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BackgroundMachine learning (ML) techniques improve disease prediction by identifying the most relevant features in multi-dimensional data. We compared the accuracy of ML algorithms for predicting incident diabetic kidney disease (DKD).MethodsWe utilized longitudinal data from 1365 Chinese, Malay and Indian participants aged 40-80 years with diabetes but free of DKD who participated in the baseline and 6-year follow-up visit of the Singapore Epidemiology of Eye Diseases Study (2004-2017). Incident DKD (11.9%) was defined as an estimated glomerular filtration rate (eGFR) 2 with at least 25% decrease in eGFR at follow-up from baseline. 339 features including participant characteristics, retinal imaging, genetic and blood metabolites were used as predictors. Performances of several ML models were compared to each other and to logic regression (LR) model based on established features of DKD (age, sex, ethnicity, duration of diabetes, systolic blood pressure, HbA1c, and body mass index) using area under the receiver operating characteristic curve (AUC).ResultsML model, Elastic Net (EN) had the best AUC (95% confidence interval) of 0.851 (0.847-0.856), which was 7.0% relatively higher than by LR 0.795 (0.790-0.801). Sensitivity and specificity of EN were 88.2% and 65.9% vs. 73.0% and 72.8% by LR. The top-15 predictors included age, ethnicity, antidiabetic medication, hypertension, diabetic retinopathy, systolic blood pressure, HbA1c, eGFR and metabolites related to lipids, lipoproteins, fatty acids and ketone bodies.ConclusionsOur results showed ML together with feature selection improves prediction accuracy of DKD risk in an asymptomatic stable population and identifies novel risk factors including metabolites.Funding SupportThis study was supported by the National Medical Research Council, NMRC/OFLCG/001/2017 and NMRC/HCSAINV/MOH-001019-00. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Conflicts of interestNone declared.

Background: Effective communication between doctors and patients leads to better compliance, health outcomes and higher doctor and patient satisfaction. Although in-person communication skills training programs are effective, they require high resource utilisation and may provide variable learner experiences due to challenges in standardisation. Objective: This study aimed to develop and implement an evidence-based, self-directed and interactive online communication skills training course to determine if the course would improve learner application of communication skills in real clinical encounters. Methods: The course design utilised the Kalamazoo Consensus framework and included videos based on common paediatric clinical scenarios. Final year medical students in academic year 2017/2018 undergoing a two-week paediatric clerkship were divided into two groups. Both groups received standard clerkship educational experiences, but only the intervention group (88 out of 146 total students) was enrolled into the course. Caregiver/patient feedback based on students’ clinical communication was obtained, together with pre- and post-video scenario self-reported confidence levels and course feedback. Results: There were minimal differences in patient feedback between intervention and control groups, but the control group was more likely to confirm caregivers’/patients’ agreement with management plans and provide a summary. However, caregivers/patients tended to feel more comfortable with the intervention compared to the control group. Median confidence levels increased post-video scenarios and learners reported gains in knowledge, attitudes and skills in paediatric-specific communication. Conclusion: Although online video-based communication courses are useful standardisation teaching tools, complementation with on-the-job training is essential for learners to demonstrate effective communication.

BACKGROUND AND AIMS We aimed to evaluate the incidence and clinical features of patients with biopsy-proven dysproteinemic kidney diseases (group 1), as well as spectrum of biopsy-proven kidney diseases of patients with monoclonal gammopathy (MG) or abnormal free light chain (FLC) ratio (group 2) at our institution. METHOD This was a single-centre retrospective study of all patients who had native kidney biopsies at the Singapore General Hospital between October 2015 and December 2021. Demographic, clinical, laboratory and histological data were retrieved from electronic medical records to identify patients with biopsy-proven dysproteinemic kidney diseases (group 1) and patients with positive MG and/or abnormal FLC (κ to λ) ratio who underwent kidney biopsy (group 2). Patients were considered to have MG if they tested positive on any of the following tests: serum protein electrophoresis, serum immunofixation, urine protein electrophoresis or urine immunofixation. Abnormal FLC ratio is defined as a ratio outside the range of 0.27–1.65 in patients with eGFR ≥60 mL/min/m2 or 0.37–3.10 in patients with eGFR RESULTS Out of 1066 patients who underwent kidney biopsy between October 2015 and December 2021, 25 (2.3%) patients were diagnosed with dysproteinemic kidney diseases (group 1). The median age of the patients at diagnosis was 65.6 years (IQR 58.6, 68.2), and majority was male (17/25; 68.0%). Haematological diagnoses present in this cohort include multiple myeloma (5/25; 20.0%), chronic lymphocytic leukaemia (2/25; 8.0%), Waldenstrom's macroglobulinaemia (2/25; 8.0%) and mantle cell lymphoma (1/25; 4.0%). Two-thirds of the patients had acute kidney injury (AKI) at time of biopsy (17/25; 68.0%). All patients presented with proteinuria, and nephrotic syndrome was noted in approximately half of the patients (15/25; 60.0%). Hypocomplementemia was present in a third (7/21; 33.3%) of the patients who had complement levels performed prior to biopsy, with low C3 and low C3/C4 observed in 5 and 2 patients, respectively. The most common histological lesion is immunoglobulin-related amyloidosis (8/25; 32.0%), followed by proliferative glomerulonephritis with monoclonal immune deposits (PGNMID) (6/25; 24.0%) and light-chain cast nephropathy (4/25; 16.0%). Sixteen (64%) patients fulfilled criteria for monoclonal gammopathy of renal significance (MGRS). All patients with PGNMID had undetectable MG and normal FLC ratio at diagnosis. Among these 1066 patients who underwent kidney biopsy, 396 patients had serum/urine electrophoresis, serum/urine immunofixation and/or FLC performed prior to biopsy. A total of 44 (11.1%) patients with detectable MG and/or abnormal FLC ratio were identified (group 2), 5 of whom had previously known haematological conditions. Dysproteinemic kidney diseases were diagnosed in 14 (31.8%) patients. Amongst patients with non-dysproteinemic diagnosis, diabetic/hypertensive nephropathy was the most frequent (15/30; 50.0%). Majority of the remaining patients had a variety of glomerulonephritides and renal vasculitides (10/30; 33.3%), or tubulointerstitial diseases (2/30; 6.7%). In univariate analysis, non-diabetic status (P CONCLUSION AKI and proteinuria are common in dysproteinemia kidney diseases. Non-diabetic status, presence of AKI and abnormal FLC ratio increased the likelihood of diagnosing dysproteinemic kidney disease.

