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Congenital disorders of glycosylation (CDGs) form a group of rare diseases characterized by hypoglycosylation. We here report the identification of 16 individuals from nine families who have either inherited or de novo heterozygous missense variants in STT3A, leading to an autosomal-dominant CDG. STT3A encodes the catalytic subunit of the STT3A-containing oligosaccharyltransferase (OST) complex, essential for protein N-glycosylation. Affected individuals presented with variable skeletal anomalies, short stature, macrocephaly, and dysmorphic features; half had intellectual disability. Additional features included increased muscle tone and muscle cramps. Modeling of the variants in the 3D structure of the OST complex indicated that all variants are located in the catalytic site of STT3A, suggesting a direct mechanistic link to the transfer of oligosaccharides onto nascent glycoproteins. Indeed, expression of STT3A at mRNA and steady-state protein level in fibroblasts was normal, while glycosylation was abnormal. In S. cerevisiae, expression of STT3 containing variants homologous to those in affected individuals induced defective glycosylation of carboxypeptidase Y in a wild-type yeast strain and expression of the same mutants in the STT3 hypomorphic stt3-7 yeast strain worsened the already observed glycosylation defect. These data support a dominant pathomechanism underlying the glycosylation defect. Recessive mutations in STT3A have previously been described to lead to a CDG. We present here a dominant form of STT3A-CDG that, because of the presence of abnormal transferrin glycoforms, is unusual among dominant type I CDGs. ispartof: AMERICAN JOURNAL OF HUMAN GENETICS vol:108 issue:11 pages:2130-2144 ispartof: location:United States status: published

OBJECTIVE: Epalrestat, an aldose reductase inhibitor increases phosphomannomutase (PMM) enzyme activity in a PMM2-congenital disorders of glycosylation (CDG) worm model. Epalrestat also decreases sorbitol level in diabetic neuropathy. We evaluated the genetic, biochemical, and clinical characteristics, including the Nijmegen Progression CDG Rating Scale (NPCRS), urine polyol levels and fibroblast glycoproteomics in patients with PMM2-CDG. METHODS: We performed PMM enzyme measurements, multiplexed proteomics, and glycoproteomics in PMM2-deficient fibroblasts before and after epalrestat treatment. Safety and efficacy of 0.8 mg/kg/day oral epalrestat were studied in a child with PMM2-CDG for 12 months. RESULTS: PMM enzyme activity increased post-epalrestat treatment. Compared with controls, 24% of glycopeptides had reduced abundance in PMM2-deficient fibroblasts, 46% of which improved upon treatment. Total protein N-glycosylation improved upon epalrestat treatment bringing overall glycosylation toward the control fibroblasts' glycosylation profile. Sorbitol levels were increased in the urine of 74% of patients with PMM2-CDG and correlated with the presence of peripheral neuropathy, and CDG severity rating scale. In the child with PMM2-CDG on epalrestat treatment, ataxia scores improved together with significant growth improvement. Urinary sorbitol levels nearly normalized in 3 months and blood transferrin glycosylation normalized in 6 months. INTERPRETATION: Epalrestat improved PMM enzyme activity, N-glycosylation, and glycosylation biomarkers in vitro. Leveraging cellular glycoproteome assessment, we provided a systems-level view of treatment efficacy and discovered potential novel biosignatures of therapy response. Epalrestat was well-tolerated and led to significant clinical improvements in the first pediatric patient with PMM2-CDG treated with epalrestat. We also propose urinary sorbitol as a novel biomarker for disease severity and treatment response in future clinical trials in PMM2-CDG. ANN NEUROL 20219999:n/a-n/a. ispartof: ANNALS OF NEUROLOGY vol:90 issue:6 pages:887-900 ispartof: location:United States status: published

