Building a Networked Improvement Community: Lessons in Organizing to Promote Diversity, Equity, and Inclusion in Science, Technology, Engineering, and Mathematics.

In 2016, 10 universities launched a Networked Improvement Community (NIC) aimed at increasing the number of scholars from Alliances for Graduate Education and the Professoriate (AGEP) populations entering science, technology, engineering, and mathematics (STEM) faculty careers. NICs bring together stakeholders focused on a common goal to accelerate innovation through structured, ongoing intervention development, implementation, and refinement. We theorized a NIC organizational structure would aid understandings of a complex problem in different contexts and accelerate opportunities to develop and improve interventions to address the problem. A distinctive feature of this NIC is its diverse institutional composition of public and private, predominantly white institutions, a historically Black university, a Hispanic-serving institution, and land grant institutions located across eight states and Washington, DC, United States. NIC members hold different positions within their institutions and have access to varied levers of change. Among the many lessons learned through this community case study, analyzing and addressing failed strategies is as equally important to a healthy NIC as is sharing learning from successful interventions. We initially relied on pre-existing relationships and assumptions about how we would work together, rather than making explicit how the NIC would develop, establish norms, understand common processes, and manage changing relationships. We had varied understandings of the depth of campus differences, sometimes resulting in frustrations about the disparate progress on goals. NIC structures require significant engagement with the group, often more intensive than traditional multi-institution organizational structures. They require time to develop and ongoing maintenance in order to advance the work. We continue to reevaluate our model for leadership, climate, diversity, conflict resolution, engagement, decision-making, roles, and data, leading to increased investment in the success of all NIC institutions. Our NIC has evolved from the traditional NIC model to become the Center for the Integration of Research, Teaching and Learning (CIRTL) AGEP NIC model with five key characteristics: (1) A well-specified aim, (2) An understanding of systems, including a variety of contexts and different organizations, (3) A culture and practice of shared leadership and inclusivity, (4) The use of data reflecting different institutional contexts, and (5) The ability to accelerate infrastructure and interventions. We conclude with recommendations for those considering developing a NIC to promote diversity, equity, and inclusion efforts.

Identification and functional characterisation of genetic variants in OLFM2 in children with developmental eye disorders.

Anophthalmia, microphthalmia, and coloboma are a genetically heterogeneous spectrum of developmental eye disorders and affect around 30 per 100,000 live births. OLFM2 encodes a secreted glycoprotein belonging to the noelin family of olfactomedin domain-containing proteins that modulate the timing of neuronal differentiation during development. OLFM2 SNPs have been associated with open angle glaucoma in a case-control study, and knockdown of Olfm2 in zebrafish results in reduced eye size. From a cohort of 258 individuals with developmental eye anomalies, we identified two with heterozygous variants in OLFM2: an individual with bilateral microphthalmia carrying a de novo 19p13.2 microdeletion involving OLFM2 and a second individual with unilateral microphthalmia and contralateral coloboma who had a novel single base change in the 5' untranslated region. Dual luciferase assays demonstrated that the latter variant causes a significant decrease in expression of OLFM2. Furthermore, RNA in situ hybridisation experiments using human developmental tissue revealed expression in relevant structures, including the lens vesicle and optic cup. Our study indicates that OLFM2 is likely to be important in mammalian eye development and disease and should be considered as a gene for human ocular anomalies.

Context and Applications of Targeted Genetic Testing, with Emphasis on Copy Number Variants.

There has been a huge acceleration in our technical ability to detect variation in the human genome in recent years, and there has been a corresponding effort in clinical diagnostic laboratories to take advantage of this progress for the benefit of patients. There has, however, not been an equivalent increase in our understanding of human genetics and disease, not for lack of effort but due to the far greater complexity of understanding variation than the difficulties of detecting it. This chapter describes how software tools can be used to target clinical genetic diagnostic testing in order to exploit technical and scientific advances both efficiently and cost-effectively, while maximizing clinical utility.

3p14 deletion is a rare contiguous gene syndrome: report of 2 new patients and an overview of 14 patients.