BACKGROUND AND AIMS Chronic kidney disease (CKD) is a growing global public health burden among aging populations and is associated with increased risks of cardiovascular disease, kidney failure and death. Early identification and treatment can amelioriate these risks. We aimed to evaluate incident CKD and risk factors among older adults with diabetes in Singapore. METHOD Retrospective cohort study of 13 028 older adults ≥65 years with diabetes mellitus who were free of CKD (eGFR ≥60 mL/min/1.73 m2) at baseline and had kidney function tested 3 years later at Singapore's largest healthcare cluster that includes the Singapore General Hospital and SingHealth Polyclinics. Demographic, clinical and laboratory data were retrieved from electronic medical records and the SingHealth Diabetes Registry. Incident CKD was present if eGFR was RESULTS In this multi-ethnic cohort (Chinese 91%, Indian 8%, Malay 8% and other ethnicities 3%), the mean age was 72.1 ± 5.6 years and the eGFR was 84.2 ± 11.1 mL/min/1.73 m2. The majority were on glucose and blood pressure lowering medications and achieved glycated haemoglobin (HbA1c), systolic blood pressure (SBP) and diastolic blood pressure (DBP) of 7.1% ± 1.1, 133 ± 16 mmHg and 68 ± 9 mmHg, respectively. Cumulative incident CKD among older adults with diabetes was 19.4% >38.5 ± 4.7 months. In the fully adjusted model, considering age, gender, ethnicity, comorbidities (hypertension, cardiovascular disease, cancer, statin use), SBP, DBP, BMI and laboratory results (eGFR, albuminuria, glucose, HbA1c, LDL- and HDL-cholesterol). Female gender {adjusted OR: 1.54, [95% confidence interval (95% CI) 1.36–1.76]}, Malay ethnicity (adjusted OR: 1.24, 95% CI 1.01–1.53), hypertension (adjusted OR: 1.40, 95% CI 1.02–1.93), albuminuria (adjusted OR: 1.49, 95% CI 1.31–1.69) and higher HbA1c (adjusted OR: 1.11, 95% CI 1.04–1.18/unit increase) were independently associated with incident CKD, while higher eGFR (adjusted OR: 0.88, 95% CI 0.87–0.88/unit increase) and statin use (adjusted OR: 0.79, 95% CI 0.64– 0.99) were associated with decreased incident CKD. CONCLUSION Incident of CKD was frequent among older adults with diabetes. The presence of risk factors for incident CKD can aid clinicians to identify those who may benefit from close surveillance and interventions.

