The opportunity cost of arthroplasty training in orthopaedic surgery.

INTRODUCTION: Training the next generation of surgeons is a crucial role fulfilled by consultant orthopaedic surgeons. However we are increasingly constrained by limited time and resources. We sought to compare operative time and length of stay (LOS) for total hip and total knee arthroplasties (THA, TKA) performed by a consultant orthopaedic surgeon with those performed by supervised trainees. MATERIALS AND METHODS: A prospective database of arthroplasty procedures performed from 2015 to 2018 was collated. Primary surgeon grade was recorded. Patient demographics, ASA grade, LOS and operative time were recorded. For THA both cemented and uncemented arthroplasties were used. SPSS version 23 was used for statistical analysis. RESULTS: 394 arthroplasty procedures were carried out during the study period. Trainee surgeons performed a high proportion of both THA (53.2%, n = 123) and TKA (44.8%, n = 73) surgeries. Trainees performed 57% of cemented THA procedures. LOS did not differ between consultant and trainee surgeons for THA (5.9 ± 4.8 days) or TKA (5.6 ± 4.1 days). Age had a significant effect on LOS (p < 0.001). For THA the mean operative time for trainees was 90.3 ± 19.23 min, 18.2 min longer than the consultant group. For TKA the mean operative time was 89.06 ± 18.87 min for trainees, 24.4 min longer than the consultant group. DISCUSSION: At our institution trainee surgeons can be expected to take between 18 and 24 min longer to perform arthroplasty procedures. This should be factored into resource planning, as the training of orthopaedic surgeons is crucial to sustaining and improving health service provision.

MRI-based response patterns during neoadjuvant chemotherapy can predict pathological (complete) response in patients with breast cancer.

BACKGROUND: The main purpose was to investigate the correlation between magnetic resonance imaging (MRI)-based response patterns halfway through neoadjuvant chemotherapy and immunotherapy (NAC) and pathological tumor response in patients with breast cancer. Secondary purposes were to compare the predictive value of MRI-based response patterns measured halfway through NAC and after NAC and to measure interobserver variability. METHODS: All consecutive patients treated with NAC for primary invasive breast cancer from 2012 to 2015 and who underwent breast MRI before, halfway through (and after) NAC were included. All breast tumors were reassessed on MRI by two experienced breast radiologists and classified into six patterns: type 0 (complete radiologic response); type 1 (concentric shrinkage); type 2 (crumbling); type 3 (diffuse enhancement); type 4 (stable disease); type 5 (progressive disease). Percentages of tumors showing pathological complete response (pCR), > 50% tumor reduction and > 50% tumor diameter reduction per MRI-based response pattern were calculated. Correlation between MRI-based response patterns and pathological tumor reduction was studied with Pearson's correlation coefficient, and interobserver agreement was tested with Cohen's Kappa. RESULTS: Patients (n = 76; mean age 53, range 29-72 years) with 80 tumors (4 bilateral) were included. There was significant correlation between these MRI-based response patterns halfway through NAC and tumor reduction on pathology assessment (reader 1 r = 0.33; p = 0.003 and reader 2 r = 0.45; p < 0.001). Type-0, type-1 or type-2 patterns halfway through NAC showed highest tumor reduction rates on pathology assessment, with > 50% tumor reduction in 90%, 78% and 65% of cases, respectively. In 83% of tumors with type 0 halfway through NAC, pathology assessment showed pCR. There was no significant correlation between MRI-based response patterns after NAC and tumor reduction rates on pathology assessment (reader 1 r = - 0.17; p = 0.145 and reader 2 r = - 0.17; p = 0.146). In 41% of tumors with type 0 after NAC, pathology assessment showed pCR. CONCLUSION: MRI-based response patterns halfway through NAC can predict pathologic response more accurately than MRI-based response patterns after NAC. Complete radiological response halfway NAC is associated with 83% pCR, while complete radiological response after NAC seems to be correct in only 41% of cases.

Vitamin D Insufficiency in Patients Undergoing Total Knee Arthroplasty in Ireland.