Introduction: Type 2 Diabetes mellitus (T2DM) is a chronic illness, caused due to resistance to insulin or poor production. FBS, PPBS and Glycated Haemoglobin (HbA1c) are the major tests that are used to monitor chronic glycemia worldwide. HbA1c level remains the gold standard test for assessment of glycemic control at follow up and it reflects the mean glucose values in the previous three - month period. HbA1c is expressed as a percentage, whereas the day-to-day monitoring and treatment of diabetes are based on blood glucose levels expressed as milligrams per deciliter (mg/dl) or millimoles per liter (mmol/L). Due to the difference in the denominators of FBS/PPBS with HbA1c, it causes confusion to the patients regards their glycaemic control. “Estimated average glucose” or eAG derived from HbA1c has been promoted by the American Diabetes Association (ADA). American Association of Clinical Chemists concludes that the correlation (r =0.92) is strong enough to justify reporting both HbA1c and eAG which indicate the 3- month control of the average sugar of the patient. This is easy for the patient as both FBS/PPBS and eAG are expressed with the same denominator for daily glucose checks and long-term control respectively, enhancing the glycaemic control. Objectives: To determine the statistical correlation between eAG derived from HBA1C using the Nathan’s regression equation with FBS and PPBS in patients with T2DM. To analyze the significance of eAG as opposed to HbA1C as a marker of long-term glycemic control in T2DM. Methodology: A retrospective analytical study done at the Department of Haematology of the Sri Jayewardenepura General Hospital, Sri Lanka. A simple random sampling technique was used, over a period of one year commencing June 2019 to June 2020, to obtain the laboratory records through laboratory information system of 201 adult patients both males and females who were diagnosed with T2DM. HbA1c, FBS, PPBS done on the same day were recorded. The eAG(mg/dl) was calculated using the Nathan’s regression equation (eAG = 28.7 x HbA1c – 46.7). Three groups were generated according to the patients’ levels of FBS and PPBS. Statistical Analysis: Data were double entered and analyzed using (SPSS) version 20. Descriptive statistical methods were used to calculate the median, mean standard deviation of age, HBA1c, FBS, and PPBS. Correlations between study variables were done with Pearson’s correlation method. The p value, lower than 0.05 was considered as statistically significant. Coefficient of determination (R Sq) was used to a statistical measure of how close the data are to the fitted regression line. Results: The total population of patients in both the FBS and PPBS groups showed a significant statistical correlation with eAG. The individual subgroups did not conform to this correlation. The results reveal no statistical correlation in both FBS and PPBS with eAG in patients with good glycaemic control. There was a significant statistical correlation in both FBS and PPBS with eAG in the groups of patients with moderately poor control. In those with markedly poor control the FBS did not show a statistical correlation with eAG, as opposed to the PPBS. Conclusion: The clinical importance of HbA1C/eAG in diagnosis and management of T2DM can be re-emphasized by this study. HbA1C along with eAG may be added as a test in the management of T2DM, for the better understanding and maintenance of good glycemic control. As eAG values, derived by the Nathan’s regression equation in our study scattered very close to the regression line, it provided a more complete and representative measure of average glucose in past 3 months. We conclude that HbA1c values were reliably translated into eAG measurements which would be easily understood by the patients being of the same denominator as the FBS/PPBS.

Fluoride is a beneficial trace element for human health as its deficiency and excess levels can cause detrimental health effects. In Sri Lanka, dry zone regions can have excessive levels of fluoride in drinking water and can cause dental and skeletal fluorosis. In addition to drinking water, traditional habits of tea consumption can cause an additional intake of fluoride in the population. A total number of 39 locally blended black tea samples were collected from a village where chronic kidney disease with undetermined origin (CKDu) is prevalent. In addition, unblended tea samples were obtained from tea-producing factories. The fluoride contents in infusions of 2% weight per volume (w/v) were measured using calibrated ion-selective fluoride electrodes. The mean fluoride content was 2.68±1.03 mg/L in loose tea, 1.87±0.57mg/L in packed tea samples, and 1.14±0.55 mg/L in unblended tea. Repeated brewing of the same tea leaves showed that over 50% of fluoride leached into the solution in the first infusion. An estimate of the daily total average fluoride intake via tea consumption per person is 2.68 mg per day. With groundwater in many dry zone regions in Sri Lanka showing high fluoride levels that exceed 0.5 mg/L, the additional daily intake can rapidly exceed recommended thresholds of 2 mg/day. This can add to adverse health impacts that might also relate to CKDu.