BACKGROUND AND AIMS Glomerulonephritis and its treatment may be associated with disease or treatment-related complications causing significant symptom burden and hospitalizations affecting physical function and quality of life (QoL). Patient-centered care harnessing patient-reported outcome measures (PROMs) can guide physicians to optimize patients’ functional well-being. Few studies have described health-related QoL (HRQOL) in patients with glomerulonephritis. We aimed to describe the HRQOL and determinants of HRQOL among patients with active glomerulonephritis. METHOD This was a cross-sectional study of adults with active glomerulonephritis recruited at the Singapore General Hospital Glomerulonephritis Disease Management Clinics between July 2020 and July 2021. HRQOL was assessed using the Short-Form Health Survey (SF-36) and Patient-Reported Outcome Measurement Informative System (PROMIS). Socio-demographic and clinical data were collected. Multivariate linear regression was used to determine predictors of HRQOL. RESULTS A total of 60 patients with glomerulonephritis (13 minimal change disease, 9 primary focal segmental glomerulosclerosis, 8 membranous nephropathy, 15 lupus nephritis, 8 IgA nephropathy and 7 other glomerulonephritis) with median age 44.5 years old (IQR 32–57) participated. Most (83%) had received immunosuppressants within 60 days of study enrolment. The scores for general health and energy were lower than other health domains of SF-36 such as physical functioning (Table 1). Health domain scores of those with nephrotic presentations (minimal change disease, FSGS and membranous nephropathy) and nephritic presentations (lupus nephritis and IgA nephropathy) were not significantly different. In the multivariable model accounting for age, gender, eGFR, ethnicity, hematuria, edema and immunosuppressant use (Table 2), age correlated positively with emotional role and social functioning while ethnicity influenced the pain scores. Hematuria was associated with lower physical role scores while eGFR correlated positively with social functioning. Calcineurin inhibitor use was associated with higher global physical health scores. CONCLUSION Sociodemographic, clinical and treatment may affect SF-36 and PROMIS HRQOL scores in patients with glomerulonephritis.

BACKGROUND AND AIMS Patients with glomerulonephritis may have an increased risk of influenza infection and morbidity, but vaccine coverage remained low with little data on acceptance in glomerulonephritis. We aimed to assess influenza vaccine awareness among patients with glomerulonephritis and identify determinants of vaccine acceptance. METHOD Single-center cross-sectional study of patients with glomerulonephritis who completed a survey in the clinic or over the telephone between June and August 2021. Sociodemographic data, health literacy measured by HLS-EU-47 questionnaire, influenza and the coronavirus disease (COVID-19) vaccine awareness and determinants of vaccine acceptance according to the World Health Organization framework. RESULTS Among 86 patients who completed the survey, influenza vaccine awareness was lower than COVID-19 vaccine awareness (75.6% versus 100%). After adjusting for the survey type, use of English language at home and at healthcare settings, higher income and professional or executive occupation were significantly associated with influenza vaccine awareness, while older age and lower education level were associated with reduced awareness. The healthcare provider was the most frequent information source and > 90% trusted that healthcare providers and the government considered the patients’ best interests and gave correct information. Only half thought their medical condition and medications would affect their vaccine decision while a quarter to half did not understand how the vaccine worked and thought there were better ways to protect against infection. CONCLUSION Healthcare providers can actively identify and advocate influenza vaccines to the unaware and overcome potential barriers to reduce influenza infections and morbidity in glomerulonephritis.

BACKGROUND Germline genetic testing currently is recommended for patients with pancreatic ductal adenocarcinoma (PDAC). In the current study, the authors assessed how often results are communicated to first-degree relatives within 3 months and the emotional impact of testing on patients. METHODS A total of 148 patients who were newly diagnosed with PDAC and who had undergone testing of 32 cancer susceptibility genes at 3 academic centers were selected; 71% participated. Subjects completed the Multidimensional Impact of Cancer Risk Assessment (MICRA) and a family communication survey. The results of both surveys were assessed at 3 months according to the genetic test result (positive, negative, or variant of unknown significance [VUS]) and whether a patient met criteria for genetic testing. RESULTS A total of 99 patients completed the MICRA survey and 104 completed the family communication survey. The average age of the patients was 67 years, 47% were female, 29% had stage III/IV (AJCC 8th edition) disease, and 42% met genetic testing criteria. Approximately 80% of patients told at least 1 first-degree relative about their result. There was a trend toward greater disclosure among patients who tested positive (93% vs 77% for those with a VUS result [P = .149] and 74% for those who tested negative [P = .069]). Patients not meeting genetic testing criteria were less likely to disclose results (69% vs 93%; P = .003). MICRA scores did not differ by test result, age, stage of disease, or sex. CONCLUSIONS The rate of result communication was high, although it was lower among patients who did not meet genetic testing criteria, those who tested negative, or those who had a VUS result. Testing-associated distress was similar across patient groups, and was comparable to that reported by other patients with cancer. Improved communication for all patients is crucial given the prognosis of PDAC, which limits time for disclosure.

The way educarers conceptualize their role in the education and care of infants can influence their pedagogical practices and interactions with infants in their care. The Early Years Development Fr...