Interstitial deletions of chromosome 3p14p12 are a rare chromosome rearrangement. Twenty-six patients have been reported in the literature to date, however, a specific clinical phenotype has not yet been delineated. We describe three patients (two new) with overlapping chromosome 3p14p12 deletions and review the clinical and molecular data of 11 well-characterized, published cases. These patients had a number of features in common, such as short stature, failure to thrive, facial dysmorphism, congenital heart defects, urogenital abnormalities, neurological problems, hearing loss, and global developmental delay, suggesting that the interstitial chromosome 3p14p12 deletion gives rise to a multiple congenital anomaly syndrome. Some of the patients show clinical overlap with other complex syndromes such as CHARGE syndrome. Genotype-phenotype analysis revealed candidate genes for parts of the clinical features suggesting that the 3p14 deletion is a contiguous gene syndrome.

Cost Effectiveness of Using Array-CGH for Diagnosing Learning Disability.

OBJECTIVE: To undertake a cost-effectiveness analysis of using microarray comparative genomic hybridisation (array-CGH) as a first-line test versus as a second-line test for the diagnosis of causal chromosomal abnormalities in patients referred to a NHS clinical genetics service in the U.K. with idiopathic learning disability, developmental delay and/or congenital anomalies. METHODS: A cost-effectiveness study was conducted. The perspective is that of a U.K. NHS clinical genetics service provider (with respect to both costs and outcomes). A cohort of patients (n = 1590) referred for array-CGH testing of undiagnosed learning disability and developmental delay by a single NHS regional clinical genetics service (South East Thames Regional Genetics Service), were split into a before-and-after design where 742 patients had array-CGH as a second-line test (before group-comparator intervention) and 848 patients had array-CGH as a first-line test (after group-evaluated intervention). The mean costs were calculated from the clinical genetics testing pathway constructed for each patient including the costs of genetic testing undertaken and clinical appointments scheduled. The outcome was the number of diagnoses each intervention produced so that a mean cost-per-diagnosis could be calculated. The cost effectiveness of the two interventions was calculated as an incremental cost-effectiveness ratio to produce an incremental cost-per-diagnosis (in 2013 GBP). Sensitivity analyses were conducted by altering both costs and effects to check the validity of the outcome. RESULTS: The incremental mean cost of testing patients using the first-line testing strategy was -GBP241.56 (95% CIs -GBP256.93 to -GBP226.19) and the incremental mean gain in the percentage diagnoses was 0.39% (95% CIs -2.73 to 3.51%), which equates to an additional 1 diagnosis per 256 patients tested. This cost-effectiveness study comparing these two strategies estimates that array-CGH first-line testing dominates second-line testing because it was both less costly and as effective. The sensitivity analyses conducted (adjusting both costs and effects) supported the dominance of the first-line testing strategy (i.e. lower cost and as effective). CONCLUSIONS: The first-line testing strategy was estimated to dominate the second-line testing strategy because it was both less costly and as effective. These findings are relevant to the wider UK NHS clinical genetics service, with two key strengths of this study being the appropriateness of the comparator interventions and the direct applicability of the patient cohort within this study and the wider UK patient population.

Procedure-related risk of miscarriage following amniocentesis and chorionic villus sampling: a systematic review and meta-analysis.

OBJECTIVES: To estimate procedure-related risks of miscarriage following amniocentesis and chorionic villus sampling (CVS) based on a systematic review of the literature and a meta-analysis. METHODS: A search of MEDLINE, EMBASE, CINHAL and The Cochrane Library (2000-2014) was performed to review relevant citations reporting procedure-related complications of amniocentesis and CVS. Only studies reporting data on more than 1000 procedures were included in this review to minimize the effect of bias from smaller studies. Heterogeneity between studies was estimated using Cochran's Q, the I(2) statistic and Egger bias. Meta-analysis of proportions was used to derive weighted pooled estimates for the risk of miscarriage before 24 weeks' gestation. Incidence-rate difference meta-analysis was used to estimate pooled procedure-related risks. RESULTS: The weighted pooled risks of miscarriage following invasive procedures were estimated from analysis of controlled studies including 324 losses in 42 716 women who underwent amniocentesis and 207 losses in 8899 women who underwent CVS. The risk of miscarriage prior to 24 weeks in women who underwent amniocentesis and CVS was 0.81% (95% CI, 0.58-1.08%) and 2.18% (95% CI, 1.61-2.82%), respectively. The background rates of miscarriage in women from the control group that did not undergo any procedures were 0.67% (95% CI, 0.46-0.91%) for amniocentesis and 1.79% (95% CI, 0.61-3.58%) for CVS. The weighted pooled procedure-related risks of miscarriage for amniocentesis and CVS were 0.11% (95% CI, -0.04 to 0.26%) and 0.22% (95% CI, -0.71 to 1.16%), respectively. CONCLUSION: The procedure-related risks of miscarriage following amniocentesis and CVS are much lower than are currently quoted.