Prior studies suggest a strong genetic influence on breast cancer prognosis. Six genome-wide association studies (GWAS) on breast cancer prognosis have been published to date. However, none of the reported loci was replicated across studies and only two passed genome-wide significance (P < 5 x 10-8). In the Pathways Study, a prospective cohort of breast cancer survivors begun in Kaiser Permanente Northern California (KPNC) in 2006, we carried out a GWAS of overall survival (OS) in 3,973 patients. Trans-ethnic meta-GWAS identified an association with OS of a locus on chromosome 15 that almost reached genome-wide significance (P = 9.42 x 10-8). This locus spanned the UACA gene, a key regulator of tumor suppressor Par-4. We found that receipt of chemotherapy modified the effect of the UACA locus on OS (Pinteraction = 2.4 x 10-4). This observation led us to hypothesize that the UACA locus effect on OS may be specific to Par-4 dependent chemotherapies, which include anti-HER2 therapy and doxorubicin. We stratified patients into two groups, those who received Par-4 dependent chemotherapy agents versus other patients. In separate trans-ethnic meta-GWAS, the UACA locus was significantly associated with OS in patients taking Par-4 dependent chemotherapies (P = 1.27 x 10-9), while no association was observed in the other patients (P = 0.21). To evaluate whether the UACA gene may be responsible for this association, we performed a transcriptome-wide association study (TWAS) of OS in White patients taking Par-4 dependent chemotherapies. Higher UACA gene expression was significantly associated with OS (P = 4.68 x 10-7), the only gene reaching transcriptome-wide significance (P < 4.34 x 10-6). These results suggest that higher UACA expression may inhibit Par-4 induced apoptosis and lead to stronger chemoresistance and worse survival. We attempted to validate our findings in the independent KPNC Genetic Epidemiology Research on Aging (GERA) cohort. The GERA cohort included only 168 White patients with incident breast cancer after DNA collection who received Par-4 dependent chemotherapies. We found a non-significant association (hazard ratio (HR) = 1.46, P = 0.66) consistent with Pathways Study findings. However, the GERA cohort also included 1,983 prevalent breast cancer patients with biospecimen collection after diagnosis. In this group, the risk allele frequency in breast cancer survivors receiving Par-4 dependent chemotherapies was significantly lower than that in the White population (P = 5.50 x 10-3) while the risk allele frequency in the those not receiving these chemotherapies was similar to the population (P = 0.07). This is consistent with Pathways Study observations that the UACA locus risk allele significantly increased risk of mortality in patients taking Par-4 dependent chemotherapies. A higher mortality in breast cancer survivors carrying the risk allele would result in decreased risk allele frequency. We further validated our findings in Shanghai Breast Cancer Survival Study (SBCSS)and Shanghai Breast Cancer Study, which were conducted from 1996 to 2006 in urban Shanghai and recruited 5,575 breast cancer patients. In this independent Asian breast cancer population, the UACA locus was modestly associated with OS in the overall population (HR = 1.18, P = 0.012), and more significantly in 1,289 SBCSS patients who received anthracyclines (HR = 1.66, P = 1.55 x 10-4). This is the first human study suggesting the Par-4 pathway affects breast cancer patient survival with UACA a key modulator of treatment outcomes by anti-Her2 therapy and doxorubicin. Our findings suggest a path toward new predictive pharmacogenetic markers for personalized medicine targeting the Par-4 pathway for breast cancer treatment. Citation Format: Lawrence H Kushi, Qianqian Zhu, Emily Schultz, Jirong Long, Janise M Roh, Emily Valice, Cecile A Laurent, Li Yan, Isaac J Ergas, Warren Davis, Dilrini K Ranatunga, Marilyn L Kwan, Ping-Ping Bao, Wei Zheng, Xiao-Ou Shu, Christine B Ambrosone, Song Yao. Genome-wide association study identifies UACA as a modulator of breast cancer chemoresistance and survival [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS2-05.

