Autosomal dominant ApoA4 mutations present as tubulointerstitial kidney disease with medullary amyloidosis.

Sporadic cases of apolipoprotein A-IV medullary amyloidosis have been reported. Here we describe five families found to have autosomal dominant medullary amyloidosis due to two different pathogenic APOA4 variants. A large family with autosomal dominant chronic kidney disease (CKD) and bland urinary sediment underwent whole genome sequencing with identification of a chr11:116692578 G>C (hg19) variant encoding the missense mutation p.L66V of the ApoA4 protein. We identified two other distantly related families from our registry with the same variant and two other distantly related families with a chr11:116693454 C>T (hg19) variant encoding the missense mutation p.D33N. Both mutations are unique to affected families, evolutionarily conserved and predicted to expand the amyloidogenic hotspot in the ApoA4 structure. Clinically affected individuals suffered from CKD with a bland urinary sediment and a mean age for kidney failure of 64.5 years. Genotyping identified 48 genetically affected individuals; 44 individuals had an estimated glomerular filtration rate (eGFR) under 60 ml/min/1.73 m2, including all 25 individuals with kidney failure. Significantly, 11 of 14 genetically unaffected individuals had an eGFR over 60 ml/min/1.73 m2. Fifteen genetically affected individuals presented with higher plasma ApoA4 concentrations. Kidney pathologic specimens from four individuals revealed amyloid deposits limited to the medulla, with the mutated ApoA4 identified by mass-spectrometry as the predominant amyloid constituent in all three available biopsies. Thus, ApoA4 mutations can cause autosomal dominant medullary amyloidosis, with marked amyloid deposition limited to the kidney medulla and presenting with autosomal dominant CKD with a bland urinary sediment. Diagnosis relies on a careful family history, APOA4 sequencing and pathologic studies.

Extending Arts-Based Interventions in Graduate Medical Education through the Positive Humanities: the Re-FRAME Workshop.

BACKGROUND: Arts-and-humanities-based interventions are commonly implemented in medical education to promote well-being and mitigate the risk of burnout. However, mechanisms for achieving these effects remain uncertain within graduate medical education. The emerging field of the positive humanities offers a lens to examine whether and how arts-based interventions support well-being in internal medicine interns. AIM: Through program evaluation of this visual art workshop, we used a positive humanities framework to elucidate potential mechanisms by which arts-based curricula support well-being in internal medicine interns. SETTING: We launched the re-FRAME workshop at the Philadelphia Museum of Art in winter 2020. PARTICIPANTS: Fifty-six PGY-1 trainees from one internal medicine residency program. PROGRAM DESCRIPTION: The 3-h re-FRAME workshop consisted of an introductory session on emotional processing followed by two previously described arts-based interventions. PROGRAM EVALUATION: Participants completed an immediate post-workshop survey (91% response rate) assessing attitudes towards the session. Analysis of open-ended survey data demonstrated 4 categories for supporting well-being among participants: becoming emotionally aware/expressive through art, pausing for reflection, practicing nonjudgmental observation, and normalizing experiences through socialization. DISCUSSION: Our project substantiated proposed mechanisms from the positive humanities for supporting well-being-including reflectiveness, skill acquisition, socialization, and expressiveness-among medical interns.

Twelve tips for excelling as an introvert in academic medicine (at all levels).

BACKGROUND: Introverted individuals comprise up to half of the population, but are often overlooked in a culture that privileges extraversion. This misunderstanding of introversion has downstream effects for introverts in academic medicine, including lower grades on clinical rotations, increased stress, and under-representation in leadership positions. AIMS: To increase support for and awareness of the unique strengths of introverted individuals at all stages of a career in academic medicine. DESCRIPTION: This article offers twelve tips, based in the educational, business, and personality literature, to empower introverted students, residents, and faculty members for success in academic medicine. While many of the tips apply broadly, certain tips may be more relevant to those in a particular career stage. CONCLUSION: Increased understanding of the natural tendencies and strengths of introversion will promote a more inclusive working environment for all personality types in medicine and allow introverts at all levels of training and practice to thrive.

