Time for change: a new training programme for morpho-molecular pathologists?

The evolution of cellular pathology as a specialty has always been driven by technological developments and the clinical relevance of incorporating novel investigations into diagnostic practice. In recent years, the molecular characterisation of cancer has become of crucial relevance in patient treatment both for predictive testing and subclassification of certain tumours. Much of this has become possible due to the availability of next-generation sequencing technologies and the whole-genome sequencing of tumours is now being rolled out into clinical practice in England via the 100 000 Genome Project. The effective integration of cellular pathology reporting and genomic characterisation is crucial to ensure the morphological and genomic data are interpreted in the relevant context, though despite this, in many UK centres molecular testing is entirely detached from cellular pathology departments. The CM-Path initiative recognises there is a genomics knowledge and skills gap within cellular pathology that needs to be bridged through an upskilling of the current workforce and a redesign of pathology training. Bridging this gap will allow the development of an integrated 'morphomolecular pathology' specialty, which can maintain the relevance of cellular pathology at the centre of cancer patient management and allow the pathology community to continue to be a major influence in cancer discovery as well as playing a driving role in the delivery of precision medicine approaches. Here, several alternative models of pathology training, designed to address this challenge, are presented and appraised

Blue cone monochromacy: causative mutations and associated phenotypes.

PurposeTo perform a phenotypic assessment of members of three British families with blue cone monochromatism (BCM), and to determine the underlying molecular genetic basis of disease.MethodsAffected members of three British families with BCM were examined clinically and underwent detailed electrophysiological and psychophysical testing. Blood samples were taken for DNA extraction. Molecular analysis involved the amplification of the coding regions of the long (L) and medium (M) wave cone opsin genes and the upstream locus control region (LCR) by polymerase chain reaction (PCR). Gene products were directly sequenced and analyzed.ResultsIn all three families, genetic analysis identified that the underlying cause of BCM involved an unequal crossover within the opsin gene array, with an inactivating mutation. Family 1 had a single 5'-L-M-3' hybrid gene, with an inactivating Cys203Arg (C203R) mutation. Family 3 had an array composed of a C203R inactivated 5'-L-M-3' hybrid gene followed by a second inactive gene. Families 1 and 3 had typical clinical, electrophysiological, and psychophysical findings consistent with stationary BCM. A novel mutation was detected in Family 2 that had a single hybrid gene lacking exon 2. This family presented clinical and psychophysical evidence of a slowly progressive phenotype.ConclusionsTwo of the BCM-causing family genotypes identified in this study comprised different hybrid genes, each of which contained the commonly described C203R inactivating mutation. The genotype in the family with evidence of a slowly progressive phenotype represents a novel BCM mutation. The deleted exon 2 in this family is not predicted to result in a shift in the reading frame, therefore we hypothesize that an abnormal opsin protein product may accumulate and lead to cone cell loss over time. This is the first report of slow progression associated with this class of mutation in the L or M opsin genes in BCM

Promoting the Health of Parents & Children: Addressing Perinatal Mental Health by Building Medical Provider Capacity Through Perinatal Psychiatry Access Programs

Mental health conditions are the most common obstetric complications of the perinatal period, impacting 1 in 5 individuals during pregnancy and the year following pregnancy. Perinatal mental health (PMH) conditions have deleterious effects on the health of perinatal individuals and their children, and are a leading and preventable cause of maternal mortality. Nevertheless, PMH conditions are underrecognized, underdiagnosed, and undertreated. To address these gaps, Massachusetts created the Massachusetts Child Psychiatry Access Program (MCPAP) for Moms to build the capacity of frontline medical providers to address PMH conditions by providing education, consultation, and resources and referrals. MCPAP for Moms has emerged as a successful and scalable model with at least 25 states or organizations implementing or developing similar Perinatal Psychiatry Access Programs. This report summarizes the Perinatal Psychiatry Access Program model and its individual and national impact

A comparison of postrelease survival parameters between single and mass stranded delphinids from Cape Cod, Massachusetts, U.S.A.