Introduction: Vitamin D is essential for bone health. We aimed to assess the vitamin D levels of patients undergoing total knee arthroplasty TKA). Methods: All TKA patients during a calendar year had their 25-hydroxyvitamin-D3 (25-OH-D3) assay levels assessed pre and post operatively. A control group comprising of patients admitted for 1-day general medical assessment was recruited. Usage of supplements containing Vitamin D was recorded for both groups. Results: There was no evidence of a difference in Vitamin D levels between the TKA group and the control group (p=0.19). Just over 40% of patients had insufficient levels of vitamin D in the TKA group (50 nmol/L cut off). There was a statistically significant drop in vitamin D levels post operatively (p=0.0001). Supplements were protective against insufficiency post operatively (p=0.0005, OR 6.0985). Discussion: This study documents a high prevalence of vitamin D insufficiency in patients undergoing TKA surgery. Our results suggest a consumption of 25-OH-D3 as part of the surgical insult.

Persistent Mycobacterium bovis-BCG is resistant to glutathione induced reductive stress killing.

This study focuses on the redox stress response in mycobacteria elicited by a host-derived, thiol-based detoxification molecule, glutathione (GSH). Although the growth and viability of Mycobacterium bovis-BCG (BCG) was hampered by exposure to 8 mM GSH, oxygen depleted, persistent BCG (NRP BCG) resisted GSH-mediated killing. Fast growing mycobacteria also resisted GSH-mediated killing. To determine the mechanisms behind these observations, we evaluated the levels of intracellular ATP in both BCG and NRP BCG exposed to 8 mM GSH. Intracellular ATP levels increased from 0.13 to 2.3 µM in BCG upon exposure to GSH. The levels of ATP remained low and unchanged when NRP BCG was exposed to GSH. Using both HPLC and a cell-based thiol detection assay, it was determined that GSH stimulates the production of mycothiol (MSH) by BCG approximately 5.7 fold. The levels of MSH did not change upon exposure of NRP BCG to GSH. MSH is an alternative, thiol-based detoxification molecule employed by mycobacteria. Changes in the cytoplasmic concentrations of this molecule are suggestive of redox imbalances. Together, GSH and MSH may introduce excess reducing equivalents into the mycobacterial cytoplasm; leading to reductive stress. The modulation of NAD(+) levels through alterations in ATP metabolism can enhance the cells ability to bind excess reducing equivalents and serve as a mechanism to restore the cellular redox balance when cells experience reductive stress. These data suggest that killing of BCG by GSH may result from reductive stress that cannot be controlled. NRP BCG appears to be resistant to GSH-induced reductive stress.

Urine congophilia associated with preeclampsia does not persist 6-months postpartum.

INTRODUCTION: Preeclampsia is a common hypertensive disorder of pregnancy. Several studies have demonstrated that protein aggregates, detected through urine congophilia, is associated with preeclampsia; however, it has yet to be investigated whether urine congophilia remains postpartum in these women. In this study, we aimed to augment prior studies and determine whether urine congophilia is present postpartum. METHODS: Women were recruited from Lyell McEwin Hospital, South Australia. Urine samples were collected during pregnancy and 6-months postpartum from women with non-preeclampsia pregnancies (n = 48) and women with pregnancies complicated by preeclampsia (n = 42). A Congo Red Dot blot test, total protein and creatinine levels from urine, as well as serum Soluble fms-like tyrosine kinase 1 to placental growth factor ratio (sFlt-1:PlGF), were assessed and correlated. RESULTS: Preeclamptic women exhibited increased urine congophilia (P < 0.01), sFlt-1:PlGF ratio (P < 0.0001) and total protein (P < 0.01) during pregnancy; with a positive correlation between urine congophilia and total protein across the entire cohort (P < 0.0001). Although urine congophilia was no longer detected 6-months postpartum in preeclamptic women, total protein remained elevated (P < 0.05). sFlt-1:PlGF ratio during pregnancy was positively correlated with congophilia across the cohort (P = 0.0007). Serum creatinine was also higher in preeclamptic women during pregnancy (P < 0.001). DISCUSSION: These results support that urine congophilia is significantly elevated in pregnancies complicated with preeclampsia and show that it does not continue postpartum, although larger cohort studies are needed to determine its feasibility as a diagnostic marker.

A systematic approach to assessing the clinical significance of genetic variants.