Müller glia-derived PRSS56 is required to sustain ocular axial growth and prevent refractive error.

A mismatch between optical power and ocular axial length results in refractive errors. Uncorrected refractive errors constitute the most common cause of vision loss and second leading cause of blindness worldwide. Although the retina is known to play a critical role in regulating ocular growth and refractive development, the precise factors and mechanisms involved are poorly defined. We have previously identified a role for the secreted serine protease PRSS56 in ocular size determination and PRSS56 variants have been implicated in the etiology of both hyperopia and myopia, highlighting its importance in refractive development. Here, we use a combination of genetic mouse models to demonstrate that Prss56 mutations leading to reduced ocular size and hyperopia act via a loss of function mechanism. Using a conditional gene targeting strategy, we show that PRSS56 derived from Müller glia contributes to ocular growth, implicating a new retinal cell type in ocular size determination. Importantly, we demonstrate that persistent activity of PRSS56 is required during distinct developmental stages spanning the pre- and post-eye opening periods to ensure optimal ocular growth. Thus, our mouse data provide evidence for the existence of a molecule contributing to both the prenatal and postnatal stages of human ocular growth. Finally, we demonstrate that genetic inactivation of Prss56 rescues axial elongation in a mouse model of myopia caused by a null mutation in Egr1. Overall, our findings identify PRSS56 as a potential therapeutic target for modulating ocular growth aimed at preventing or slowing down myopia, which is reaching epidemic proportions.

Association of Rare CYP39A1 Variants With Exfoliation Syndrome Involving the Anterior Chamber of the Eye.

Importance: Exfoliation syndrome is a systemic disorder characterized by progressive accumulation of abnormal fibrillar protein aggregates manifesting clinically in the anterior chamber of the eye. This disorder is the most commonly known cause of glaucoma and a major cause of irreversible blindness. Objective: To determine if exfoliation syndrome is associated with rare, protein-changing variants predicted to impair protein function. Design, Setting, and Participants: A 2-stage, case-control, whole-exome sequencing association study with a discovery cohort and 2 independently ascertained validation cohorts. Study participants from 14 countries were enrolled between February 1999 and December 2019. The date of last clinical follow-up was December 2019. Affected individuals had exfoliation material on anterior segment structures of at least 1 eye as visualized by slit lamp examination. Unaffected individuals had no signs of exfoliation syndrome. Exposures: Rare, coding-sequence genetic variants predicted to be damaging by bioinformatic algorithms trained to recognize alterations that impair protein function. Main Outcomes and Measures: The primary outcome was the presence of exfoliation syndrome. Exome-wide significance for detected variants was defined as P < 2.5 × 10-6. The secondary outcomes included biochemical enzymatic assays and gene expression analyses. Results: The discovery cohort included 4028 participants with exfoliation syndrome (median age, 78 years [interquartile range, 73-83 years]; 2377 [59.0%] women) and 5638 participants without exfoliation syndrome (median age, 72 years [interquartile range, 65-78 years]; 3159 [56.0%] women). In the discovery cohort, persons with exfoliation syndrome, compared with those without exfoliation syndrome, were significantly more likely to carry damaging CYP39A1 variants (1.3% vs 0.30%, respectively; odds ratio, 3.55 [95% CI, 2.07-6.10]; P = 6.1 × 10-7). This outcome was validated in 2 independent cohorts. The first validation cohort included 2337 individuals with exfoliation syndrome (median age, 74 years; 1132 women; n = 1934 with demographic data) and 2813 individuals without exfoliation syndrome (median age, 72 years; 1287 women; n = 2421 with demographic data). The second validation cohort included 1663 individuals with exfoliation syndrome (median age, 75 years; 587 women; n = 1064 with demographic data) and 3962 individuals without exfoliation syndrome (median age, 74 years; 951 women; n = 1555 with demographic data). Of the individuals from both validation cohorts, 5.2% with exfoliation syndrome carried CYP39A1 damaging alleles vs 3.1% without exfoliation syndrome (odds ratio, 1.82 [95% CI, 1.47-2.26]; P < .001). Biochemical assays classified 34 of 42 damaging CYP39A1 alleles as functionally deficient (median reduction in enzymatic activity compared with wild-type CYP39A1, 94.4% [interquartile range, 78.7%-98.2%] for the 34 deficient variants). CYP39A1 transcript expression was 47% lower (95% CI, 30%-64% lower; P < .001) in ciliary body tissues from individuals with exfoliation syndrome compared with individuals without exfoliation syndrome. Conclusions and Relevance: In this whole-exome sequencing case-control study, presence of exfoliation syndrome was significantly associated with carriage of functionally deficient CYP39A1 sequence variants. Further research is needed to understand the clinical implications of these findings.

