The effect of following best practice reporting recommendations on legal and community evaluations of forensic examiners reports.

Commentators have recommended that forensic scientists' reports contain various disclosures to facilitate comprehension. However, little research has explored whether following best practice recommendations for disclosure impacts on receivers' impressions of the evidence. We examined whether forensic science reports that are more compliant with these best practice recommendations reduced overvaluing of the evidence and sensitized legal and community decision-makers to evidence quality. Across three experiments, 240 legal practitioners/trainees and 566 community decision-makers were presented with a fingerprint or footwear report that was either compliant or non-compliant with best practice recommendations. Participants were then asked to make evaluations and decisions based on the report. We found mixed effects of report compliance. Report compliance affected community participant's evaluations of the persuasiveness of the evidence but had limited impact on the judgments of legal practitioners/trainees. When presented with compliant reports, we found that community participants regarded unknown reliability evidence as less reliable and less persuasive than high reliability evidence, suggesting disclosures helped reduce overvaluing of the evidence and create sensitivity to differences in evidence quality. These results suggest compliance with reporting recommendations does affect community impressions, while only minimally influencing legal impressions of forensic science evidence. The costs and/or benefits of this outcome require further examination.

Risk of Subsequent Events in Patients With Minor Ischemic Stroke or High-Risk Transient Ischemic Attack.

This study aimed to present the prognosis after minor acute ischemic stroke (AIS) or transient ischemic attack (TIA), using a definition of subsequent stroke in accordance with recent clinical trials. In total, 9,506 patients with minor AIS (National Institutes of Health Stroke Scale ≤ 5) or high-risk TIA (acute lesions or ≥ 50% cerebral artery steno-occlusion) admitted between November 2010 and October 2013 were included. The primary outcome was the composite of stroke (progression of initial event or a subsequent event) and all-cause mortality. The cumulative incidence of stroke or death was 11.2% at 1 month, 13.3% at 3 months and 16.7% at 1 year. Incidence rate of stroke or death in the first month was 12.5 per 100 person-months: highest in patients with large artery atherosclerosis (17.0). The risk of subsequent events shortly after a minor AIS or high-risk TIA was substantial, particularly in patients with large artery atherosclerosis.

Risk of Subsequent Events in Patients With Minor Ischemic Stroke or HighRisk Transient Ischemic Attack

This study aimed to present the prognosis after minor acute ischemic stroke (AIS) or transient ischemic attack (TIA), using a definition of subsequent stroke in accordance with recent clinical trials. In total, 9,506 patients with minor AIS (National Institutes of Health Stroke Scale ≤ 5) or high-risk TIA (acute lesions or ≥ 50% cerebral artery steno-occlusion) admitted between November 2010 and October 2013 were included. The primary outcome was the composite of stroke (progression of initial event or a subsequent event) and all-cause mortality. The cumulative incidence of stroke or death was 11.2% at 1 month, 13.3% at 3 months and 16.7% at 1 year. Incidence rate of stroke or death in the first month was 12.5 per 100 person-months: highest in patients with large artery atherosclerosis (17.0). The risk of subsequent events shortly after a minor AIS or high-risk TIA was substantial, particularly in patients with large artery atherosclerosis.

Genomic Analysis of Mycobacterium abscessus Complex Isolates Collected in Ireland between 2006 and 2017.

Members of the Mycobacterium abscessus complex (MABC) are multidrug-resistant nontuberculous mycobacteria and cause opportunistic pulmonary infections in individuals with cystic fibrosis (CF). In this study, genomic analysis of MABC isolates was performed to gain greater insights into the epidemiology of circulating strains in Ireland. Whole-genome sequencing (WGS) was performed on 70 MABC isolates that had been referred to the Irish Mycobacteria Reference Laboratory between 2006 and 2017 across nine Irish health care centers. The MABC isolates studied comprised 52 isolates from 27 CF patients and 18 isolates from 10 non-CF patients. WGS identified 57 (81.4%) as M. abscessus subsp. abscessus, 10 (14.3%) as M. abscessus subsp. massiliense, and 3 (4.3%) as M. abscessus subsp. bolletii Forty-nine (94%) isolates from 25 CF patients were identified as M. abscessus subsp. abscessus, whereas 3 (6%) isolates from 2 CF patients were identified as M. abscessus subsp. massiliense Among the isolates from non-CF patients, 44% (8/18) were identified as M. abscessus subsp. abscessus, 39% (7/18) were identified as M. abscessus subsp. massiliense, and 17% (3/18) were identified as M. abscessus subsp. bolletii WGS detected two clusters of closely related M. abscessus subsp. abscessus isolates that included isolates from different CF centers. There was a greater genomic diversity of MABC isolates among the isolates from non-CF patients than among the isolates from CF patients. Although WGS failed to show direct evidence of patient-to-patient transmission among CF patients, there was a predominance of two different strains of M. abscessus subsp. abscessus Furthermore, some MABC isolates were closely related to global strains, suggesting their international spread. Future prospective real-time epidemiological and clinical data along with contemporary MABC sequence analysis may elucidate the sources and routes of transmission among patients infected with MABC.