Molecular genetic testing informs diagnosis, prognosis, and risk assessment for patients and their family members. Recent advances in low-cost, high-throughput DNA sequencing and computing technologies have enabled the rapid expansion of genetic test content, resulting in dramatically increased numbers of DNA variants identified per test. To address this challenge, our laboratory has developed a systematic approach to thorough and efficient assessments of variants for pathogenicity determination. We first search for existing data in publications and databases including internal, collaborative and public resources. We then perform full evidence-based assessments through statistical analyses of observations in the general population and disease cohorts, evaluation of experimental data from in vivo or in vitro studies, and computational predictions of potential impacts of each variant. Finally, we weigh all evidence to reach an overall conclusion on the potential for each variant to be disease causing. In this report, we highlight the principles of variant assessment, address the caveats and pitfalls, and provide examples to illustrate the process. By sharing our experience and providing a framework for variant assessment, including access to a freely available customizable tool, we hope to help move towards standardized and consistent approaches to variant assessment.

Implementing Contralateral Surgical Exploration during Hernia Repair in Children with Unilateral Inguinal Hernia: A Dutch Qualitative Study.

A total of 10-15% of children undergoing unilateral inguinal hernia repair develop a metachronous contralateral inguinal hernia (MCIH) that necessitates second anesthesia and surgery. Contralateral exploration can be performed to prevent MCIH development. This study investigates (1) factors that promote or hinder the adoption and (de-)implementation of contralateral groin exploration in children ≤ 6 months undergoing unilateral hernia repair and (2) strategies to overcome these barriers. A qualitative interview study was conducted using 14 semi-structured interviews and two focus groups involving healthcare professionals, stakeholders involved from a patients' perspective and stakeholders at the organizational/policy level. The results show that the effectiveness of surgical treatment and stakeholders' motivation and attitudes towards the intervention were reported as barriers for implementation, whereas patient and family outcomes and experience and strategies to overcome these barriers were identified as facilitating factors for future implementation. This study is unique in its contributions towards insights into facilitators and barriers for (de-)implementation of contralateral groin exploration in children with a unilateral inguinal hernia. In case the HERNIIA trial shows that contralateral exploration is beneficial for specific patient and family outcomes or a subgroup of children, the results of this study can help in the decision-making process as to whether contralateral exploration should be performed or not.

[A new technique for inguinal hernia repair in children: laparoscopic percutaneous inguinal ring suturing]. / Nieuwe behandeling voor kinderen met een liesbreuk.

Inguinal hernia repair is one of the most frequently performed operations in the pediatric population and laparoscopic hernia repair is currently increasingly performed in Dutch academic and non-academic hospitals. The laparoscopic PIRS-technique is invented by Prof. Dr. D. Patkowski and is an extra-corporeal technique that uses one trocar for the camera and uses an subcutaneous knotted suture. Compared to the open technique, the PIRS-technique offers the possibility for contralateral inspection without making an extra incision and, in case of a contralateral patent processus vaginalis (CPPV), offers the possibility for the simultaneous repair of the CPPV. This prevents the development of a metachronous contralateral inguinal hernia (MCIH), one of the most frequent reason for re-operation after open inguinal hernia repair. This will result in less operations, less exposure to general anesthesia, less hospital admissions and less visits to the general practitioner and emergency department.

One-Stop Surgery: An Innovation to Limit Hospital Visits in Children.