Germline mutations in MAP3K6 are associated with familial gastric cancer.

Gastric cancer is among the leading causes of cancer-related deaths worldwide. While heritable forms of gastric cancer are relatively rare, identifying the genes responsible for such cases can inform diagnosis and treatment for both hereditary and sporadic cases of gastric cancer. Mutations in the E-cadherin gene, CDH1, account for 40% of the most common form of familial gastric cancer (FGC), hereditary diffuse gastric cancer (HDGC). The genes responsible for the remaining forms of FGC are currently unknown. Here we examined a large family from Maritime Canada with FGC without CDH1 mutations, and identified a germline coding variant (p.P946L) in mitogen-activated protein kinase kinase kinase 6 (MAP3K6). Based on conservation, predicted pathogenicity and a known role of the gene in cancer predisposition, MAP3K6 was considered a strong candidate and was investigated further. Screening of an additional 115 unrelated individuals with non-CDH1 FGC identified the p.P946L MAP3K6 variant, as well as four additional coding variants in MAP3K6 (p.F849Sfs*142, p.P958T, p.D200Y and p.V207G). A somatic second-hit variant (p.H506Y) was present in DNA obtained from one of the tumor specimens, and evidence of DNA hypermethylation within the MAP3K6 gene was observed in DNA from the tumor of another affected individual. These findings, together with previous evidence from mouse models that MAP3K6 acts as a tumor suppressor, and studies showing the presence of somatic mutations in MAP3K6 in non-hereditary gastric cancers and gastric cancer cell lines, point towards MAP3K6 variants as a predisposing factor for FGC.

Attitudes of parents toward the return of targeted and incidental genomic research findings in children.

PURPOSE: We describe parental attitudes toward the return of targeted and incidental genomic research results in the setting of high-risk pediatric cancer and inherited childhood diseases. METHODS: A validated 36-item questionnaire was mailed to participants in three large-scale genome research consortia examining attitudes toward receipt of genomic research results and the influence of certainty, severity, and onset of the condition, in addition to responsibilities to extended family and provision of results even after death of the proband. RESULTS: Of the 563 participants who were sent questionnaires, 362 (64%) responded. Most of them stated a positive right to receive results related to the target condition (97%) or to incidental findings (86%); no difference was found in results between participants with cancer and those with orphan diseases. Furthermore, 92% indicated that genomic research for childhood-onset conditions should occur. The majority wanted incidental results predicting susceptibility even to untreatable fatal conditions (83%), to multiple conditions (87%), or to those with uncertain impact (70%). Most felt sibling genomic results showing serious conditions, whether treatable (93%) or not (88%), and/or results discovered after death of the proband should be shared with family (74%). CONCLUSION: Many parents of children in pediatric genomic research indicated a strong desire to receive a broader range of results than is described in consensus recommendations. Clear delineation of what will be offered should be established at the time of consent.

A novel hospitalist peer observation program to improve educational and operational rounding practices.

Academic hospitalists must balance trainee education with operational demands to round efficiently and optimize hospital throughput. Peer observation has been shown to support educator development, however, few hospitalists have formal training to optimize both skill sets. We sought to extend and adapt peer observation programs to equally focus on education and operations-based outcomes. During the 2-year study period, 76 of 98 (78%) eligible faculty participated in a structured, real-time peer observation program. Immediately after observing a peer, 42% of respondents planned to adopt an operations-related rounding behavior. Following program completion, 77% of respondents endorsed the implementation of a new rounding behavior learned from a peer, with a third of these behaviors related to clinical operations. Ninety-five percent of respondents endorsed at least a moderate degree of program satisfaction. High levels of engagement and sustained behavior change following program participation suggest clinical operations are an important addition to peer observation programs and faculty development initiatives.