Sezary syndrome: diagnosis and management.

We describe a case of a delayed diagnosis of Sezary syndrome in a patient with longstanding generalised pruritus, erythroderma, alopecia and nail dystrophy. We highlight some of the difficulties in diagnosis despite the fact that all patients have a characteristic circulating malignant T-cell lymphocyte in peripheral blood. These cells with cerebriform nuclei should be sought in peripheral blood films and further evaluated using flow cytometry in all patients with an erythrodermatous presentation. We summarise current treatment options although, as with all rare diseases, there are few randomised controlled clinical trials to inform decisions on optimal therapy for each individual patient.

Delayed puberty from partial 17-alpha hydroxylase enzyme deficiency.

An 18-year-old woman with primary amenorrhoea and pubertal delay was investigated for mild labile hypertension and secondary hypogonadism. Low renin and normal aldosterone levels combined with evidence of primary adrenal insufficiency suggested partial 17-alpha hydroxylase enzyme deficiency. The diagnosis was confirmed by measurement of 24-hour urine steroid metabolites and whole gene sequencing of CYP17A1 that demonstrated c.160_162delTTC (p.Phe54del) homozygous mutation. Ultrasound showed bilateral small ovaries with multiple cysts. The serum anti-mullerian hormone concentration was unremarkable at 6.6 (normal <12.6 ng/ml) but the outlook for her future ovulatory potential is uncertain. Dexamethasone 0.25 mg pre-bed and hydrocortisone 5 mg on waking normalised her hormonal profile and her blood pressure without side-effects.

Five novel locations of Neocentromeres in human: 18q22.1, Xq27.1∼27.2, Acro p13, Acro p12, and heterochromatin of unknown origin.

Since the first report in 1993, an ectopic centromere, i.e. neocentromere formation, has been reported in more than 100 small supernumerary marker chromosomes (sSMC), in 7 instances of centromere repositioning, and in about a dozen cases with more complex chromosomal rearrangements. Here we report 2 new cases with centromere repositioning and 3 neocentric sSMC consisting exclusively of heterochromatic material. Yet, no centromere formation was reported for the regions 18q22.1 and Xq27.1∼27.2 as it was observed in the 2 cases with centromere repositioning here; in both cases, cytogenetically an inversion was suggested. Two of the 3 neocentric sSMC were derived from a short arm of an acrocentric chromosome. The remainder neocentric sSMC case was previously reported and was stainable only by material derived from itself.

Outpatient imaging for pulmonary embolism may only be suitable for a minority.

In this study we model the impact of introducing outpatient investigation of pulmonary thrombo-embolism (PTE) to the acute medical unit (AMU) using the Pulmonary Embolism Severity Index (PESI) decision rule. Specifically, we ask what proportion of patients requiring imaging could be investigated without admission, and how many bed-days this would save.  We obtained records for all medical patients who had imaging for PTE in a six-month period at a large teaching hospital with a 40-bedded AMU. The patients were categorized into suitability for outpatient investigation using a combination of the PESI rule and practical considerations. Three hundred and fifty-nine separate presentations were identified. From available records, 31 patients (9.2%, 95% confidence interval [CI] 6.6-12.8%) had no contraindications to outpatient management. These patients used a total of 79 bed-days in the six-month period, or 1.1% (95% CI 0.8-1.5%) of the maximum AMU bed occupancy. Around 10% of patients who require imaging for suspected PTE could be triaged to outpatient investigation using the PESI tool. Adopting this method to triage patients of ambulatory care, would have only a modest effect on acute medical bed occupancy, but remains a valid option for motivated patients in the low-risk category.

A novel microdeletion syndrome at 3q13.31 characterised by developmental delay, postnatal overgrowth, hypoplastic male genitals, and characteristic facial features.