INTRODUCTION: One-stop surgery (OSS) allows for same-day outpatient clinic visit, preoperative assessment, and surgical repair. This study aims to determine the efficiency, (cost-)effectiveness, and family satisfaction of one-stop inguinal hernia surgery compared with usual care. MATERIAL AND METHODS: Children (≥ 3 months) with inguinal hernia and American Society of Anesthesiologists (ASA) grades I-II, scheduled for OSS (intervention) or regular treatment (control) between March 1, 2017, and December 1, 2018, were eligible for inclusion. Exclusion criteria consisted of age less than 3 months and ASA grades III-IV. The primary outcome measure was treatment efficiency (i.e., total number of hospital visits and waiting time [days] between referral and surgery). Secondary outcome measures were the effectiveness in terms of complication and recurrence rate, and parent-reported satisfaction and cost-effectiveness using the Dutch Pediatric Quality of Life Healthcare Satisfaction and Institute for Medical Technology Assessment Productivity Cost Questionnaire. RESULTS: Ninety-one (intervention: 54; control: 37) patients (56% boys) were included. Median (interquartile range) number of hospital visits was lower in the intervention group (1 vs 3; p < 0.001). All but one of the OSS patients (98%) were discharged home on the day of surgery. Postoperative complication (1.9% vs 2.7%; p = 0.787) and recurrence rates (0% vs 2.7%; p = 0.407) did not differ between the intervention and control patients. "General satisfaction," "satisfaction with communication," and "inclusion of family" were higher after OSS, while satisfaction about "information," "technical skills," and "emotional needs" were similar. Median (range) follow-up was 28 (15-36) months. CONCLUSIONS: Pediatric one-stop inguinal hernia repair seems to be an effective treatment strategy that limits the number of hospital visits and provides enhanced family satisfaction without compromising the quality of care.

Surgical Management of Pediatric Inguinal Hernia: A Systematic Review and Guideline from the European Pediatric Surgeons' Association Evidence and Guideline Committee.

INTRODUCTION: Inguinal hernia repair represents the most common operation in childhood; however, consensus about the optimal management is lacking. Hence, recommendations for clinical practice are needed. This study assesses the available evidence and compiles recommendations on pediatric inguinal hernia. MATERIALS AND METHODS: The European Pediatric Surgeons' Association Evidence and Guideline Committee addressed six questions on pediatric inguinal hernia repair with the following topics: (1) open versus laparoscopic repair, (2) extraperitoneal versus transperitoneal repair, (3) contralateral exploration, (4) surgical timing, (5) anesthesia technique in preterm infants, and (6) operation urgency in girls with irreducible ovarian hernia. Systematic literature searches were performed using PubMed, MEDLINE, Embase (Ovid), and The Cochrane Library. Reviews and meta-analyses were conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement. RESULTS: Seventy-two out of 5,173 articles were included, 27 in the meta-analyses. Laparoscopic repair shortens bilateral operation time compared with open repair. In preterm infants, hernia repair after neonatal intensive care unit (NICU)/hospital discharge is associated with less respiratory difficulties and recurrences, regional anesthesia is associated with a decrease of postoperative apnea and pain. The review regarding operation urgency for irreducible ovarian hernia gained insufficient evidence of low quality. CONCLUSION: Laparoscopic repair may be beneficial for children with bilateral hernia and preterm infants may benefit using regional anesthesia and postponing surgery. However, no definite superiority was found and available evidence was of moderate-to-low quality. Evidence for other topics was less conclusive. For the optimal management of inguinal hernia repair, a tailored approach is recommended taking into account the local facilities, resources, and expertise of the medical team involved.

Replication of 13 genome-wide association (GWA)-validated risk variants for type 2 diabetes in Pakistani populations.

AIMS/HYPOTHESIS: Recent genome-wide association (GWA) studies and subsequent replication studies have greatly increased the number of validated type 2 diabetes susceptibility variants, but most of these have been conducted in European populations. Despite the high prevalence of the disease in South Asians, studies investigating GWA-validated type 2 diabetes risk variants in this ethnic group are limited. We investigated 30 single nucleotide polymorphisms (SNPs), predominantly derived from recent GWA studies, to determine if and to what extent these variants affect type 2 diabetes risk in two Punjabi populations, originating predominantly from the District of Mirpur, Pakistan. METHODS: Thirty SNPs were genotyped in 1,678 participants with type 2 diabetes and 1,584 normoglycaemic control participants from two populations; one resident in the UK and one indigenous to the District of Mirpur. RESULTS: SNPs in or near PPARG, TCF7L2, FTO, CDKN2A/2B, HHEX/IDE, IGF2BP2, SLC30A8, KCNQ1, JAZF1, IRS1, KLF14, CHCHD9 and DUSP9 displayed significant (p < 0.05) associations with type 2 diabetes, with similar effect sizes to those seen in European populations. A constructed genetic risk score was associated with type 2 diabetes (p = 5.46 × 10(-12)), BMI (p = 2.25 × 10(-4)) and age at onset of diabetes (p = 0.002). CONCLUSIONS/INTERPRETATION: We have demonstrated that 13 variants confer an increased risk of type 2 diabetes in our Pakistani populations; to our knowledge this is the first time that SNPs in or near KCNQ1, JAZF1, IRS1, KLF14, CHCHD9 and DUSP9 have been significantly associated with the disease in South Asians. Large-scale studies and meta-analyses of South Asian populations are needed to further confirm the effect of these variants in this ethnic group.

