analysis was used to assess the experienced symptom clusters. RESULTS: A total of 353 patients with CKD were recruited with 225 (64%) participants categorised as frail. Frail participants reported more symptoms, had higher symptom scores and worse HRQOL scores. Frailty was independently associated with higher total symptom score and lower HRQOL scores. Frailty was also independently associated with higher odds of frequently experiencing 9 out of 12 reported symptoms. Finally, frail participants experienced an additional symptom cluster that included loss of appetite, tiredness, feeling cold and poor concentration. CONCLUSIONS: Frailty is independently associated with high symptom-burden and poor HRQOL in CKD. Moreover, people living with frailty and CKD have a distinctive symptom experience. Proactive interventions are needed that can effectively identify and address problematic symptoms to mitigate their impact on HRQOL.

Investigation of the safety and feasibility of AAV1/SERCA2a gene transfer in patients with chronic heart failure supported with a left ventricular assist device - the SERCA-LVAD TRIAL.

The SERCA-LVAD trial was a phase 2a trial assessing the safety and feasibility of delivering an adeno-associated vector 1 carrying the cardiac isoform of the sarcoplasmic reticulum calcium ATPase (AAV1/SERCA2a) to adult chronic heart failure patients implanted with a left ventricular assist device. The SERCA-LVAD trial was one of a program of AAV1/SERCA2a cardiac gene therapy trials including CUPID1, CUPID 2 and AGENT trials. Enroled subjects were randomised to receive a single intracoronary infusion of 1 × 1013 DNase-resistant AAV1/SERCA2a particles or a placebo solution in a double-blinded design, stratified by presence of neutralising antibodies to AAV. Elective endomyocardial biopsy was performed at 6 months unless the subject had undergone cardiac transplantation, with myocardial samples assessed for the presence of exogenous viral DNA from the treatment vector. Safety assessments including ELISPOT were serially performed. Although designed as a 24 subject trial, recruitment was stopped after five subjects had been randomised and received infusion due to the neutral result from the CUPID 2 trial. Here we describe the results from the 5 patients at 3 years follow up, which confirmed that viral DNA was delivered to the failing human heart in 2 patients receiving gene therapy with vector detectable at follow up endomyocardial biopsy or cardiac transplantation. Absolute levels of detectable transgene DNA were low, and no functional benefit was observed. There were no safety concerns in this small cohort. This trial identified some of the challenges of performing gene therapy trials in this LVAD patient cohort which may help guide future trial design.

Multiple digit camptodactyly caused by anomalous ulnar sided flexor digitorum superficialis insertions.

We report an anomalous insertion of the flexor digitorum superficialis (FDS) tendon causing multiple digit camptodactyly. The abnormal tendon was present in the ring and middle fingers, passing from the FDS tendon (proximal to the proximal interphalangeal-PIP-joint) to the extensor expansion (distal to the PIP joint). It was present on the ulnar aspect only, with no corresponding structure on the radial side. Division of the anomalous insertion corrected the fixed flexion deformity at the PIP joint. This anomaly has not been reported in clinical or cadaveric studies and could have been overlooked if a volar approach had been used.

Whiplash-Associated Dysphagia: Considerations of Potential Incidence and Mechanisms.

Non-specific self-reports of dysphagia have been described in people with whiplash-associated disorders (WAD) following motor vehicle collision (MVC); however, incidence and mechanistic drivers remain poorly understood. Alterations in oropharyngeal dimensions on magnetic resonance imaging (MRI), along with heightened levels of stress, pain, and changes in stress-dependent microRNA expression (e.g., miR-320a) have been also associated with WAD, suggesting multi-factorial issues may underpin any potential swallowing changes. In this exploratory paper, we examine key biopsychosocial parameters in three patients with persistent WAD reporting swallowing change and three nominating full recovery after whiplash with no reported swallowing change. Parameters included (1) oropharyngeal volume with 3D MRI, (2) peritraumatic miR-320a expression, and (3) psychological distress. These factors were explored to highlight the complexity of patient presentation and propose future considerations in relation to a potential deglutition disorder following WAD. The three participants reporting changes in swallowing all had smaller oropharyngeal volumes at < 1 week and at 3 months post injury and lower levels of peritraumatic miR-320a. At 3 months post MVC, oropharyngeal volumes between groups indicated a large effect size (Hedge's g = 0.96). Higher levels of distress were reported at both time points for those with persistent symptomatology, including self-reported dysphagia, however, this was not featured in those nominating recovery. This paper considers current evidence for dysphagia as a potentially under-recognized feature of WAD and highlights the need for future, larger-scaled, multidimensional investigation into the incidence and mechanisms of whiplash-associated dysphagia.