BACKGROUND: Congenital deletions affecting 3q11q23 have rarely been reported and only five cases have been molecularly characterised. Genotype-phenotype correlation has been hampered by the variable sizes and breakpoints of the deletions. In this study, 14 novel patients with deletions in 3q11q23 were investigated and compared with 13 previously reported patients. METHODS: Clinical data were collected from 14 novel patients that had been investigated by high resolution microarray techniques. Molecular investigation and updated clinical information of one cytogenetically previously reported patient were also included. RESULTS: The molecular investigation identified deletions in the region 3q12.3q21.3 with different boundaries and variable sizes. The smallest studied deletion was 580 kb, located in 3q13.31. Genotype-phenotype comparison in 24 patients sharing this shortest region of overlapping deletion revealed several common major characteristics including significant developmental delay, muscular hypotonia, a high arched palate, and recognisable facial features including a short philtrum and protruding lips. Abnormal genitalia were found in the majority of males, several having micropenis. Finally, a postnatal growth pattern above the mean was apparent. The 580 kb deleted region includes five RefSeq genes and two of them are strong candidate genes for the developmental delay: DRD3 and ZBTB20. CONCLUSION: A newly recognised 3q13.31 microdeletion syndrome is delineated which is of diagnostic and prognostic value. Furthermore, two genes are suggested to be responsible for the main phenotype.

Meiotic segregation of Robertsonian translocations ascertained in cleavage-stage embryos--implications for preimplantation genetic diagnosis.

BACKGROUND: The aim of this study was to ascertain the prevalence of meiotic segregation products in embryos from carriers of 13/14 and 14/21 Robertsonian translocations and to estimate the predictive value of testing single cells using the fluorescence in situ hybridization (FISH) technique, to provide more information for decision-making about PGD. METHODS: In this prospective cohort study, the copy number of translocation chromosomes in nuclei from lysed blastomeres of cleavage-stage embryos was ascertained using locus-specific FISH probes. Logistic regression analysis, controlling for translocation type, female age and fertility status, was used to calculate the odds ratio (OR) of unbalanced segregation products for female and male heterozygotes. The primary diagnostic measure was the predictive value of the test result. The primary outcome measure was the live birth rate per couple. RESULTS: Female carriers were four times more likely than male carriers to produce embryos with an unbalanced translocation product (OR 3.8, 95% confidence interval 2.0-7.2, P < 0.001). The prevalence of abnormality for the chromosomes tested in embryos from female or male heterozygotes was estimated to be 43 or 28%, respectively, while estimates of the predictive value were 93-100 or 96-100% for a normal test result and 79 or 57% for an abnormal test result. The live birth rate per couple was 58% for female carriers and 50% for male carriers. CONCLUSIONS: For female carriers, PGD using FISH could reduce the risk of miscarriage from either translocation or the risk of Down syndrome from the 14/21 Robertsonian translocation. PGD using FISH for male carriers is unlikely to be indicated given the relatively low prevalence of chromosome imbalance and low predictive value.

Dopamine agonists in the treatment of prolactinoma: are they still first choice?

Dopamine agonist therapy has been the cornerstone treatment for prolactinoma since the 1970s, replacing surgery in the primary management of this condition. These agents are effective in the management of prolactin excess, have a low side-effect profile, and in some cases may even be curative. However, recent studies of high dose dopamine agonists used in Parkinson's disease have raised the possibility that these drugs may be associated with cardiac valvulopathy. This paper discusses the modern use of dopamine agonists in a patient with prolactinoma.

Is karyotyping couples experiencing recurrent miscarriage worth the cost?

Karyotyping couples that have had recurrent miscarriages detects balanced rearrangements in carrier parents who can be offered prenatal cytogenetic analysis to prevent the birth of a subsequent child with an unbalanced rearrangement. In four UK centres, over periods of 5-30 years, balanced rearrangements were found in 406 out of 20,432 parents that had experienced miscarriage (1.9%), but only four unbalanced rearrangements were found after referral for prenatal diagnosis because of a balanced parental translocation ascertained for recurrent miscarriages. At an estimated cost of 3-4 million pounds, these data raise doubts about the cost effectiveness of current policies on the routine karyotyping of couples experiencing repeated miscarriages.