Characterization of the ABCA4 gene in Stargardt's Disease in Trinidad and Tobago

Objectives: Stargardt's disease is an autosomal recessive macular dystrophy caused by mutations in the photoreceptor cell-specific ATP-binding cassette sub-family A member 4, transporter (ABCA4) gene. We studied (i) the predicted effects of mutations on the function of the ABCA4 transporter and (ii) the existence of four common mutations in local Stargardt patients. Design and Methodology: (i) The freeware PROVEAN (Protein VariationEffect Analyzer; J. Craig Venter Institute, CA,USA) was used to predict the deleterious effect257 mutations in the ABCA4 gene. PROVEANscores below -2.5 were considered deleterious.One-way ANOVAs were used to detect anysignificant differences in mean (±SE) PROVEANscores among mutation types or protein domains I,II, III or IV. (ii) Using saliva, DNA was isolated from three Stargardt patients. Chromosomal regions were amplified by PCR, sequenced (Macrogen Inc., Seoul, Korea) and sequence alignment (NCBI, MD, USA) used to detect the presence of four mutations; c.768G>T (p.Val256=), c.4469G>A (p.Cys1490Tyr), c.6079C>T (p.Leu2027Phe) and c.1804C>T (p.Arg602Trp). Results: (i) Sixty-three percent of mutations predicted deleterious effects. There were no significant (p<0.05) differences between mean PROVEAN scores among mutation types (substitutions, - 4.49±0.20; deletions/insertions, -6.35±0.67) or protein domains (domain I, -4.79 ± 0.39; domain II, -4.65 ± 0.36; domain III, -5.48 ± 0.51; domain IV, -4.39 ± 0.34). (ii) These mutations were not detected in Stargardt's patients. Conclusion: (i) Functionality of the ABCA4 protein is affected by multiple mutations. (ii) Novel mutations are present in local patients. Currently, we seek to profile novel mutations in six families using molecular inversion probes.

Efficacy and Safety of IDegAsp Versus BIAsp 30, Both Twice Daily, in Elderly Patients with Type 2 Diabetes: Post Hoc Analysis of Two Phase 3 Randomized Controlled BOOST Trials.

INTRODUCTION: The majority of elderly patients (≥ 65 years of age) with type 2 diabetes mellitus (T2DM) will eventually require insulin therapy, but they are particularly vulnerable to hypoglycemia and challenging to treat. Insulin degludec/insulin aspart (IDegAsp) is a novel co-formulation of 70% insulin degludec and 30% insulin aspart administered in a single injection, either once or twice daily with main meals. METHODS: A combined analysis of the phase 3 BOOST INTENSIFY PREMIX I (NCT01009580) and BOOST INTENSIFY ALL (NCT01059812) trials has previously reported lower rates of hypoglycemia during the maintenance period in patients with T2DM treated with IDegAsp twice daily (BID) versus biphasic insulin aspart 30 (BIAsp 30) BID. This post hoc analysis examined the safety and efficacy of IDegAsp versus BIAsp 30 in elderly patients from the global population of these two trials, and also from the Japanese cohort of BOOST INTENSIFY ALL. RESULTS: Change in HbA1c was similar for IDegAsp versus BIAsp 30 (p > 0.5). Compared with BIAsp 30, IDegAsp resulted in significant reductions in fasting plasma glucose (p < 0.0001), numerically lower rates of overall and nocturnal hypoglycemia (global estimated rate ratios: 0.92 [0.67; 1.26]95% confidence interval [CI], p = 0.5980 and 0.67 [0.39; 1.18]95% CI, p = 0.1676, respectively), and a significantly lower total daily insulin dose at end of trial (global estimated treatment difference 0.79 [0.73; 0.87]95% CI, p < 0.0001) in elderly patients. CONCLUSION: The results described here are consistent with those of the overall trial populations, demonstrating that IDegAsp BID is efficacious in elderly patients and suggesting that there is no need for special safety precautions. FUNDING: Novo Nordisk. TRIAL REGISTRATION: ClinicalTrials.gov identifiers, NCT01009580 and NCT01059812. Plain language summary available for this article.