Crizotinib inhibition of ROS1-positive tumours in advanced non-small-cell lung cancer: a Canadian perspective.

The ros1 kinase is an oncogenic driver in non-small-cell lung cancer (nsclc). Fusion events involving the ROS1 gene are found in 1%-2% of nsclc patients and lead to deregulation of a tyrosine kinase-mediated multi-use intracellular signalling pathway, which then promotes the growth, proliferation, and progression of tumour cells. ROS1 fusion is a distinct molecular subtype of nsclc, found independently of other recognized driver mutations, and it is predominantly identified in younger patients (<50 years of age), women, never-smokers, and patients with adenocarcinoma histology. Targeted inhibition of the aberrant ros1 kinase with crizotinib is associated with increased progression-free survival (pfs) and improved quality-of-life measures. As the sole approved treatment for ROS1-rearranged nsclc, crizotinib has been demonstrated, through a variety of clinical trials and retrospective analyses, to be a safe, effective, well-tolerated, and appropriate treatment for patients having the ROS1 rearrangement. Canadian physicians endorse current guidelines which recommend that all patients with nonsquamous advanced nsclc, regardless of clinical characteristics, be tested for ROS1 rearrangement. Future integration of multigene testing panels into the standard of care could allow for efficient and cost-effective comprehensive testing of all patients with advanced nsclc. If a ROS1 rearrangement is found, treatment with crizotinib, preferably in the first-line setting, constitutes the standard of care, with other treatment options being investigated, as appropriate, should resistance to crizotinib develop.

Correction: Mitochondrial oxodicarboxylate carrier deficiency is associated with mitochondrial DNA depletion and spinal muscular atrophy-like disease.

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A ZPR1 mutation is associated with a novel syndrome of growth restriction, distinct craniofacial features, alopecia, and hypoplastic kidneys.

A novel autosomal recessive disorder characterized by pre- and postnatal growth restriction with microcephaly, distinctive craniofacial features, congenital alopecia, hypoplastic kidneys with renal insufficiency, global developmental delay, severe congenital sensorineural hearing loss, early mortality, hydrocephalus, and genital hypoplasia was observed in 4 children from 3 families of New Mexican Hispanic heritage. Three of the children died before 3 years of age from uremia and/or sepsis. Exome sequencing of the surviving individual identified a homozygous c.587T>C (p.Ile196Thr) mutation in ZPR1 Zinc Finger (ZPR1) that segregated appropriately in her family. In a second family, the identical variant was shown to be heterozygous in the affected individual's parents and not homozygous in any of her unaffected siblings. ZPR1 is a ubiquitously expressed, highly conserved protein postulated to transmit proliferative signals from the cell membrane to the nucleus. Structural modeling reveals that p.Ile196Thr disrupts the hydrophobic core of ZPR1. Patient fibroblast cells showed no detectable levels of ZPR1 and the cells showed a defect in cell cycle progression where a significant number of cells remained arrested in the G1 phase. We provide genetic and molecular evidence that a homozygous missense mutation in ZPR1 is associated with a rare and recognizable multisystem syndrome.

Experiences of being diagnosed with osteoporosis: a meta-synthesis.

This systematic review provides synthesised knowledge and guidance to health professionals on the experiences and perspectives of being diagnosed with osteoporosis from the patient's point of view. Using individuals' experiences and meanings can promote tailored and targeted information and guidance on osteoporosis, bone care and treatment at different stages of the osteoporosis trajectory. INTRODUCTION: To be diagnosed with osteoporosis with or without fragility fractures affects individuals differently. The aim of this review was firstly to aggregate existing qualitative evidence regarding an individual's experience of being diagnosed with osteoporosis at different stages, and secondly, to use a systematic approach to develop a conceptual understanding of central issues relevant for health professionals in order to provide support and guidance to patients/individuals. METHODS: This study used a systematic review methodology and methods for qualitative synthesis as recommended by Cochrane and integrated the findings of qualitative research from eight databases (Medline, PubMed, CINAHL, Embase, SweMed+, PsycINFO, ERIC, Web of Science) to July 2016. Selection and assessment were performed by three authors while four authors were involved in the analysis. Findings were cross-checked with the original article to ensure consistency with the individual's accounts. RESULTS: Our findings have revealed that individuals diagnosed with osteoporosis do not perceive osteoporosis as a biomedical trajectory but as a self-perceived continuum of severity and health. To be diagnosed with osteoporosis affects individuals differently depending on, for example, personal experience, pre-conceived notions of or knowledge about the disease, fragility fractures or pain. Hence, individuals will create a meaning of the diagnosis based on self-perceived fracture risk, self-perceived severity of osteoporosis and at the same time, self-perceived health. CONCLUSIONS: This meta-synthesis provides knowledge for health professionals on the experiences and perspectives of being diagnosed with osteoporosis from the patient's point of view. The experience, meaning and significance of osteoporosis must be taken into consideration and can be used to promote tailored and targeted information and guidance on osteoporosis, bone care and treatment at different stages of the osteoporosis trajectory.