A novel rearrangement of occludin causes brain calcification and renal dysfunction.

Pediatric intracranial calcification may be caused by inherited or acquired factors. We describe the identification of a novel rearrangement in which a downstream pseudogene translocates into exon 9 of OCLN, resulting in band-like brain calcification and advanced chronic kidney disease in early childhood. SNP genotyping and read-depth variation from whole exome sequencing initially pointed to a mutation in the OCLN gene. The high degree of identity between OCLN and two pseudogenes required a combination of multiplex ligation-dependent probe amplification, PCR, and Sanger sequencing to identify the genomic rearrangement that was the underlying genetic cause of the disease. Mutations in exon 3, or at the 5-6 intron splice site, of OCLN have been reported to cause brain calcification and polymicrogyria with no evidence of extra-cranial phenotypes. Of the OCLN splice variants described, all make use of exon 9, while OCLN variants that use exons 3, 5, and 6 are tissue specific. The genetic rearrangement we identified in exon 9 provides a plausible explanation for the expanded clinical phenotype observed in our individuals. Furthermore, the lack of polymicrogyria associated with the rearrangement of OCLN in our patients extends the range of cranial defects that can be observed due to OCLN mutations.

Mutations in centrosomal protein CEP152 in primary microcephaly families linked to MCPH4.

Primary microcephaly is a rare condition in which brain size is substantially diminished without other syndromic abnormalities. Seven autosomal loci have been genetically mapped, and the underlying causal genes have been identified for MCPH1, MCPH3, MCPH5, MCPH6, and MCPH7 but not for MCPH2 or MCPH4. The known genes play roles in mitosis and cell division. We ascertained three families from an Eastern Canadian subpopulation, each with one microcephalic child. Homozygosity analysis in two families using genome-wide dense SNP genotyping supported linkage to the published MCPH4 locus on chromosome 15q21.1. Sequencing of coding exons of candidate genes in the interval identified a nonconservative amino acid change in a highly conserved residue of the centrosomal protein CEP152. The affected children in these two families were both homozygous for this missense variant. The third affected child was compound heterozygous for the missense mutation plus a second, premature-termination mutation truncating a third of the protein and preventing its localization to centrosomes in transfected cells. CEP152 is the putative mammalian ortholog of Drosphila asterless, mutations in which affect mitosis in the fly. Published data from zebrafish are also consistent with a role of CEP152 in centrosome function. By RT-PCR, CEP152 is expressed in the embryonic mouse brain, similar to other MCPH genes. Like some other MCPH genes, CEP152 shows signatures of positive selection in the human lineage. CEP152 is a strong candidate for the causal gene underlying MCPH4 and may be an important gene in the evolution of human brain size.

Mutation in the gene encoding ubiquitin ligase LRSAM1 in patients with Charcot-Marie-Tooth disease.

Charcot-Marie-Tooth disease (CMT) represents a family of related sensorimotor neuropathies. We studied a large family from a rural eastern Canadian community, with multiple individuals suffering from a condition clinically most similar to autosomal recessive axonal CMT, or AR-CMT2. Homozygosity mapping with high-density SNP genotyping of six affected individuals from the family excluded 23 known genes for various subtypes of CMT and instead identified a single homozygous region on chromosome 9, at 122,423,730-129,841,977 Mbp, shared identical by state in all six affected individuals. A homozygous pathogenic variant was identified in the gene encoding leucine rich repeat and sterile alpha motif 1 (LRSAM1) by direct DNA sequencing of genes within the region in affected DNA samples. The single nucleotide change mutates an intronic consensus acceptor splicing site from AG to AA. Direct analysis of RNA from patient blood demonstrated aberrant splicing of the affected exon, causing an obligatory frameshift and premature truncation of the protein. Western blotting of immortalized cells from a homozygous patient showed complete absence of detectable protein, consistent with the splice site defect. LRSAM1 plays a role in membrane vesicle fusion during viral maturation and for proper adhesion of neuronal cells in culture. Other ubiquitin ligases play documented roles in neurodegenerative diseases. LRSAM1 is a strong candidate for the causal gene for the genetic disorder in our kindred.