BACKGROUND The objective of this study was to investigate the prevalence of pathogenic germline variants (PGVs) in 32 cancer susceptibility genes in individuals with newly diagnosed pancreatic ductal adenocarcinoma (PDAC). A key secondary objective was to evaluate how often PGVs would have been undetected with existing genetic testing criteria. METHODS From May 2016 through May 2017, this multicenter cohort study enrolled consecutive patients aged 18 to 89 years with histologically confirmed PDAC diagnosed within the previous 12 weeks. Demographics, medical histories, and 3-generation pedigrees were collected from participants who provided samples for germline DNA analysis. RESULTS Four hundred nineteen patients were deemed eligible, 302 were enrolled, and 298 were included in the final cohort. Clinically actionable variants were reported in 29 PDAC patients (9.7%), with 23 (7.7%) having a PGV associated with an increased risk for PDAC. Six of 23 individuals (26%) with PDAC-associated gene mutations did not meet currently established genetic testing criteria. According to guideline-based genetic testing, only 11 of the 23 PGVs (48%) in known PDAC genes would have been detected. Six additional patients (2%) had PGVs associated with an increased risk for other cancers. CONCLUSIONS These findings support the significant prevalence of PGVs associated with PDAC and the limitations of current paradigms for selecting patients for genetic testing, and they thereby lend support for universal germline multigene genetic testing in this population.

Introduction: Studies have found that AML pts treated at high pt volume, academic or NCI-designated cancer centers have improved outcomes compared to pts treated at smaller community hospitals. But little is known about the treatment patterns and outcomes as related to a combined academic and community based health system. Therefore, in a real-world cohort that included both academic and community hospitals that collaborate with one another, we evaluated pt characteristics, frequency of genomic testing, frequency of chemotherapy treatment (Tx) or any targeted therapy as a function of age, and outcomes in ND AML pts. Methods: This was a retrospective observational study of patients treated within a comprehensive health system in the Midwest US that includes both metropolitan and rural populations. Pts ≥18 years (yrs) with ND AML between 1 Jan 2011 and 31 Dec 2018 were identified using ICD-9 / ICD-10 codes for AML within the Health System or from one of two local cancer registries, with a follow-up period that ended with the pt's death, 2 years after initial diagnosis or 31 Dec 2018, whichever came first. Date of diagnosis served as the index date. Kaplan-Meier estimates were used to visualize overall survival. Results: A total of 629 pts with ND AML were identified in the 3 data sources and included in the cohort for analysis (Figure 1). At the index date, majority (55%) of the pts were older (61 yrs or more), male (55%) and White (89%) (Table 1). Majority of the identified pts (76%) died before the end of the study; higher proportion of older pts died vs younger pts (≥75 yrs: 89%; 61 - 74 yrs: 85% vs. ≤60 yrs: 62%). Most common comorbidities were renal disease (30%), cardiovascular diseases (24%), and diabetes (18%). Of the 500 pts with available cytogenetics data, majority had ELN-defined intermediate risk (49%), then adverse (25%) and favorable (6%); no pt ≥75 yrs had favorable risk profile. Only 82 pts (13%) had evidence of a sequencing genomic report; 78% of the pts had at least 1 mutation and 56% had 2 - 5 mutations (Table 2). By age, pts ≥75 yrs had the highest proportion of multiple (≥3) mutations (46%); most common overall were ASXL1, NPM1, and FLT3. By age, mutations with the highest frequencies were: ≥75 yrs - ASXL1, RUNX1 and TET2; 61 - 74 yrs - ASXL1, NPM1 and TP53; and ≤60 yrs - NPM1, FLT3 and DNMT3A. As expected, pts with TP53 mutations had a lower overall probability of survival vs pts with wild type TP53 or NPM1 mutations (Figure 2). Overall, 69% of pts had records for either standard induction chemotherapy (IC) or other chemotherapy (OC; includes targeted therapy) during the study period; 31% did not have records for chemotherapy (Table 3). Of the 54% of pts with IC, majority (63%) were ≤60 yrs. A higher proportion of pts ≥75 yrs (23%) received OC, which includes hypomethylating agents (HMAs), but 66% of pts ≥75 yrs did not have records for receiving any chemotherapy. Overall probability of survival for pts who received Tx (IC + OC) was higher than for pts who did not receive any Tx (Figure 3). Pts ≥75 years received proportionally more HMAs vs other age groups (Table 3). Anthracyclines and cytarabine records were similar within each age group, suggesting they were given together. In pts with genomic data, 84% received chemotherapy (IC 68%; OC 16%) while 16% did not (Table 4); proportion of pts ≤60 yrs who received IC (91%) was much higher in those with a genomic report than for the entire cohort (75%), and fewer older pts ≥75 yrs with a genomic report did not receive any chemotherapy (31%) vs 66% for the entire cohort. Conclusions: Results of this retrospective study showed 55% of the ND AML pts were >60 yrs, younger pts (≤60 yrs) are more likely to receive IC and 66% of those ≥75 yrs did not receive any chemotherapy or alternative treatment. Additionally, only 13% of pts had evidence of a genomic report although it has been used for prognostication for at least the last decade. With newer Tx options including targeted therapies, access to genomic analysis and Tx needs to increase across all environments (rural and metropolitan) given the impact that such treatments can have on patient outcome. Figure 1 Figure 1. Disclosures Byrd: Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria; Newave: Membership on an entity's Board of Directors or advisory committees. Mims: Leukemia and Lymphoma Society's Beat AML clinical study: Consultancy, Research Funding; Aptevo: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Glycomemetics: Research Funding; Kartos Pharmaceuticals: Research Funding; Xencor: Research Funding; Genentech: Consultancy; Abbvie: Consultancy; BMS: Consultancy; Kura Oncology: Consultancy; Syndax Pharmaceuticals: Consultancy; BMS: Consultancy; Jazz Pharmaceuticals: Consultancy; Aptevo: Research Funding. Borate: AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Blueprint Medicine: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rampal: Membership on an entity's Board of Directors or advisory committees; Galecto, Inc.: Consultancy; Promedior: Consultancy.