© The Author(s), 2015. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Marine Mammal Science 32 (2016): 161–180, doi:10.1111/mms.12255.The viability of healthy single stranded dolphins as immediate release candidates has received little attention. Responders have been reluctant to release lone delphinids due to their social needs, even when they pass the same health evaluations as mass stranded animals. This study tracked postrelease success of 34 relocated and released satellite tagged delphinids from single and mass strandings. Three postrelease survival parameters (transmission duration, swim speed, and daily distance) were examined to evaluate whether they differed among single stranded/single released (SS/SR), mass stranded/single released (MS/SR), or mass stranded/mass released (MS/MR) dolphin groups. Comparisons were also made between healthy and borderline release candidates. Satellite tags transmitted for a mean of 21.2 d (SD = 19.2, range = 1–79), daily distance traveled was 42.0 km/d (11.25, 20.96–70.72), and swim speed was 4.3 km/h (1.1, 2.15–8.54). Postrelease parameters did not differ between health status groups, however, SS/SR dolphins transmitted for a shorter mean duration than MS/MR and MS/SR groups. Postrelease vessel-based surveys confirmed conspecific group location for two healthy, MS/SR dolphins. Overall, these results support the potential to release healthy stranded single delphinids; however, further refinement of health assessment protocols for these challenging cases is needed.National Oceanic and Atmospheric Administration's National Marine Fisheries Service (NOAA NMFS); John H. Prescott Marine Mammal Rescue Assistance Program Grant Numbers: NA11NMF4390078, NA11NMF4390079, NA11NMF439009

The infrared imaging spectrograph (IRIS) for TMT: the science case

The InfraRed Imaging Spectrograph (IRIS) is a first-light instrument being designed for the Thirty Meter Telescope (TMT). IRIS is a combination of an imager that will cover a 16.4" field of view at the diffraction limit of TMT (4 mas sampling), and an integral field unit spectrograph that will sample objects at 4-50 mas scales. IRIS will open up new areas of observational parameter space, allowing major progress in diverse fields of astronomy. We present the science case and resulting requirements for the performance of IRIS. Ultimately, the spectrograph will enable very well-resolved and sensitive studies of the kinematics and internal chemical abundances of high-redshift galaxies, shedding light on many scenarios for the evolution of galaxies at early times. With unprecedented imaging and spectroscopy of exoplanets, IRIS will allow detailed exploration of a range of planetary systems that are inaccessible with current technology. By revealing details about resolved stellar populations in nearby galaxies, it will directly probe the formation of systems like our own Milky Way. Because it will be possible to directly characterize the stellar initial mass function in many environments and in galaxies outside of the the Milky Way, IRIS will enable a greater understanding of whether stars form differently in diverse conditions. IRIS will reveal detailed kinematics in the centers of low-mass galaxies, allowing a test of black hole formation scenarios. Finally, it will revolutionize the characterization of reionization and the first galaxies to form in the universe.Comment: to appear in Proc. SPIE 773

Smoking Social Norms Among Spanish-Speaking Mexican-Origin Persons Who Smoke

In the United States, smoking rates increase with greater acculturation among Mexican-origin women, but not among men. Conversely, greater acculturation is associated with higher likelihood of quitting among Mexican-origin men who smoke, but not among women who smoke. Long-standing speculation is that adoption of smoking social norms in the U.S. that are less restrictive for women and more restrictive for men compared to smoking social norms in Mexico may account for these patterns. However, it is unknown whether persons who smoke actually perceive such differential norms. The current study characterized smoking social norms in the U.S. and Mexico among Spanish-speaking Mexican-origin persons who smoke. Two hundred and ninety Mexican-origin persons who smoke were surveyed on descriptive and injunctive norms for men and women in the U.S. and Mexico. Estimated means for smoking social norms in the U.S. and Mexico were compared separately among men and women. Among men, mean descriptive and injunctive norms in Mexico were significantly higher than those for the U.S. Among women, neither mean descriptive nor injunctive norms were significantly different between the U.S. and Mexico. Mexican-origin women who smoke perceive smoking among women as equally common and similarly unacceptable in the U.S. and Mexico. Findings do not support speculation that differential social norms may explain the acculturation-smoking relationship among Mexican-origin women. Mexican-origin men who smoke perceive smoking among men both less common and less acceptable in the U.S. compared to Mexico. Social norms should be investigated as a mechanism of the acculturation-cessation relationship among Mexican-origin men. Understanding direct and indirect influences of social norms on cessation among Mexican-origin men stands to inform tailoring of interventions