TaskMaster: The Subintern Adventure Game-Game-Based Learning for Medical Subintern Task Prioritization.

Introduction: The medical subinternship (also known as an acting internship) offers postclerkship medical students an opportunity for significant professional development. However, the skills required of a successful subintern-efficiency, patient triage, and advanced organization-are distinct from skills generally refined during the medicine clerkship. Few published curricula exist to prepare postclerkship students for success in this new role. To address this training gap, we introduced a novel tabletop role-playing game to equip medical subinterns with the necessary skills to deliver safe and efficient patient care. Methods: We created an hour-long game-based learning session for rising internal medicine and family medicine subinterns. Led by a single facilitator, students worked together to triage and complete tasks in a gamified simulated environment of a morning on the wards. To assess the session, we surveyed participants (N = 130) immediately after activity completion. Results: Eighty-three participants completed the postactivity survey, for a response rate of 64%. A majority of students agreed that TaskMaster: The Subintern Adventure Game met its educational goals of increasing comfort with task prioritization, organization, and patient triage. Ninety-three percent of respondents (77 of 83) either agreed or strongly agreed that they felt more prepared to be a covering provider for patients after the activity. Participants also reported high engagement with the activity. Discussion: Leveraging the interactivity, teamwork, and contextualized practice of game-based learning can offer low-cost and adaptable opportunities to teach higher-order clinical skills and increase preparedness for the subinternship.

Mutation in pyrroline-5-carboxylate reductase 1 gene in families with cutis laxa type 2.

Autosomal-recessive cutis laxa type 2 (ARCL2) is a multisystem disorder characterized by the appearance of premature aging, wrinkled and lax skin, joint laxity, and a general developmental delay. Cutis laxa includes a family of clinically overlapping conditions with confusing nomenclature, generally requiring molecular analyses for definitive diagnosis. Six genes are currently known to mutate to yield one of these related conditions. We ascertained a cohort of typical ARCL2 patients from a subpopulation isolate within eastern Canada. Homozygosity mapping with high-density SNP genotyping excluded all six known genes, and instead identified a single homozygous region near the telomere of chromosome 17, shared identically by state by all genotyped affected individuals from the families. A putative pathogenic variant was identified by direct DNA sequencing of genes within the region. The single nucleotide change leads to a missense mutation adjacent to a splice junction in the gene encoding pyrroline-5-carboxylate reductase 1 (PYCR1). Bioinformatic analysis predicted a pathogenic effect of the variant on splice donor site function. Skipping of the associated exon was confirmed in RNA from blood lymphocytes of affected homozygotes and heterozygous mutation carriers. Exon skipping leads to deletion of the reductase functional domain-coding region and an obligatory downstream frameshift. PYCR1 plays a critical role in proline biosynthesis. Pathogenicity of the genetic variant in PYCR1 is likely, given that a similar clinical phenotype has been documented for mutation carriers of another proline biosynthetic enzyme, pyrroline-5-carboxylate synthase. Our results support a significant role for proline in normal development.

Remanufacturing of single-use medical devices: a case study on cross-border collaboration between the UK and Nigeria.

This paper aims to evaluate the current state of the remanufacturing of medical devices, considering the differences between developed and developing countries. With reference to various socio-economic factors, the impact of remanufacturing to sustainability was evaluated and from this, single-use medical devices were deemed to be critical in minimising waste within the medical industry. This is even more critical with increasing use of single-use devices in the Coronavirus disease 2019 (COVID 19) pandemic. It was identified that cleaning is a key consideration for ensuring a safe remanufacturing process that would minimise the risk of infection to patients. Therefore, this process was evaluated and appropriate recommendations made. Although there may be some challenges, further research would be required for integration of the methodology and process outlined into the medical sector.

OxVent: Design and evaluation of a rapidly-manufactured Covid-19 ventilator.