The objective of this study was to investigate the prevalence of pathogenic germline variants (PGVs) in 32 cancer susceptibility genes in individuals with newly diagnosed pancreatic ductal adenocarcinoma (PDAC). A key secondary objective was to evaluate how often PGVs would have been undetected with existing genetic testing criteria.From May 2016 through May 2017, this multicenter cohort study enrolled consecutive patients aged 18 to 89 years with histologically confirmed PDAC diagnosed within the previous 12 weeks. Demographics, medical histories, and 3-generation pedigrees were collected from participants who provided samples for germline DNA analysis.Four hundred nineteen patients were deemed eligible, 302 were enrolled, and 298 were included in the final cohort. Clinically actionable variants were reported in 29 PDAC patients (9.7%), with 23 (7.7%) having a PGV associated with an increased risk for PDAC. Six of 23 individuals (26%) with PDAC-associated gene mutations did not meet currently established genetic testing criteria. According to guideline-based genetic testing, only 11 of the 23 PGVs (48%) in known PDAC genes would have been detected. Six additional patients (2%) had PGVs associated with an increased risk for other cancers.These findings support the significant prevalence of PGVs associated with PDAC and the limitations of current paradigms for selecting patients for genetic testing, and they thereby lend support for universal germline multigene genetic testing in this population.

The enterohepatic circulation of bile salts is an important physiological route to recycle bile salts and ensure intestinal absorption of dietary lipids. The Na+-taurocholate cotransporting polypeptide SLC10A1 (NTCP) plays a key role in this process as the major transporter of conjugated bile salts from the plasma compartment into the hepatocyte. Here we present the first patient with NTCP deficiency, who was clinically characterized by mild hypotonia, growth retardation, and delayed motor milestones. Total bile salts in plasma were extremely elevated (up to 1,500 μM, ref.

While there has been extensive research exploring the quality of caregiver–child interactions in programmes for preschool children, comparatively less international research has explored the nature of caregiver–child interactions in centre-based infant-care programmes. Nine caregivers in six Singapore infant-care settings were observed and interviewed in this study to explore the qualitative nature of caregiver–child interactions and the caregivers' talk about the education and care of infants. Some of the caregivers expressed beliefs that infants learn through quality interactions. However, not all caregivers were observed to provide interactions, especially during routine care. Some caregivers held the view that their primary role was providing physical care rather than education. Such differences in views and practices could have been influenced by the cultural backgrounds of individual caregivers. Implications for professional development of infant caregivers are discussed.

Despite the clinical significance of balanced chromosomal abnormalities (BCAs), their characterization has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and demonstrated complexity that was cryptic to karyotyping in 21% of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADs) encompassing known syndromic loci. Remarkably, BCA breakpoints in eight subjects altered a single TAD encompassing MEF2C, a known driver of 5q14.3 microdeletion syndrome, resulting in decreased MEF2C expression. We propose that sequence-level resolution dramatically improves prediction of clinical outcomes for balanced rearrangements and provides insight into new pathogenic mechanisms, such as altered regulation due to changes in chromosome topology. info:eu-repo/semantics/publishedVersion

The Los Angeles Unified School District (LAUSD) serves a large majority of socioeconomically disadvantaged students who are struggling academically and are underprepared for high school graduation and college. This article describes the partnership between LAUSD and the Los Angeles Education Research Institute, and how this collaboration endeavors to produce accessible and high-quality research to inform pressing problems of practice. The article also presents findings from an ongoing partnership research project analyzing a district policy focused on improving college readiness by aligning high school graduation and college-eligibility requirements. In a cohort that went through high school before the policy became mandatory for all students, less than 1/5 of all students (and 30% of graduates) met the college eligibility criteria. Our findings indicate that academic and behavioral indicators from 8th and 9th grade can help identify for possible intervention students who are not on track to meet these new graduation requirements.