An FTO variant is associated with Type 2 diabetes in South Asian populations after accounting for body mass index and waist circumference.

AIMS: A common variant, rs9939609, in the FTO (fat mass and obesity) gene is associated with adiposity in Europeans, explaining its relationship with diabetes. However, data are inconsistent in South Asians. Our aim was to investigate the association of the FTO rs9939609 variant with obesity, obesity-related traits and Type 2 diabetes in South Asian individuals, and to use meta-analyses to attempt to clarify to what extent BMI influences the association of FTO variants with diabetes in South Asians. METHODS: We analysed rs9939609 in two studies of Pakistani individuals: 1666 adults aged ≥40 years from the Karachi population-based Control of Blood Pressure and Risk Attenuation (COBRA) study and 2745 individuals of Punjabi ancestry who were part of a Type 2 diabetes case-control study (UK Asian Diabetes Study/Diabetes Genetics in Pakistan; UKADS/DGP). The main outcomes were BMI, waist circumference and diabetes. Regression analyses were performed to determine associations between FTO alleles and outcomes. Summary estimates were combined in a meta-analysis of 8091 South Asian individuals (3919 patients with Type 2 diabetes and 4172 control subjects), including those from two previous studies. RESULTS: In the 4411 Pakistani individuals from this study, the age-, sex- and diabetes-adjusted association of FTO variant rs9939609 with BMI was 0.45 (95%CI 0.24-0.67) kg/m(2) per A-allele (P=3.0 × 10(-5) ) and with waist circumference was 0.88 (95% CI 0.36-1.41) cm per A-allele (P=0.001). The A-allele (30% frequency) was also significantly associated with Type 2 diabetes [per A-allele odds ratio (95%CI) 1.18 (1.07-1.30); P=0.0009]. A meta-analysis of four South Asian studies with 8091 subjects showed that the FTO A-allele predisposes to Type 2 diabetes [1.22 (95%CI 1.14-1.31); P=1.07 × 10(-8) ] even after adjusting for BMI [1.18 (95%CI 1.10-1.27); P=1.02 × 10(-5) ] or waist circumference [1.18 (95%CI 1.10-1.27); P=3.97 × 10(-5) ]. CONCLUSIONS: The strong association between FTO genotype and BMI and waist circumference in South Asians is similar to that observed in Europeans. In contrast, the strong association of FTO genotype with diabetes is only partly accounted for by BMI.

Contralateral surgical exploration during inguinal hernia repair in infants (HERNIIA trial): study protocol for a multi-centre, randomised controlled trial.

BACKGROUND: The incidence of metachronous contralateral inguinal hernia (MCIH) is high in infants with an inguinal hernia (5-30%), with the highest risk in infants aged 6 months or younger. MCIH is associated with the risk of incarceration and necessitates a second operation. This might be avoided by contralateral exploration during primary surgery. However, contralateral exploration may be unnecessary, leads to additional operating time and costs and may result in additional complications of surgery and anaesthesia. Thus, there is no consensus whether contralateral exploration should be performed routinely. METHODS: The Hernia-Exploration-oR-Not-In-Infants-Analysis (HERNIIA) study is a multicentre randomised controlled trial with an economic evaluation alongside to study the (cost-)effectiveness of contralateral exploration during unilateral hernia repair. Infants aged 6 months or younger who need to undergo primary unilateral hernia repair will be randomised to contralateral exploration or no contralateral exploration (n = 378 patients). Primary endpoint is the proportion of infants that need to undergo a second operation related to inguinal hernia within 1 year after primary repair. Secondary endpoints include (a) total duration of operation(s) (including anaesthesia time) and hospital admission(s); (b) complications of anaesthesia and surgery; and (c) participants' health-related quality of life and distress and anxiety of their families, all assessed within 1 year after primary hernia repair. Statistical testing will be performed two-sided with α = .05 and according to the intention-to-treat principle. Logistic regression analysis will be performed adjusted for centre and possible confounders. The economic evaluation will be performed from a societal perspective and all relevant costs will be measured, valued and analysed. DISCUSSION: This study evaluates the effectiveness and cost-effectiveness of contralateral surgical exploration during unilateral inguinal hernia repair in children younger than 6 months with a unilateral inguinal hernia. TRIAL REGISTRATION: ClinicalTrials.gov NCT03623893 . Registered on August 9, 2018 Netherlands Trial Register NL7194. Registered on July 24, 2018 Central Committee on Research Involving Human Subjects (CCMO) NL59817.029.18. Registered on July 3, 2018.