Introduction Congenital disorders of glycosylation (CDG) are inborn errors of glycan metabolism with high clinical variability. Only a few antenatal cases have been described with CDG. Due to a lack of reliable biomarker, prenatal CDG diagnostics relies primarily on molecular studies. In the presence of variants of uncertain significance prenatal glycosylation studies are very challenging. Case report A consanguineous couple had a history of second-trimester fetal demise with tetralogy of Fallot and skeletal dysplasia. In the consecutive pregnancy, the second trimester ultrasonography showed skeletal dysplasia, vermian hypoplasia, congenital heart defects, omphalocele and dysmorphic features. Prenatal chromosomal microarray revealed a large region of loss of heterozygosity. Demise occurred at 30 weeks. Fetal whole exome sequencing showed a novel homozygous likely pathogenic variant in ALG3 and a variant of uncertain significance in COG5. Methods Western blot was used to quantify ALG3, COG5, COG6, and the glycosylation markers ICAM-1 and LAMP2. RT-qPCR was used for ALG3 and COG5 expression in cultured amniocytes and compared to age matched controls. Results ALG3 and COG5 mRNA levels were normal. ICAM-1, LAMP2, ALG3 and COG5 levels were decreased in cultured amniocytes, suggesting the possible involvement of both genes in the complex phenotype. Conclusion This is the first case of successful use of glycosylated biomarkers in amniocytes, providing further options of functional antenatal testing in CDG.

Background Accidental awareness during general anaesthesia (AAGA) is a complex and rare outcome to investigate in surgical patient populations, particularly obstetric patients. We report the protocol of the Direct Reporting of Awareness in Maternity patients (DREAMY) study, illustrating how the research was designed to address practical and methodological challenges for investigating AAGA in an obstetric cohort. Methods This is the trial protocol of a prospective, multicentre cohort study of patients undergoing obstetric surgery under general anaesthesia. Accidental awareness during general anaesthesia will be detected using three repetitions of standardised direct questioning over 30 days, with responses indicating memories during general anaesthesia verified using structured interviews. Reports will be adjudicated, then classified, in accordance with pre-defined and pre-validated structures, including the Michigan Awareness Classification tool. Quantitative data will be collected on general anaesthesia conduct for all participants. This descriptive study is being conducted in England and aims to recruit a minimum of 2015 patients. Results The DREAMY study was prospectively registered (ClinicalTrials.gov Identifier: NCT03100396) and ethical approval granted. Participant recruitment began in May 2017 and one year follow up concluded in August 2019. Publication of the results is anticipated in 2020. Conclusions The DREAMY study will provide data on incidence, experience and implications of AAGA for obstetric patients, using a robust methodology that will reliably detect and translate subjective AAGA reports into objective outcomes. In addition, the study is expected to improve vigilance for AAGA in participating hospitals and encourage adoption of recommendations for support of patients experiencing AAGA.

BackgroundIn type 2 Diabetes Mellitus (T2DM) chronic hyperglycemia leads to multi-organ damage. It is a chronic low-grade inflammation resulting in reduced antioxidants leading to many complications. Hyperglycemia causes glycation of serum proteins forming advanced glycation end products (AGEs). HBA1c is an AGE of haemoglobin. Bilirubin considered a waste product of the heme catabolic pathway, has proven to be a natural antioxidant associated with a lower prevalence of oxidative stress-mediated diseases. Bilirubin prevents glycation of proteins providing benefit in T2DM. General objective - To evaluate the association of serum bilirubin levels with HBA1c, FBS, PPBS in diabetes patients. Specific objectives - 1) To compare the serum bilirubin levels in diabetes patients with good and poor control. 2) To evaluate the association of HbA1c with FBS, PPBS and age in controlled and uncontrolled diabetes mellitusMethodology -A retrospective analytical study done at the department of Haematology of the Sri Jayewardenepura General Hospital.Sample selection and sample size -A random sampling technique used. Data obtained through laboratory information system of 201 adult patients diagnosed with T2DM. The study population grouped as poorly and well controlled using HbA1c value over and below 7% respectively. Normal ranges for serum bilirubin, FBS and PPBS was (0.3-1.2) mg/dl, (75- 110) mg/dl and (80-140) mg/dl respectively. Data were entered and analyzed using statistical package for social sciences (SPSS) version 20. Descriptive statistics used to calculate the median, mean and the standard deviation of age, serum bilirubin, HBA1c, FBS, and PPBS. Correlations between variables were done using Pearson’s Correlation method. The p value Results. A negative correlation between total bilirubin and HbA1c (r = -0.234, p value = 0.001) with a low linear relationship (R Sq of 0.055, figure 02) observed. No statistical significance between total bilirubin level with FBS, PPBS and age (p value >0.05) but the mean values of these in the two groups were statistically significant (p value < 0.05). A statistically positive co-relation observed between HbA1c with FBS and PPBS, not with age. Conclusion. The significant negative correlation between total bilirubin and HbA1c, infers that a lower blood glucose level will result in reducing the oxidant stress mediated damage by the antioxidant and anti- inflammatory action of the increased oxygen free radicals produced by a high bilirubin.