Integrated genome and transcriptome sequencing identifies a noncoding mutation in the genome replication factor DONSON as the cause of microcephaly-micromelia syndrome.

While next-generation sequencing has accelerated the discovery of human disease genes, progress has been largely limited to the "low hanging fruit" of mutations with obvious exonic coding or canonical splice site impact. In contrast, the lack of high-throughput, unbiased approaches for functional assessment of most noncoding variants has bottlenecked gene discovery. We report the integration of transcriptome sequencing (RNA-seq), which surveys all mRNAs to reveal functional impacts of variants at the transcription level, into the gene discovery framework for a unique human disease, microcephaly-micromelia syndrome (MMS). MMS is an autosomal recessive condition described thus far in only a single First Nations population and causes intrauterine growth restriction, severe microcephaly, craniofacial anomalies, skeletal dysplasia, and neonatal lethality. Linkage analysis of affected families, including a very large pedigree, identified a single locus on Chromosome 21 linked to the disease (LOD > 9). Comprehensive genome sequencing did not reveal any pathogenic coding or canonical splicing mutations within the linkage region but identified several nonconserved noncoding variants. RNA-seq analysis detected aberrant splicing in DONSON due to one of these noncoding variants, showing a causative role for DONSON disruption in MMS. We show that DONSON is expressed in progenitor cells of embryonic human brain and other proliferating tissues, is co-expressed with components of the DNA replication machinery, and that Donson is essential for early embryonic development in mice as well, suggesting an essential conserved role for DONSON in the cell cycle. Our results demonstrate the utility of integrating transcriptomics into the study of human genetic disease when DNA sequencing alone is not sufficient to reveal the underlying pathogenic mutation.

A de novo deletion in a boy with cerebral palsy suggests a refined critical region for the 4q21.22 microdeletion syndrome.

We present an 18-year-old boy with cerebral palsy, intellectual disability, speech delay, and seizures. He carries a likely pathogenic 1.3 Mb de novo heterozygous deletion in the 4q21.22 microdeletion syndrome region. He also carries a 436 kb maternally-inherited duplication impacting the first three exons of CHRNA7. The majority of previously published cases with 4q21.22 syndrome shared common features including growth restriction, muscular hypotonia, and absent or severely delayed speech. Using copy number variation (CNV) data available for other subjects, we defined a minimal critical region of 170.8 kb within the syndromic region, encompassing HNRNPD. We also identified a larger 2 Mb critical region encompassing ten protein-coding genes, of which six (PRKG2, RASGEF1B, HNRNPDL, HNRNPD, LIN54, COPS4) have a significantly low number of truncating loss-of-function mutations. Long-range chromatin interaction data suggest that this deletion may alter chromatin interactions at the 4q21.22 microdeletion region. We suggest that the deletion or misregulation of these genes is likely to contribute to the neurodevelopmental and neuromuscular abnormalities in 4q21.22 syndrome.

A Review of Insulin Degludec/Insulin Aspart: Pharmacokinetic and Pharmacodynamic Properties and Their Implications in Clinical Use.