Initiation codon mutation in βB1-crystallin (CRYBB1) associated with autosomal recessive nuclear pulverulent cataract

PurposeTo identify the molecular basis for autosomal recessively inherited congenital non-syndromic pulverulent cataracts in a consanguineous family with four affected children.MethodsAn autozygosity mapping strategy using high density SNP microarrays and microsatellite markers was employed to detect regions of homozygosity. Subsequently good candidate genes were screened for mutations by direct sequencing.ResultsThe SNP microarray data demonstrated a 24.96 Mb region of homozygosity at 22q11.21-22q13.2 which was confirmed by microsatellite marker analysis. The candidate target region contained the beta-crystallin gene cluster and direct sequencing in affected family members revealed a novel mutation in CRYBB1 (c.2T>A; p.Met1Lys).ConclusionsTo our knowledge this is the first case of an initiation codon mutation in a human crystallin gene, and only the second report of a CRYBB1 mutation associated with autosomal recessive congenital cataracts. In addition, although a number of genetic causes of autosomal dominant pulverulent cataracts have been identified (including CRYBB1) this is the first gene to have been implicated in autosomal recessive nuclear pulverulent cataract

The Effect of Cone Opsin Mutations on Retinal Structure and the Integrity of the Photoreceptor Mosaic

Purpose. To evaluate retinal structure and photoreceptor mosaic integrity in subjects with OPN1LW and OPN1MW mutations. Methods. Eleven subjects were recruited, eight of whom have been previously described. Cone and rod density was measured using images of the photoreceptor mosaic obtained from an adaptive optics scanning light ophthalmoscope (AOSLO). Total retinal thickness, inner retinal thickness, and outer nuclear layer plus Henle fiber layer (ONL+HFL) thickness were measured using cross-sectional spectral-domain optical coherence tomography (SD-OCT) images. Molecular genetic analyses were performed to characterize the OPN1LW/OPN1MW gene array. Results. While disruptions in retinal lamination and cone mosaic structure were observed in all subjects, genotype-specific differences were also observed. For example, subjects with “L/M interchange” mutations resulting from intermixing of ancestral OPN1LW and OPN1MW genes had significant residual cone structure in the parafovea (∼25% of normal), despite widespread retinal disruption that included a large foveal lesion and thinning of the parafoveal inner retina. These subjects also reported a later-onset, progressive loss of visual function. In contrast, subjects with the C203R missense mutation presented with congenital blue cone monochromacy, with retinal lamination defects being restricted to the ONL+HFL and the degree of residual cone structure (8% of normal) being consistent with that expected for the S-cone submosaic. Conclusions. The photoreceptor phenotype associated with OPN1LW and OPN1MW mutations is highly variable. These findings have implications for the potential restoration of visual function in subjects with opsin mutations. Our study highlights the importance of high-resolution phenotyping to characterize cellular structure in inherited retinal disease; such information will be critical for selecting patients most likely to respond to therapeutic intervention and for establishing a baseline for evaluating treatment efficacy

Periconceptional environment predicts leukocyte telomere length in a cross-sectional study of 7-9 year old rural Gambian children

Early life exposures are important predictors of adult disease risk. Although the underlying mechanisms are largely unknown, telomere maintenance may be involved. This study investigated the relationship between seasonal differences in parental exposures at time of conception and leukocyte telomere length (LTL) in their offspring. LTL was measured in two cohorts of children aged 2 yrs (N = 487) and 7–9 yrs (N = 218). The association between date of conception and LTL was examined using Fourier regression models, adjusted for age, sex, leukocyte cell composition, and other potential confounders. We observed an effect of season in the older children in all models [likelihood ratio test (LRT) χ²2 = 7.1, p = 0.03; fully adjusted model]. LTL was greatest in children conceived in September (in the rainy season), and smallest in those conceived in March (in the dry season), with an effect size (LTL peak–nadir) of 0.60 z-scores. No effect of season was evident in the younger children (LRT χ²2 = 0.87, p = 0.65). The different results obtained for the two cohorts may reflect a delayed effect of season of conception on postnatal telomere maintenance. Alternatively, they may be explained by unmeasured differences in early life exposures, or the increased telomere attrition rate during infancy