sBackgroundRandomized-controlled trials demonstrate that high coronary heart disease (CHD) polygenic risk score modifies statin CHD relative risk reduction, but it is unknown if the association extends to statin users undergoing routine care.ObjectivesThe primary objective was to determine how statin effectiveness is modified by CHD polygenic risk score in a real-world cohort of primary prevention participants.MethodsWe determined polygenic risk scores in participants of the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. Cox regression models were used to compare the risk of the cardiovascular outcomes between statin users and matched nonusers.ResultsThe hazard ratio (HR) for statin effectiveness on incident myocardial infarction was similar within 10-year atherosclerotic cardiovascular disease (ASCVD) risk score groups at 0.65 (95% confidence interval [CI] 0.39-1.08; P=0.10), 0.65 (95% CI 0.56-0.77; P=2.1E-7), and 0.67 (95% CI 0.57-0.80; P=4.3E-6) for borderline, intermediate, and high ASCVD groups, respectively. In contrast, statin effectiveness by polygenic risk was largest in the high polygenic risk score group (HR 0.62, 95% CI 0.50-0.77; P=1.4E-5), intermediate in the intermediate polygenic risk score group (HR 0.70, 95% CI 0.61-0.80; P=5.7E-7), and smallest in the low polygenic risk score group (HR 0.86, 95% CI 0.65-1.16; P=0.33). ASCVD risk and statin LDL-C lowering did not differ across polygenic risk score groups.ConclusionsIn primary prevention patients undergoing routine care, CHD polygenic risk modified statin relative risk reduction of incident myocardial infarction independent of statin LDL-C lowering. Our findings extend prior work by identifying a subset of patients with attenuated clinical benefit from statins.

Introduction Portal hypertension (PH) is associated with complications including refractory ascites and variceal haemorrhage and can be treated endovascularly with a Transjugular Intrahepatic Portosystemic Shunt (TIPS). Portal vein puncture during TIPS using real-time transabdominal ultrasound guidance is one of many portal vein puncture techniques and is seldom used compared with other methods. The purpose of this manuscript is to describe this technique and its associated procedural outcomes at a quaternary liver transplant hospital. Methods Clinical data of all patients who underwent ultrasound-guided TIPS at our institution between 1 January 2009 and 1 January 2019 were retrospectively obtained from electronic medical records and reviewed. Patient demographics, indications, procedural outcomes and complications were recorded. Results Forty-four ultrasound-guided TIPS procedures were performed during the study period. The most common indication for TIPS was refractory ascites (n = 26; 57%) and variceal haemorrhage (n = 12; 26%). Technical success rate was 100%. No intraprocedural complications occurred. Periprocedural complication rate was 35% (n = 16) with encephalopathy (n = 8; 17%) and sepsis (n = 5; 11%) the most common. One patient with sepsis died. No other TIPS-related deaths occurred. Median fluoroscopy time, contrast volume, air kerma and dose area product values for all procedures were 35 minutes (IQR 24-51), 100 ml (IQR 70-160), 0.95 Gy (IQR 0.50-1.53) and 127 Gycm2 (IQR 68.75-206), respectively. Conclusion Transabdominal ultrasound-guided portal vein puncture during TIPS is safe and technically feasible. When compared to fluoroscopically guided methods, it is associated with lower intraprocedural complication rates, fluoroscopy times, contrast volumes and radiation doses in our experience. Radiation doses, FTs and contrast volumes were also considerably lower than recommended limits.