Myxoma Virus M083 Is a Virulence Factor Which Mediates Systemic Dissemination.

Poxviruses are large, DNA viruses whose protein capsid is surrounded by one or more lipid envelopes. Embedded into these lipid envelopes are three conserved viral proteins which are thought to mediate binding of virions to target cells. While the function of these proteins has been studied in vitro, their specific roles during the pathogenesis of poxviral disease remain largely unclear. Here we present data demonstrating that the putative chondroitin binding protein M083 from the leporipoxvirus myxoma virus is a significant virulence factor during infection of susceptible Oryctolagus rabbits. Removal of M083 results in a reduced capacity of virus to spread beyond the regional lymph nodes and completely eliminates infection-mediated mortality. In vitro, removal of M083 results in only minor intracellular replication defects but causes a significant reduction in the ability of myxoma virus to spread from infected epithelial cells onto primary lymphocytes. We hypothesize that the physiological role of M083 is therefore to mediate the spread of myxoma virus onto rabbit lymphocytes, allowing these cells to disseminate virus throughout infected rabbits.IMPORTANCE Poxviruses represent both a class of human pathogens and potential therapeutic agents for the treatment of human malignancy. Understanding the basic biology of these agents is therefore significant to human health in a variety of ways. While the mechanisms mediating poxviral binding have been well studied in vitro, how these mechanisms impact poxviral pathogenesis in vivo remains unclear. The current study advances our understanding of how poxviral binding impacts viral pathogenesis by demonstrating that the putative chondroitin binding protein M083 plays a critical role during the pathogenesis of myxoma virus in susceptible Oryctolagus rabbits by impacting viral dissemination through changes in the transfer of virions onto primary splenocytes.

MicroRNAs regulate synaptic plasticity underlying drug addiction.

Chronic use of drugs of abuse results in neurochemical, morphological and behavioral plasticity that underlies the emergence of compulsive drug seeking and vulnerability to relapse during periods of attempted abstinence. Identifying and reversing addiction-relevant plasticity is seen as a potential point of pharmacotherapeutic intervention in drug-addicted individuals. Despite considerable advances in our understanding of the actions of drugs of abuse in the brain, this information has thus far yielded few novel treatment options addicted individuals. MicroRNAs are small noncoding RNAs that can each regulate the translation of hundreds to thousands of messenger RNAs. The highly pleiotropic nature of miRNAs has focused attention on their contribution to addiction-relevant structural and functional plasticity in the brain and their potential utility as targets for medications development. In this review, we discuss the roles of miRNAs in synaptic plasticity underlying the development of addiction and then briefly discuss the possibility of using circulating miRNA as biomarkers for addiction.

Effect of fixation time on breast biomarker expression: a controlled study using cell line-derived xenografted (CDX) tumours.

AIMS: Altering the length of time specimens are placed in fixative without compromising analytical testing accuracy is a continuous challenge in the anatomical pathology lab. The aim of this study was to determine under controlled conditions the effects of variable fixation time on breast biomarker expression in human breast cancer cell line-derived xenografted (CDX) tumours. METHODS: CDX tumours using strong oestrogen receptor (ER)-positive, Her2-negative (MCF7) and weak ER-positive, Her2 equivocal (T47D) breast cancer cell lines were fixed for various times ranging from 1 to 336 hours in 10% neutral buffered formalin. CDX tumours were processed according to routine biomarker testing protocols and stained for ER and Her2 immunohistochemistry (IHC) and processed for HER2 fluorescence in situ hybridisation (FISH). The tumours were evaluated using Allred scoring for ER and current ASCO/CAP guidelines for Her2, and by objective cell counting methodology. RESULTS: No differences were found in expression of ER in either MCF7 or T47D CDX tumours under variable fixation. T47D tumours displayed equivocal Her2 staining when fixed for 24 hours, but fixation for ≤8 hours resulted in consistently negative staining while tumours fixed for >72 hours demonstrated consistent equivocal staining (p<0.01). Cell counting assays revealed only a significant increase in sensitivity in tumours fixed for >72 hours (p<0.01). As expected, FISH results were unaffected by variable fixation. CONCLUSIONS: Neither shortened nor prolonged fixation affects ER expression, consistent with previous findings. In equivocal Her2-expressing tumours, however, increasing fixation increased the sensitivity of Her2 IHC reporting while not affecting FISH.