1501 Background: The aim of this study is to assess the prevalence of known heritable germline mutations in unselected PDAC patients and to determine how well current guidelines for genetic testing identify mutation carriers. Methods: Consecutive, unselected patients with recently diagnosed PDAC from three centers were enrolled from May to December 2016 in an ongoing prospective study. A three-generation pedigree was obtained. Germline mutations in 12 genes associated with PDAC risk ( APC, ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, PALB2, PMS2, STK11, TP53) and in 19 genes related to other cancer risks were screened for by NGS. American College of Gastroenterology and NCCN criteria for genetic testing for BRCA1/2, Lynch syndrome, and Familial Pancreatic Cancer (FPC) were assessed. Results: Among 183 patients, 46% are female, 79% are Caucasian and 10% are Ashkenazi Jewish, with median (IQR) age 68 (62,75) years at diagnosis. 41% of patients met ³1 criteria for genetic testing (35.5% BRCA1/2, 2.7% Lynch, 9.3% FPC). Twenty patients (11%) were found to have a total of 21 pathogenic mutations (table). Mutation status was not associated with age at diagnosis, sex, or personal history of cancer (all p > 0.05). Six mutation carriers (30% of positives) did not meet current criteria for genetic testing. Conclusions: Preliminary results show that 6.6% of unselected PDAC patients carry a germline mutation in a gene known to increase PDAC risk and 4.3% have a mutation in genes not previously linked to PDAC. Existing testing criteria did not identify 30% of carriers. Continued refinement of guidelines is necessary to align genetic testing with inherited PDAC risk. Clinical trial information: NCT02790944. [Table: see text]

The 17p13.1 microdeletion syndrome is a recently described genomic disorder with a core clinical phenotype of intellectual disability, poor to absent speech, dysmorphic features, and a constellation of more variable clinical features, most prominently microcephaly. We identified five subjects with copy-number variants (CNVs) on 17p13.1 for whom we performed detailed clinical and molecular studies. Breakpoint mapping and retrospective analysis of published cases refined the smallest region of overlap (SRO) for microcephaly to a genomic interval containing nine genes. Dissection of this phenotype in zebrafish embryos revealed a complex genetic architecture: dosage perturbation of four genes (ASGR1, ACADVL, DVL2, and GABARAP) impeded neurodevelopment and decreased dosage of the same loci caused a reduced mitotic index in vitro. Moreover, epistatic analyses in vivo showed that dosage perturbations of discrete gene pairings induce microcephaly. Taken together, these studies support a model in which concomitant dosage perturbation of multiple genes within the CNV drive the microcephaly and possibly other neurodevelopmental phenotypes associated with rearrangements in the 17p13.1 SRO.

We study ligand exchange between the carboxylic acid group and 5.0 nm oleic-acid capped CdS nanocrystals (NCs) using fluorescence resonance energy transfer (FRET). This is the first measurement of the initial binding events between cadmium chalcogenide NCs and carboxylic acid groups. The binding behavior can be described as an interaction between a ligand with single binding group and a substrate with multiple, identical binding sites. Assuming Poissonian binding statistics, our model fits both steady-state and time-resolved photoluminescence (SSPL and TRPL, respectively) data well. A modified Langmuir isotherm reveals that a CdS nanoparticle has an average of 3.0 new carboxylic acid ligands and binding constant, Ka, of 3.4 × 10(5) M(-1).

The issue of systemic change is receiving prominent attention. This article presents three case studies of the initial efforts of change agents in a large urban school district as they develop mechanisms to coordinate resources at school sites and to establish linkages with community agencies. The process of change is described as well as the barriers encountered. The case studies demonstrate that implementation of change differed according to the local context and the personal vision of the change agents. Among the barriers faced were difficulties due to multiple reforms being implemented simultaneously and the administrative structure of the change agent position.

Context Autosomal dominant inactivating sprouty-related EVH1 domain–containing protein 1 (SPRED1) mutations have recently been described in individuals presenting mainly with cafe au lait macules (CALMs), axillary freckling, and macrocephaly. The extent of the clinical spectrum of this new disorder needs further delineation. Objective To determine the frequency, mutational spectrum, and phenotype of neurofibromatosis type 1–like syndrome (NFLS) in a large cohort of patients. Design, Setting, and Participants In a cross-sectional study, 22 unrelated probands carrying a SPRED1 loss-of-function (LOF) mutation identified through clinical testing participated with their families in a genotype-phenotype study (2007-2008). In a second cross-sectional study, 1318 unrelated anonymous samples collected in 2003-2007 from patients with a broad range of signs typically found in neurofibromatosis type 1 (NF1) but no detectable NF1 germline mutation underwent SPRED1 mutation analysis. Main Outcome Measures Comparison of aggregated clinical features in patients with or without a SPRED1 or NF1 mutation. Functional assays were used to evaluate the pathogenicity of missense mutations. Results Among 40 SPRED1 LOF-positive individuals from the clinical cohort, 20 (50%; 95% confidence interval [CI], 34%-66%) fulfilled National Institutes of Health (NIH) NF1 diagnostic criteria based on the presence of more than 5 CALMs with or without freckling or an NF1-compatible family history. None of the 40 SPRED1 LOF-positive individuals (0%; 95% CI, 0%-7%) had discrete cutaneous or plexiform neurofibromas, typical NF1 osseous lesions, or symptomatic optic pathway gliomas. In the anonymous cohort of 1318 individuals, 34 different SPRED1 mutations in 43 probands were identified: 26 pathogenic mutations in 33 probands and 8 probable nonpathogenic missense or silent mutations in 10 probands. Of 94 probands with familial CALMs with or without freckling and no other NF1 features, 69 (73%; 95% CI, 63%-80%) had an NF1 mutation and 18 (19%; 95% CI, 12%-29%) had a pathogenic SPRED1 mutation. In the anonymous cohort, 1.9% (95% CI, 1.2%-2.9%) of individuals with the clinical diagnosis of NF1 according to the NIH criteria had NFLS. Conclusions A high SPRED1 mutation detection rate was found in NF1 mutation–negative families with an autosomal dominant phenotype of CALMs with or without freckling and no other NF1 features. Among individuals in this study, NFLS was not associated with the peripheral and central nervous system tumors seen in NF1.