First use of preimplantation genotyping in prevention of recurrent diandric complete hydatidiform mole.

Complete hydatidiform moles have a diploid chromosome constitution, generally with only paternal genetic material present (diandry). Diandric complete moles are thought to arise either by fertilization of an anucleate oocyte by two spermatozoa or, more commonly, doubling of a single sperm genotype. Molar pregnancies are usually sporadic, and may be accompanied by malignant transformation; however, recurrence is associated with increased risk of further affected pregnancies and of persistent trophoblastic neoplasia or choriocarcinoma. This study presents the first use of preimplantation genotyping to ensure biparental inheritance in a woman presenting with recurrent diandric complete hydatidiform mole. Following an IVF cycle, a single cell from each of 11 embryos was tested by whole genome amplification and genotyping at 16 different simple tandem repeat loci. All embryos showed normal biparental inheritance; one blastocyst was transferred, resulting in the delivery of healthy monozygotic twin girls.

PEComa of the Upper Extremity: A Unique Case and Description of an Initial Response to Neoadjuvant Chemotherapy.

Purpose. Tumors of the perivascular epithelial cell tumor (PEComa), first described in 1992, represent a rare soft tissue neoplasm of varying malignant potential. Cases of PEComa have been previously described in a few somatic and visceral sites, most notably in the gastrointestinal tract, genitourinary tract, and one extremity case in the thigh. To date, most malignant cases of PEComa have been resistant to chemotherapy, and as such, an appropriate therapy is not known. Case report. Here we describe the first case of PEComa of the upper extremity. Open biopsy revealed a high-grade malignant lesion, and the patient subsequently underwent both neoadjuvant therapy with doxorubicin, ifosfamide and mensa, and radiation therapy prior to wide surgical resection. After six cycles of chemotherapy, the tumor underwent an 80% reduction in size. Subsequent neoadjuvant radiation therapy of 5000 cGy did not further reduce the size of the tumor. Following limb sparing radical resection, pathology showed 20% necrosis within a high-grade malignant lesion. Twenty one months after beginning treatment, the patient shows no sign of local recurrence, but metastatic disease was confirmed after resection of a lung nodule. Conclusion. Given the favorable albeit partial response seen in this patient, the course of therapy outlined here may represent a good starting point for neoadjuvant treatment in a tumor with a historically bleak prognosis. In addition, the diagnosis of PEComa must now be entertained in the differential diagnosis of upper extremity soft tissue sarcoma.

Three hundred and thirty cycles of preimplantation genetic diagnosis for serious genetic disease: clinical considerations affecting outcome.

OBJECTIVE: To report on our experience with preimplantation genetic diagnosis (PGD) cycles performed for serious genetic disease in relation to the clinical factors affecting outcome. DESIGN: Retrospective review of data from a single centre. SETTING: Tertiary referral PGD centre in a London teaching hospital. METHODS: The PGD cycles included 172 cycles for chromosome rearrangements, 96 cycles for single-gene disorders and 62 cycles for X-linked disorders. In vitro fertilisation was the preferred method in chromosome rearrangement and X-linked cases, while intra cytoplasmic sperm injection was used in all single-gene disorders. Appropriate in situ hybridisation fluorescence probes were used in chromosome rearrangement and X-linked cases and polymerase chain reaction was used in single-gene disorders. All pregnancies were followed till delivery. MAIN OUTCOME MEASURE: Live birth rate per PGD cycle started. RESULTS: Eighty-six percent of cycles started (283) reached oocyte retrieval and 3743 eggs were collected, of which 2086 fertilised normally (55.7%). Two hundred and fifty cycles (76%) had embryos sutiable for biopsy on day 3 of in vitro culture, 1714 embryos were biopsied, and in 205 cycles (62%), there was at least one unaffected embryo available for transfer, resulting in 90 pregnancies, 68 clinical pregnancies and 58 live birth. The live birth rate was 18% per cycle started, 21% per egg retrieval and 28% per embryo transfer which significantly affected the live birth outcome. Woman age, number of eggs collected and achieving cryopreservation of surplus embryos had no statistically significant effect on treatment outcome. CONCLUSIONS: The live birth outcome of PGD cycles for serious genetic disorder is modest and is affected by the number of embryos genetically suitable for transfer.