The increasing specialisation of medical care in larger centres is contributing to the declining use of rural hospitals that are close to larger centres, risking bed closures or even facility closure. An allied health-led model of care supported by telehealth geriatrician services was developed and implemented in eight beds in a rural hospital to manage older patients needing geriatric evaluation and management. The project was set in Kilcoy Hospital, a small facility north of Caboolture in Queensland, Australia. The feeder hospital was Caboolture Hospital, the regional centre. Occupancy rates at the rural hospital along with length of stay, discharge destination and functional independence measure. A project officer was employed 1 day a week to facilitate the implementation of the new model of care. Training and education were provided to medical and nursing staff to understand and implement the geriatric evaluation and management model of care. Over the project time frame, 93 patients were successfully managed in the rural hospital with improved occupancy rates. Outcomes were as effective and safe as compared to the group managed at the regional centre. The model of care is now routine practice. Using excess capacity in rural hospitals by employing a geriatric evaluation and management approach is a viable strategy to address declining rural hospital usage.

To identify rare variants associated with prostate cancer susceptibility and better characterize the mechanisms and cumulative disease risk associated with common risk variants, we conducted an integrated study of prostate cancer genetic etiology in two cohorts using custom genotyping microarrays, large imputation reference panels, and functional annotation approaches. Specifically, 11,984 men (6,196 prostate cancer cases and 5,788 controls) of European ancestry from Northern California Kaiser Permanente were genotyped and meta-analyzed with 196,269 men of European ancestry (7,917 prostate cancer cases and 188,352 controls) from the UK Biobank. Three novel loci, including two rare variants (European ancestry minor allele frequency < 0.01, at 3p21.31 and 8p12), were significant genome wide in a meta-analysis. Gene-based rare variant tests implicated a known prostate cancer gene (HOXB13), as well as a novel candidate gene (ILDR1), which encodes a receptor highly expressed in prostate tissue and is related to the B7/CD28 family of T-cell immune checkpoint markers. Haplotypic patterns of long-range linkage disequilibrium were observed for rare genetic variants at HOXB13 and other loci, reflecting their evolutionary history. In addition, a polygenic risk score (PRS) of 188 prostate cancer variants was strongly associated with risk (90th vs. 40th–60th percentile OR = 2.62, P = 2.55 × 10−191). Many of the 188 variants exhibited functional signatures of gene expression regulation or transcription factor binding, including a 6-fold difference in log-probability of androgen receptor binding at the variant rs2680708 (17q22). Rare variant and PRS associations, with concomitant functional interpretation of risk mechanisms, can help clarify the full genetic architecture of prostate cancer and other complex traits. Significance: This study maps the biological relationships between diverse risk factors for prostate cancer, integrating different functional datasets to interpret and model genome-wide data from over 200,000 men with and without prostate cancer. See related commentary by Lachance, p. 1637

Pathogenic alterations in the DPM2 gene have been previously described in patients with hypotonia, progressive muscle weakness, absent psychomotor development, intractable seizures, and early death. We identified biallelic DPM2 variants in a 23-year-old male with truncal hypotonia, hypertonicity, congenital heart defects, intellectual disability, and generalized muscle wasting. His clinical presentation was much less severe than that of the three previously described patients. This is the second report on this ultra-rare disorder. Here we review the characteristics of previously reported individuals with a defect in the DPM complex while expanding the clinical phenotype of DPM2-Congenital Disorders of Glycosylation. In addition, we offer further insights into the pathomechanism of DPM2-CDG disorder by introducing glycomics and lipidomics analysis. ispartof: MOLECULAR GENETICS AND METABOLISM vol:132 issue:1 pages:27-37 ispartof: location:United States status: published