In October, 2008, a 23-year-old woman presented with sudden onset of left-sided chest pain and shortness of breath. She had a history of chronic cough with exertional dyspnoea for 2 years. She had been admitted twice to diff erent hospitals in the previous year for spontaneous pneumothoraces. She had refused further investigation and defaulted follow-up. She had been a smoker for 11 years. Over the previous year, she also noted itchy, nodular rashes aff ecting her armpits and vulva, as well as nocturia and polydipsia. Her primary care physician had managed her cough and rash symptomatically and reassured her that she did not have diabetes mellitus. On presentation, chest radiograph showed a left pneumothorax, so a chest tube was inserted urgently. Severe respiratory distress followed, and she was intubated. Examination showed ulcerative, nodular lesions aff ecting her armpits and vulva. She had notable polyuria with hypernatraemia (157 mmol/L). Desmo pressin was given, resulting in lower serum sodium (140 mmol/L); a diagnosis of cranial diabetes insipidus was made. MRI of the pituitary fossa showed thickening of the infundibulum. CT showed diff use cystic lesions in the lungs (fi gure A) and multiple small bony focal defects (fi gure B). Histological examination of skin lesion biopsy samples showed heavy infi ltrates of histiocytes with strong immunohistochemical staining to CD1a, confi rming the diagnosis of systemic Langerhans’ cell histiocytosis. She was successfully extubated on day 3 of admission and underwent a left thoracotomy for her pneumothorax, after which long-term corticosteroid treatment was started. When seen in February, 2009, she was no longer smoking, and her condition had improved. Her rash had subsided and the lesions seen on CT of the chest and bones remained stable. The aetiology of Langerhans’ cell histiocytosis is unknown, although smoking is the main risk factor for isolated pulmonary disease. Whether Langerhans’ cell histio cytosis is a neoplastic or reactive disorder is controversial. In contrast to paediatric Langerhans’ cell histiocytosis, which is monoclonal in nature, adult lung disease is polyclonal. The Histiocyte Society has developed a simplifi ed classifi cation system for adult Langerhans’ cell histiocytosis, consisting of single organ and multisystem involvement. The incidence in adults is around 1–2 cases per million with a mean age at diagnosis of 35 years. Up to a quarter of cases are asymptomatic. Presenting symptoms depend on the pattern of organ involvement, with bony pain, weight loss, and fever being the most common. Diabetes insipidus from pituitary involvement is a characteristic manifestation of the disease–as in our patient. Patients with lung involvement typically have non-productive cough and dyspnoea. The chest radiograph is usually abnormal, with bilateral reticulomicronodular infi ltrates being the most common pattern. High-resolution CT is mandatory in suspected cases of pulmonary Langerhans’ cell histiocytosis. Defi nitive diagnosis relies on demonstration of CD1a antigen on immunohistochemical studies or identifi cation of Birbeck’s granules on electron micrograph. Smoking cessation is essential in pulmonary Langerhans’ cell histiocytosis. Single organ disease can be managed with watchful waiting; multisystem disease may respond to corticosteroids and systemic chemotherapy. Most patients experience a favourable outcome, although isolated pulmonary Langerhans’ cell histiocytosis has the worst outcome. Lung transplant can be considered in advanced disease, but there may be recurrence in the allograft. Diagnosis of Langerhans’ cell histiocytosis is often delayed with a median time of 4 months. There was substantial delay in diagnosis in our patient, confi rming suboptimal awareness for this uncommon condition.

The mitochondrial 13513G>A (D393N) mutation in the ND5 subunit of the respiratory chain complex I was initially described in association with MELAS syndrome. Recent observations have linked this mutation to Leigh disease. We screened for the 13513G>A mutation in a cohort of 265 patients with Leigh and Leigh-like disease. The mutation was found in a total of 5 patients. An additional patient who had clinical presentation consistent with a Leigh-like phenotype but with a normal brain MRI was added to the cohort. None of an additional 88 patients meeting MELAS disease criteria, nor 56 patients with respiratory chain deficiency screened for the 13513G>A were found positive for the mutation. The most frequent clinical manifestations in our patients were hypotonia, ocular and cerebellar involvement. Low mutation heteroplasmy in the range of 20-40% was observed in all 6 patients. This observation is consistent with the previously reported low heteroplasmy of this mutation in some patients with the 13513G>A mutation and complex I deficiency. However, normal complex I activity was observed in two patients in our cohort. As most patients with Leigh-like disease and the 13513G>A mutation have been described with complex I deficiency, this report adds to the previously reported subset of patients with normal respiratory complex function. We conclude that in any patient with Leigh or Leigh-like disease, testing for the 13513G>A mutation is clinically relevant and low mutant loads in blood or muscle may be considered pathogenic, in the presence of normal respiratory chain enzyme activities.