Ambulatory function in motor incomplete spinal cord injury: a magnetic resonance imaging study of spinal cord edema and lower extremity muscle morphometry.

STUDY DESIGN: This research utilized a cross-sectional design. OBJECTIVES: Spinal cord edema length has been measured with T2-weighted sagittal MRI to predict motor recovery following spinal cord injury. The purpose of our study was to establish the correlational value of axial spinal cord edema using T2-weighted MRI. We hypothesized a direct relationship between the size of damage on axial MRI and walking ability, motor function and distal muscle changes seen in motor incomplete spinal cord injury (iSCI). SETTING: University-based laboratory in Chicago, IL, USA. METHODS: Fourteen participants with iSCI took part in the study. Spinal cord axial damage ratios were assessed using axial T2-weighted MRI. Walking ability was investigated using the 6-min walk test and daily stride counts. Maximum plantarflexion torque was quantified using isometric dynomometry. Muscle fat infiltration (MFI) and relative muscle cross-sectional area (rmCSA) were quantified using fat/water separation magnetic resonance imaging. RESULTS: Damage ratios were negatively correlated with distance walked in 6 min, average daily strides and maximum plantarflexion torque, and a negative linear trend was found between damage ratios and lower leg rmCSA. While damage ratios were not significantly correlated with MFI, we found significantly higher MFI in the wheelchair user participant group compared to community walkers. CONCLUSIONS: Damage ratios may be useful in prognosis of motor recovery in spinal cord injury. The results warrant a large multi-site research study to investigate the value of high-resolution axial T2-weighted imaging to predict walking recovery following motor incomplete spinal cord injury.

Debunking Occam's razor: Diagnosing multiple genetic diseases in families by whole-exome sequencing.

BACKGROUND: Recent clinical whole exome sequencing (WES) cohorts have identified unanticipated multiple genetic diagnoses in single patients. However, the frequency of multiple genetic diagnoses in families is largely unknown. AIMS: We set out to identify the rate of multiple genetic diagnoses in probands and their families referred for analysis in two national research programs in Canada. MATERIALS & METHODS: We retrospectively analyzed WES results for 802 undiagnosed probands referred over the past 5 years in either the FORGE or Care4Rare Canada WES initiatives. RESULTS: Of the 802 probands, 226 (28.2%) were diagnosed based on mutations in known disease genes. Eight (3.5%) had two or more genetic diagnoses explaining their clinical phenotype, a rate in keeping with the large published studies (average 4.3%; 1.4 - 7.2%). Seven of the 8 probands had family members with one or more of the molecularly diagnosed diseases. Consanguinity and multisystem disease appeared to increase the likelihood of multiple genetic diagnoses in a family. CONCLUSION: Our findings highlight the importance of comprehensive clinical phenotyping of family members to ultimately provide accurate genetic counseling.

NEW IMPROVEMENTS TO MFIRE TO ENHANCE FIRE MODELING CAPABILITIES.

NIOSH's mine fire simulation program, MFIRE, is widely accepted as a standard for assessing and predicting the impact of a fire on the mine ventilation system and the spread of fire contaminants in coal and metal/nonmetal mines, which has been used by U.S. and international companies to simulate fires for planning and response purposes. MFIRE is a dynamic, transient-state, mine ventilation network simulation program that performs normal planning calculations. It can also be used to analyze ventilation networks under thermal and mechanical influence such as changes in ventilation parameters, external influences such as changes in temperature, and internal influences such as a fire. The program output can be used to analyze the effects of these influences on the ventilation system. Since its original development by Michigan Technological University for the Bureau of Mines in the 1970s, several updates have been released over the years. In 2012, NIOSH completed a major redesign and restructuring of the program with the release of MFIRE 3.0. MFIRE's outdated FORTRAN programming language was replaced with an object-oriented C++ language and packaged into a dynamic link library (DLL). However, the MFIRE 3.0 release made no attempt to change or improve the fire modeling algorithms inherited from its previous version, MFIRE 2.20. This paper reports on improvements that have been made to the fire modeling capabilities of MFIRE 3.0 since its release. These improvements include the addition of fire source models of the t-squared fire and heat release rate curve data file, the addition of a moving fire source for conveyor belt fire simulations, improvement of the fire location algorithm, and the identification and prediction of smoke rollback phenomena. All the improvements discussed in this paper will be termed as MFIRE 3.1 and released by NIOSH in the near future.