Insulin degludec/insulin aspart (IDegAsp; 70 % IDeg and 30 % IAsp) is a soluble combination of two individual insulin analogues in one product, designed to provide mealtime glycaemic control due to the IAsp component and basal glucose-lowering effect from the IDeg component. The pharmacokinetic and pharmacodynamic characteristics of IDegAsp have been investigated in a series of clinical pharmacology studies with generally comparable designs, methodologies and patient inclusion/exclusion criteria. The glucose-lowering effect profile of IDegAsp during once-daily dosing at steady state shows distinct and clearly separated action from the prandial and basal components of IDegAsp. The IAsp component provides rapid onset and peak glucose-lowering effect followed by a flat glucose-lowering effect lasting beyond 30 h due to IDeg. During twice-daily dosing, the distinct peak effect and the flat basal effect are retained following each dose. The pharmacological properties of IDegAsp are maintained in the elderly, children, adolescents, Japanese patients and those with hepatic or renal impairment. The potential clinical benefits associated with the pharmacological properties of IDegAsp have been verified in phase III clinical trials comparing IDegAsp with three other currently available treatment options: premixed insulin, basal-bolus regimens and basal-only therapy. IDegAsp shows favourable clinical benefits compared with biphasic insulin aspart 30 and is a viable alternative to basal-bolus and basal-only therapy. This review presents the results from clinical pharmacology studies conducted with IDegAsp to date, and extrapolates these results to clinical use of IDegAsp in the context of findings from the IDegAsp clinical therapeutic studies.

A novel NDUFS4 frameshift mutation causes Leigh disease in the Hutterite population.

Leigh disease is a progressive, infantile-onset, neurodegenerative disorder characterized by feeding difficulties, failure to thrive, hypotonia, seizures, and central respiratory compromise. Metabolic and neuroimaging investigations typically identify abnormalities consistent with a disorder of mitochondrial energy metabolism. Mutations in more than 35 genes affecting the mitochondrial respiratory chain encoded from both the nuclear and mitochondrial genomes have been associated with Leigh disease. The clinical presentations of five individuals of Hutterite descent with Leigh disease are described herein. An identity-by-descent mapping and candidate gene approach was used to identify a novel homozygous c.393dupA frameshift mutation in the NADH dehydrogenase (ubiquinone) Fe-S protein 4 (NDUFS4) gene. The carrier frequency of this mutation was estimated in >1,300 Hutterite individuals to be 1 in 27. © 2017 Wiley Periodicals, Inc.

Disrupted auto-regulation of the spliceosomal gene SNRPB causes cerebro-costo-mandibular syndrome.

Elucidating the function of highly conserved regulatory sequences is a significant challenge in genomics today. Certain intragenic highly conserved elements have been associated with regulating levels of core components of the spliceosome and alternative splicing of downstream genes. Here we identify mutations in one such element, a regulatory alternative exon of SNRPB as the cause of cerebro-costo-mandibular syndrome. This exon contains a premature termination codon that triggers nonsense-mediated mRNA decay when included in the transcript. These mutations cause increased inclusion of the alternative exon and decreased overall expression of SNRPB. We provide evidence for the functional importance of this conserved intragenic element in the regulation of alternative splicing and development, and suggest that the evolution of such a regulatory mechanism has contributed to the complexity of mammalian development.

Complex genomic rearrangements in the dystrophin gene due to replication-based mechanisms.

Genomic rearrangements such as intragenic deletions and duplications are the most prevalent type of mutations in the dystrophin gene resulting in Duchenne and Becker muscular dystrophy (D/BMD). These copy number variations (CNVs) are nonrecurrent and can result from either nonhomologous end joining (NHEJ) or microhomology-mediated replication-dependent recombination (MMRDR). We characterized five DMD patients with complex genomic rearrangements using a combination of MLPA/mRNA transcript analysis/custom array comparative hybridization arrays (CGH) and breakpoint sequence analysis to investigate the mechanisms for these rearrangements. Two patients had complex rearrangements that involved microhomologies at breakpoints. One patient had a noncontiguous insertion of 89.7 kb chromosome 4 into intron 43 of DMD involving three breakpoints with 2-5 bp microhomology at the junctions. A second patient had an inversion of exon 44 flanked by intronic deletions with two breakpoint junctions each showing 2 bp microhomology. The third patient was a female with an inherited deletion of exon 47 in DMD on the maternal allele and a de novo noncontiguous duplication of exons 45-49 in DMD and MID1 on the paternal allele. The other two patients harbored complex noncontiguous duplications within the dystrophin gene. We propose a replication-based mechanisms for all five complex DMD rearrangements. This study identifies additional underlying mechanisms in DMD, and provides insight into the molecular bases of these genomic rearrangements.