Roles of charge interactions on astringency of whey proteins at low pH.

Whey proteins are a major ingredient in sports drink and functional beverages. At low pH, whey proteins are astringent, which may be undesirable in some applications. Understanding the astringency mechanism of whey proteins at low pH could lead to developing ways to minimize the astringency. This study compared the astringency of beta-lactoglobulin (beta-LG) at low pH with phosphate buffer controls having the same amount of phosphate and at similar pH. Results showed that beta-LG samples were more astringent than phosphate buffers, indicating that astringency was not caused by acid alone and that proteins contribute to astringency. When comparing among various whey protein isolates (WPI) and lactoferrin at pH 3.5, 4.5, and 7.0, lactoferrin was astringent at pH 7.0 where no acid was added. In contrast, astringency of all WPI decreased at pH 7.0. This can be explained by lactoferrin remaining positively charged at pH 7.0 and able to interact with negatively charged saliva proteins, whereas the negatively charged WPI would not interact. Charge interactions were further supported by beta-LG or lactoferrin and salivary proteins precipitating when mixed at conditions where beta-LG, lactoferrin, or saliva themselves did not precipitate. It can be concluded that interactions between positively charged whey proteins and salivary proteins play a role in astringency of proteins at low pH.

Holographic Declarative Memory: Distributional Semantics as the Architecture of Memory.

We demonstrate that the key components of cognitive architectures (declarative and procedural memory) and their key capabilities (learning, memory retrieval, probability judgment, and utility estimation) can be implemented as algebraic operations on vectors and tensors in a high-dimensional space using a distributional semantics model. High-dimensional vector spaces underlie the success of modern machine learning techniques based on deep learning. However, while neural networks have an impressive ability to process data to find patterns, they do not typically model high-level cognition, and it is often unclear how they work. Symbolic cognitive architectures can capture the complexities of high-level cognition and provide human-readable, explainable models, but scale poorly to naturalistic, non-symbolic, or big data. Vector-symbolic architectures, where symbols are represented as vectors, bridge the gap between the two approaches. We posit that cognitive architectures, if implemented in a vector-space model, represent a useful, explanatory model of the internal representations of otherwise opaque neural architectures. Our proposed model, Holographic Declarative Memory (HDM), is a vector-space model based on distributional semantics. HDM accounts for primacy and recency effects in free recall, the fan effect in recognition, probability judgments, and human performance on an iterated decision task. HDM provides a flexible, scalable alternative to symbolic cognitive architectures at a level of description that bridges symbolic, quantum, and neural models of cognition.

Analysis of differential gene expression in colorectal cancer and stroma using fluorescence-activated cell sorting purification.

Tumour stroma gene expression in biopsy specimens may obscure the expression of tumour parenchyma, hampering the predictive power of microarrays. We aimed to assess the utility of fluorescence-activated cell sorting (FACS) for generating cell populations for gene expression analysis and to compare the gene expression of FACS-purified tumour parenchyma to that of whole tumour biopsies. Single cell suspensions were generated from colorectal tumour biopsies and tumour parenchyma was separated using FACS. Fluorescence-activated cell sorting allowed reliable estimation and purification of cell populations, generating parenchymal purity above 90%. RNA from FACS-purified and corresponding whole tumour biopsies was hybridised to Affymetrix oligonucleotide microarrays. Whole tumour and parenchymal samples demonstrated differential gene expression, with 289 genes significantly overexpressed in the whole tumour, many of which were consistent with stromal gene expression (e.g., COL6A3, COL1A2, POSTN, TIMP2). Genes characteristic of colorectal carcinoma were overexpressed in the FACS-purified cells (e.g., HOX2D and RHOB). We found FACS to be a robust method for generating samples for gene expression analysis, allowing simultaneous assessment of parenchymal and stromal compartments. Gross stromal contamination may affect the interpretation of cancer gene expression microarray experiments, with implications for hypotheses generation and the stability of expression signatures used for predicting clinical outcomes.