Purpose: The advent of molecular cytogenetic technologies has altered the means by which new microdeletion syndromes are identified. Whereas the cytogenetic basis of microdeletion syndromes has traditionally depended on the serendipitous ascertainment of a patient with established clinical features and a chromosomal rearrangement visible by G-banding, comparative genomic hybridization using microarrays has enabled the identification of novel, recurrent imbalances in patients with mental retardation and apparently nonspecific features. Compared with the “phenotype-first” approach of traditional cytogenetics, array-based comparative genomic hybridization has enabled the detection of novel genomic disorders using a “genotype-first” approach. We report as an illustrative example the characterization of a novel microdeletion syndrome of 1q41q42. Methods: We tested more than 10,000 patients with developmental disabilities by array-based comparative genomic hybridization using our targeted microarray. High-resolution microarray analysis was performed using oligonucleotide microarrays for patients in whom deletions of 1q41q42 were identified. Fluorescence in situ hybridization was performed to confirm all 1q deletions in the patients and to exclude deletions or other chromosomal rearrangements in the parents. Results: Seven cases were found with de novo deletions of 1q41q42. The smallest region of overlap is 1.17 Mb and encompasses five genes, including DISP1, a gene involved in the sonic hedgehog signaling pathway, the deletion of which has been implicated in holoprosencephaly in mice. Although none of these patients showed frank holoprosencephaly, many had other midline defects (cleft palate, diaphragmatic hernia), seizures, and mental retardation or developmental delay. Dysmorphic features are present in all patients at varying degrees. Some patients showed more severe phenotypes and carry the clinical diagnosis of Fryns syndrome. Conclusions: This new microdeletion syndrome with its variable clinical presentation may be responsible for a proportion of Fryns syndrome patients and adds to the increasing number of new syndromes identified with array-based comparative genomic hybridization. The genotype-first approach to identifying recurrent chromosome abnormalities is contrasted with the traditional phenotype-first approach. Targeting developmental pathways in a functional approach to diagnostics may lead to the identification of additional microdeletion syndromes.

Reports of small proximal 1q duplications are rare. We report a 1 month-old female who was referred to clinic because she was believed to have features suggestive of Turner syndrome. The patient's dysmorphic features included a prominent nose, low-set and crumpled ears, slightly high palate, short neck, high-pitched cry, mild micrognathia, hypoplastic labia majora, and somewhat deep palmar creases. Traditional G-band chromosome studies of the patient were interpreted as 46,XX,dup(1)(q12q21). To further evaluate the extent of the chromosome 1 duplication, Spectral Karyotyping and a series of six fluorescence in situ hybridization (FISH) probes were utilized. The FISH probes refined the extent of the duplication to involve the region 1(q12q22) indicating the duplicated segment was larger than interpreted by the G-banding studies. This first case of non-mosaic proximal duplication of 1q to be characterized by multiple locus specific FISH probes should allow a more refined delineation of the phenotypic findings and clinical significance associated with this rare chromosomal duplication.

Monosomy of distal 1p36 represents the most common terminal deletion in humans and results in one of the most frequently diagnosed mental retardation syndromes. This deletion is considered a contiguous gene deletion syndrome, and has been shown to vary in deletion sizes that contribute to the spectrum of phenotypic anomalies seen in patients with monosomy 1p36. We report on an 8-year-old female with characteristics of the monosomy 1p36 syndrome who demonstrated a novel der(1)t(1;18)(p36.3;q23). Initial G-banded karyotype analysis revealed a deleted chromosome 1, with a breakpoint within 1p36.3. Subsequent FISH and array-based comparative genomic hybridization not only confirmed and partially characterized the deletion of chromosome 1p36.3, but also uncovered distal trisomy for 18q23. In this patient, the duplicated 18q23 is translocated onto the deleted 1p36.3 region, suggesting telomere capture. Molecular characterization of this novel der(1)t(1;18)(p36.3;q23), guided by our clinical array-comparative genomic hybridization, demonstrated a 3.2 Mb terminal deletion of chromosome 1p36.3 and a 200 kb duplication of 18q23 onto the deleted 1p36.3, presumably stabilizing the deleted chromosome 1. DNA sequence analysis around the breakpoints demonstrated no homology, and therefore this telomere capture of distal 18q is apparently the result of a non-homologous recombination. Partial trisomy for 18q23 has not been previously reported. The importance of mapping the breakpoints of all balanced and unbalanced translocations found in the clinical laboratory, when phenotypic abnormalities are found, is discussed.