Extreme intra-familial variability of congenital central hypoventilation syndrome: a case series.

INTRODUCTION: Congenital central hypoventilation syndrome is an autosomal dominant disorder that classically presents as sudden death in infancy secondary to central hypoventilation. Most cases are caused by polyalanine repeat mutations in the paired-like homeobox 2B gene, PHOX2B. More severe disease is typically associated with nonpolyalanine repeat mutations. We report the case of a family with nonpolyalanine repeat mutations that uncharacteristically has many individuals who were mildly symptomatic and only diagnosed after genetic testing. We highlight the highly variable clinical presentation of this condition and the need for clinicians to remain vigilant. CASE PRESENTATION: We identified 10 individuals in a large extended Caucasian family of German and Austrian background with congenital central hypoventilation syndrome.Case 1: A 16-year old male proband presented for reproductive counseling. He had a previous history of apneic spells and Hirschsprung disease in the neonatal period. A PHOX2B nonpolyalanine repeat mutation was identified in the proband and used to screen his extended family.Cases 2 to 10: Several mildly symptomatic family members (males aged 5, 13, 42 and 80 years; females aged 28, 44, 46 and 48 years) spanning four generations were identified after genetic screening. A newborn boy from this family was also recently diagnosed with Hirschsprung disease and went on to have an abnormal sleep study. CONCLUSIONS: In this report, we highlight the significant phenotypic variability of congenital central hypoventilation syndrome, previously thought to be a rare genetic condition. Given the extreme clinical variability, it is possible that the prevalence of congenital central hypoventilation syndrome in the general population is much higher than previous estimates. This is of major importance to all clinicians who will need to maintain a high index of suspicion for this not so rare and highly clinically variable genetic condition that spans all ages. As the familial mutation has been identified, presymptomatic and prenatal diagnostic testing are available options for family members.

GPSM2 mutations cause the brain malformations and hearing loss in Chudley-McCullough syndrome.

Autosomal-recessive inheritance, severe to profound sensorineural hearing loss, and partial agenesis of the corpus callosum are hallmarks of the clinically well-established Chudley-McCullough syndrome (CMS). Although not always reported in the literature, frontal polymicrogyria and gray matter heterotopia are uniformly present, whereas cerebellar dysplasia, ventriculomegaly, and arachnoid cysts are nearly invariant. Despite these striking brain malformations, individuals with CMS generally do not present with significant neurodevelopmental abnormalities, except for hearing loss. Homozygosity mapping and whole-exome sequencing of DNA from affected individuals in eight families (including the family in the first report of CMS) revealed four molecular variations (two single-base deletions, a nonsense mutation, and a canonical splice-site mutation) in the G protein-signaling modulator 2 gene, GPSM2, that underlie CMS. Mutations in GPSM2 have been previously identified in people with profound congenital nonsyndromic hearing loss (NSHL). Subsequent brain imaging of these individuals revealed frontal polymicrogyria, abnormal corpus callosum, and gray matter heterotopia, consistent with a CMS diagnosis, but no ventriculomegaly. The gene product, GPSM2, is required for orienting the mitotic spindle during cell division in multiple tissues, suggesting that the sensorineural hearing loss and characteristic brain malformations of CMS are due to defects in asymmetric cell divisions during development.

Evaluation of screening risk and nonrisk patients for methicillin-resistant Staphylococcus aureus on admission in an acute care hospital.

BACKGROUND: Screening for methicillin-resistant Staphylocccus aureus (MRSA) is advocated as part of control measures, but screening all patients on admission to hospital may not be cost-effective. OBJECTIVE: Our objective was to evaluate the additional yield of screening all patients on admission compared with only patients with risk factors and to assess cost aspects. METHODS: A prospective, nonrandomized observational study of screening nonrisk patients ≤72 hours of admission compared with only screening patients with risk factors over 3 years in a tertiary referral hospital was conducted. We also assessed the costs of screening both groups. RESULTS: A total of 48 of 892 (5%) patients was MRSA positive; 28 of 314 (9%) during year 1, 12 of 257 (5%) during year 2, and 8 of 321 (2%) during year 3. There were significantly fewer MRSA-positive patients among nonrisk compared with MRSA-risk patients: 4 of 340 (1%) versus 44 of 552 (8%), P ≤ .0001, respectively. However, screening nonrisk patients increased the number of screening samples by 62% with a proportionate increase in the costs of screening. A backward stepwise logistic regression model identified age > 70 years, diagnosis of chronic pulmonary disease, previous MRSA infection, and admission to hospital during the previous 18 months as the most important independent predictors to discriminate between MRSA-positive and MRSA-negative patients on admission (94.3% accuracy, P < .001). CONCLUSION: Screening patients without risk factors increased the number of screenings and costs but resulted in few additional cases being detected. In a hospital where MRSA is endemic, targeted screening of at-risk patients on admission remains the most efficient strategy for the early identification of MRSA-positive patients.