Differential expression of HLA-DQ alleles in peripheral blood mononuclear cells: alleles associated with susceptibility to and protection from autoimmune type 1 diabetes.

Differential expression of human leucocyte antigen (HLA) class II genes has been postulated to influence the risk of developing autoimmune disease. In this study, we investigated the relationship between the level of mRNA expression of DQA1 and DQB1 alleles in peripheral blood mononuclear cells and the influence of the alleles on susceptibility to type 1 diabetes (T1D). Transcripts from pairs of DQA1 and DQB1 alleles were quantified in 59 DQ-heterozygous individuals (29 patients with T1D and 30 healthy control subjects). Luciferase reporter gene assays were used to investigate the relative promoter activities of the alleles associated with high and low risk of disease. DQA1*0301 and the DQB1*06 group of alleles (*0601, *0602, *0603 and *0604) were generally overexpressed in comparison to other alleles. In contrast, mRNA for DQB1*0201/*0202 was generally less abundant than other DQB1 transcripts. These data correlated well with the relative promoter activities observed for the diabetes-associated alleles; the strongest promoters were those derived from DQA1*0301 and DQB1*0602, while a 700-bp fragment derived from the DQB1*0201 promoter showed the lowest activity of the DQB1 constructs. There was no simple correlation between the level of expression of specific DQ alleles and their influence on the risk of diabetes. The functional relevance of our findings and their implications for the pathogenesis of autoimmunity remain to be determined.

Quantifying the polygenic contribution to variable expressivity in eleven rare genetic disorders.

Rare genetic disorders (RGDs) often exhibit significant clinical variability among affected individuals, a disease characteristic termed variable expressivity. Recently, the aggregate effect of common variation, quantified as polygenic scores (PGSs), has emerged as an effective tool for predictions of disease risk and trait variation in the general population. Here, we measure the effect of PGSs on 11 RGDs including four sex-chromosome aneuploidies (47,XXX; 47,XXY; 47,XYY; 45,X) that affect height; two copy-number variant (CNV) disorders (16p11.2 deletions and duplications) and a Mendelian disease (melanocortin 4 receptor deficiency (MC4R)) that affect BMI; and two Mendelian diseases affecting cholesterol: familial hypercholesterolemia (FH; LDLR and APOB) and familial hypobetalipoproteinemia (FHBL; PCSK9 and APOB). Our results demonstrate that common, polygenic factors of relevant complex traits frequently contribute to variable expressivity of RGDs and that PGSs may be a useful metric for predicting clinical severity in affected individuals and for risk stratification.

Capturing coastal water clarity variability with Landsat 8.

Coastal water clarity varies at high temporal and spatial scales due to weather, climate, and human activity along coastlines. Systematic observations are crucial to assessing the impact of water clarity change on aquatic habitats. In this study, Secchi disk depths (ZSD) from Boston Harbor, Buzzards Bay, Cape Cod Bay, and Narragansett Bay water quality monitoring organizations were compiled to validate ZSD derived from Landsat 8 (L8) imagery, and to generate high spatial resolution ZSD maps. From 58 L8 images, acceptable agreement was found between in situ and L8 ZSD in Buzzards Bay (N = 42, RMSE = 0.96 m, MAPD = 28%), Cape Cod Bay (N = 11, RMSE = 0.62 m, MAPD = 10%), and Narragansett Bay (N = 8, RMSE = 0.59 m, MAPD = 26%). This work demonstrates the value of merging in situ ZSD with high spatial resolution remote sensing estimates for improved coastal water quality monitoring.