BACKGROUND: The manufacturing of any standard mechanical ventilator cannot rapidly be upscaled to several thousand units per week, largely due to supply chain limitations. The aim of this study was to design, verify and perform a pre-clinical evaluation of a mechanical ventilator based on components not required for standard ventilators, and that met the specifications provided by the Medicines and Healthcare Products Regulatory Agency (MHRA) for rapidly-manufactured ventilator systems (RMVS). METHODS: The design utilises closed-loop negative feedback control, with real-time monitoring and alarms. Using a standard test lung, we determined the difference between delivered and target tidal volume (VT) at respiratory rates between 20 and 29 breaths per minute, and the ventilator's ability to deliver consistent VT during continuous operation for >14 days (RMVS specification). Additionally, four anaesthetised domestic pigs (3 male-1 female) were studied before and after lung injury to provide evidence of the ventilator's functionality, and ability to support spontaneous breathing. FINDINGS: Continuous operation lasted 23 days, when the greatest difference between delivered and target VT was 10% at inspiratory flow rates >825 mL/s. In the pre-clinical evaluation, the VT difference was -1 (-90 to 88) mL [mean (LoA)], and positive end-expiratory pressure (PEEP) difference was -2 (-8 to 4) cmH2O. VT delivery being triggered by pressures below PEEP demonstrated spontaneous ventilation support. INTERPRETATION: The mechanical ventilator presented meets the MHRA therapy standards for RMVS and, being based on largely available components, can be manufactured at scale. FUNDING: Work supported by Wellcome/EPSRC Centre for Medical Engineering,King's Together Fund and Oxford University.

Defining specific lipid binding sites for a peripheral membrane protein in situ using subtesla field-cycling NMR.

Despite the profound physiological consequences associated with peripheral membrane protein localization, only a rudimentary understanding of the interactions of proteins with membrane surfaces exists because these questions are inaccessible by commonly used structural techniques. Here, we combine high resolution field-cycling (31)P NMR relaxation methods with spin-labeled proteins to delineate specific interactions of a bacterial phospholipase C with phospholipid vesicles. Unexpectedly, discrete binding sites for both a substrate analogue and a different phospholipid (phosphatidylcholine) known to activate the enzyme are observed. The lifetimes for the occupation of these sites (when the protein is anchored transiently to the membrane) are >1-2 micros (but <1 ms), which represents the first estimate of an off-rate for a lipid dissociating from a specific site on the protein and returning to the bilayer. Furthermore, analyses of the spin-label induced NMR relaxation corroborates the presence of a discrete tyrosine-rich phosphatidylcholine binding site whose location is consistent with that suggested by modeling studies. The methodology illustrated here may be extended to a wide range of peripheral membrane proteins.

Mutations in a novel serine protease PRSS56 in families with nanophthalmos.

PURPOSE: Nanophthalmos is a rare genetic ocular disorder in which the eyes of affected individuals are abnormally small. Patients suffer from severe hyperopia as a result of their markedly reduced axial lengths, but otherwise are capable of seeing well unlike other more general forms of microphthalmia. To date one gene for nanophthalmos has been identified, encoding the membrane-type frizzled related protein MFRP. Identification of additional genes for nanophthalmos will improve our understanding of normal developmental regulation of eye growth. METHODS: We ascertained a cohort of families from eastern Canada and Mexico with familial nanophthalmos. We performed high density microsatellite and high density single nucleotide polymorphism (SNP) genotyping to identify potential chromosomal regions of linkage. We sequenced coding regions of genes in the linked interval by traditional PCR-based Sanger capillary electrophoresis methods. We cloned and sequenced a novel cDNA from a putative causal gene to verify gene structure. RESULTS: We identified a linked locus on chromosome 2q37 with a peak logarithm (base 10) of odds (LOD) score of 4.7. Sequencing of coding exons of all genes in the region identified multiple segregating variants in one gene, recently annotated as serine protease gene (PRSS56), coding for a predicted trypsin serine protease-like protein. One of our families was homozygous for a predicted pathogenic missense mutation, one family was compound heterozygous for two predicted pathogenic missense mutations, and one family was compound heterozygous for a predicted pathogenic missense mutation plus a frameshift leading to obligatory truncation of the predicted protein. The PRSS56 gene structure in public databases is based on a virtual transcript assembled from overlapping incomplete cDNA clones; we have now validated the structure of a full-length transcript from embryonic mouse brain RNA. CONCLUSIONS: PRSS56 is a good candidate for the causal gene for nanophthalmos in our families.