Perinatal and childhood morbidity and mortality in congenital analbuminemia.

Albumin, a serum transport protein, provides 80% of colloid osmotic pressure. Congenital analbuminemia (CAA) is an autosomal recessive disorder characterized by absence of serum albumin. Fifty cases of CAA have been reported throughout the world; however, little is known about its clinical impact. Most reported cases have few clinical signs and symptoms. Twelve local cases from the northwestern central plains region in Saskatchewan were identified and reviewed to ascertain morbidity and mortality related with CAA. All the cases are from two remote First Nations communities. Cases had frequent hospital admissions and recurrent respiratory tract infections. Placental abnormalities included hydropic placentas, placental infarcts and microcalcifications. One-half of the cases were born preterm and one-quarter were small for their gestational age. There were three mortalities in the case series. The present case series suggests increased morbidity and mortality during infancy in patients with CAA. The long-term risks of CAA in this population are unknown and a longitudinal study is recommended.

L'albumine, une protéine du transport sérique, fournit 80 % de la pression colloïdo-osmotique. L'analbuminémie congénitale (AAC) est un trouble autosomique récessif caractérisé par l'absence d'albumine sérique. Cinquante cas d'AAC ont été signalés dans le monde, mais on ne sait pas grand-chose de ses répercussions cliniques. La plupart des cas déclarés s'associaient à peu de signes et symptômes cliniques. Les chercheurs ont dépisté 12 cas locaux, originaires de la région du nord-ouest des plaines centrales, en Saskatchewan, et les ont analysés afin de déterminer la morbidité et la mortalité liées à l'AAC. Tous les cas provenaient de deux communautés éloignées des Premières nations. Ils étaient souvent hospitalisés et avaient des infections respiratoires récurrentes. Les anomalies placentaires incluaient des placentas hydropiques, des infarctus placentaires et des microcalcifications. La moitié des cas étaient prématurés et le quart d'entre eux étaient petits par rapport à leur âge gestationnel. Trois mortalités ont été constatées. Cette série a démontré une augmentation de la morbidité et de la mortalité pendant l'enfance chez les patients ayant une AAC. On ne connaît pas les risques à long terme de l'AAC au sein de cette population. Une étude longitudinale est recommandée.

Further expansion of the phenotypic spectrum associated with mutations in ALDH18A1, encoding Δ¹-pyrroline-5-carboxylate synthase (P5CS).

We report on the third case of cutis laxa and progeroid features caused by a homozygous mutation in ALDH18A1 that encodes Δ¹-pyrroline-5-carboxylate-synthase (P5CS). This severely affected child, born to consanguineous parents of Pakistani origin, presented with lax, wrinkled and thin skin with dilated and tortuous subcutaneous blood vessels, corneal clouding, and hypotonia. The child had severe global developmental delay and feeding difficulties and died in infancy for an unknown reason. The proband was homozygous for a mutation in ALDH18A1, c.1923 + 1G > A which results in the production of two anomalous transcripts that are predicted to encode proteins lacking the catalytic site for the enzyme. The cellular phenotype is characterized by diminished production of collagen types I and III, altered elastin ultrastructure, and diminished cell proliferation of cultured dermal fibroblasts. This severe clinical and cellular phenotype overlaps with a broad group of neurocutaneous syndromes that include cutis laxa type II, wrinkly skin syndrome, de Barsy syndrome, and gerodermia osteodysplastica. The findings presented here emphasize the pleiotropic presentation of this group of conditions and suggest that multiple components of the extracellular matrix are perturbed in these disorders.