Familial Optic Disc Pits in 2 Father-Son Pairs: Clinical Features and Genetic Analysis.

Congenital optic disc pits (ODPs) are well-circumscribed depressions within the optic disc. Thought to arise from anomalous closure of the optic fissure during embryonic development, they are now considered to lie on a broader spectrum of congenital optic disc anomaly (CODA). An increasing number of reports describe clustering of these cases within families, suggesting that inherited genetic elements play a role in disease predisposition. Here, we highlight the clinical features of 2 sets of father-son pairs affected with ODPs and provide preliminary molecular genetic analysis. Subjects underwent complete ophthalmological examination and imaging. In addition, whole-exome sequencing was carried out following informed consent. The resulting datasets were examined for potentially causal genetic variants, both in genes already known to be linked to CODA as well as those likely to lie in the same or similar genetic pathways. In this instance, no unambiguously causal variants were identified. This case series highlights the familial inheritance of ODPs, adding to the existing body of literature supporting an underlying genetic cause for this rare clinical entity. The inclusion here of specific molecular findings raises the hope that the genetic pathophysiology underlying rare entities like ODPs might be clarified in the future by the addition of similarly molecular-documented reports.

Spatial heterogeneity and environmental predictors of permafrost region soil organic carbon stocks.

Large stocks of soil organic carbon (SOC) have accumulated in the Northern Hemisphere permafrost region, but their current amounts and future fate remain uncertain. By analyzing dataset combining >2700 soil profiles with environmental variables in a geospatial framework, we generated spatially explicit estimates of permafrost-region SOC stocks, quantified spatial heterogeneity, and identified key environmental predictors. We estimated that Pg C are stored in the top 3 m of permafrost region soils. The greatest uncertainties occurred in circumpolar toe-slope positions and in flat areas of the Tibetan region. We found that soil wetness index and elevation are the dominant topographic controllers and surface air temperature (circumpolar region) and precipitation (Tibetan region) are significant climatic controllers of SOC stocks. Our results provide first high-resolution geospatial assessment of permafrost region SOC stocks and their relationships with environmental factors, which are crucial for modeling the response of permafrost affected soils to changing climate.

The Fostering Resilience through Art in Medical Education (FRAME) workshop: a partnership with the Philadelphia Museum of Art.

Background: Provider burnout remains a serious problem facing medical training programs and has been shown to affect more than half of internal medicine residents. In addition to broader efforts to revamp a health care system that contributes to this epidemic, exposure to the medical humanities offers potential to promote engagement, resilience, and restoration of meaning in residents' daily lives. Objective: We aim to create a reproducible, evidence-based workshop utilizing artful thinking routines to prepare trainees to combat burnout with reflection, perspective-taking, and community-building. Methods: A single, 4-hour workshop for senior internal medicine residents, centered on visual artistic analysis, was offered in June 2017 at the Philadelphia Museum of Art. Pre- and post-workshop burnout metrics and survey evaluation data were analyzed using a mixed-methods approach. Results: Workshop participation was offered to 29 internal medicine residents, of whom 17 (59%) participated. All survey respondents (n=13) rated the workshop as excellent and would recommend it to colleagues. Moderate decreases in the observed frequencies of both high emotional exhaustion scores (64.7% before the workshop to 55.5% following the workshop) and high depersonalization scores (70.6% before the workshop to 55.5% following the workshop) were observed. Conclusions: While results are preliminary in nature, the workshop was received favorably and demonstrated modest decreases in emotional exhaustion and depersonalization. We are encouraged to explore and repeat this workshop with modifications to identify its optimal position in the broader landscape of emerging wellness curricula.