Introduction: Classical Hairy Cell Leukaemia (cHCL) and Hairy Cell Leukaemia variant (HCL-v) are both rare and slow-growing mature B cell neoplasms. According to flowcytometry data, they fall into the group classified as CD5- CD10- B cell lymphoproliferative disorders. Methods: Two cases with features atypical to two neoplasms at the time of diagnosis were studied. Results: Case 1 was a 15 year old male with right cervical lymph nodes (1x1 cm) in the posterior triangle, a few ecchymotic patches on the arm and a massive splenomegaly. C-reactive protein (CRP) level was 53 mg/dL. Erythrocyte Sedimentation Rate (ESR) was 98 mm/1 st hour. Full Blood Count (FBC) revealed typical features of pancytopenia with monocytopenia. The liver and renal profiles were normal. Morphology of bone marrow was suggestive of cHCL. Flowcytometry and BRAF V600E mutation was positive confirming the diagnosis of cHCL. Case 2 was a 55 year old male presenting with moderate splenomegaly and absolute lymphocytosis. The FBC revealed leukocytosis which is commonly seen with monocytopenia. Blood pictures revealed many hairy cells with moderately basophilic cytoplasm and visible nucleoli suggesting HCL-v. Flowcytometry findings and negative BRAF V600E mutation confirmed HCL-v. Conclusions: Clinical findings, blood images, morphology of bone marrow, flowcytometric findings and positive BRAF V600E mutation confirmed the diagnosis of cHCL in case 1 (15 year old boy) making it as a very rare case. The morphological findings on blood, the presence of characteristic CD markers on flowcytometry and negativity of BRAF V600E confirmed the case 2 as HCL-v, despite having CD10 positivity and monocytopenia.Keywords: Flowcytometric immunophenotyping, Hairy cell leukaemia, Hairy cell leukaemia variant

Objective: Mid-maxillary osteodistraction (MMOD) is a novel technique. This study seeks to assess the occlusal and functional improvement of patients with midfacial hypoplasia secondary to cleft lip and palate. Design: This was done as a retrospective study at the Regional Cleft Centre of the Teaching Hospital-Karapitiya (THK). Participants: A total of 81 patient records were accessed on those who underwent MMOD with a tooth-borne intraoral device from January 1, 2007, to December 31, 2016, at THK. Methods: Records of the patients included pre- and post-treatment lateral cephalograms, study models, speech assessments, and photographs. Results: An advancement ranging from 5 to 12 mm (mean, 8.14 mm) was achieved in all patients; 80% (n = 63) and 87.65% (n = 71) showed improvement in consonant production and quality of speech. These were statistically significant (P < .05). With regard to the Peer Assessment Rating score assessing the occlusal improvement, 97.6% showed an improvement whereas only 2 patients showed no improvement. There was a significant improvement in sella (S), nasion (N), and point A (SNA) angle; point A, the nasion, and point B (ANB) angle; and the maxillary length over the treatment period (P < .05). The change in the ANB angle and maxillary length significantly differed between genders with males having a comparatively higher improvement. The profile improvements were noteworthy on the profile photographs. Conclusion: This relatively novel approach to maxillary advancement by maxillary distraction using a combined surgical and modified orthodontic technique has proven to be successful. This protocol and the technique have improved function, occlusion, and the aesthetics.

Background: Left ventricular ejection fraction (EF) is an indicator of cardiac function, usually assessed in individuals with heart failure and other cardiac conditions. Although family studies indicate that EF has an important genetic component with heritability estimates up to 0.61, to date only 6 EF-associated loci have been reported. Methods: Here, we conducted a genome-wide association study (GWAS) of EF in 26 638 adults from the Genetic Epidemiology Research on Adult Health and Aging and the UK Biobank cohorts. Results: A meta-analysis combining results from Genetic Epidemiology Research on Adult Health and Aging and UK Biobank identified a novel locus: TMEM40 on chromosome 3p25 (rs11719526; β=0.47 and P =3.10×10 −8 ) that replicated in Biobank Japan and confirmed recent findings implicating the BAG3 locus on chromosome 10q26 in EF variation, with the strongest association observed for rs17617337 (β=−0.83 and P =8.24×10 −17 ). Although the minor allele frequencies of TMEM40 rs11719526 were generally common (between 0.13 and 0.44) in different ethnic groups, BAG3 rs17617337 was rare (minor allele frequenciesTMEM40 or BAG3 on EF are largely independent of these conditions. Conclusions: In this large and multiethnic study, we identified 2 loci, TMEM40 and BAG3 , associated with EF at a genome-wide significance level. Identifying and understanding the genetic determinants of EF is important to better understand the pathophysiology of this strong correlate of cardiac outcomes and to help target the development of future therapies.

Introduction: Iron deficiency anemia (IDA) is the commonest nutritional deficiency in all parts of the world. In developing countries, the commonest cause is inadequate dietary intake [1]. The red cell indices raise the suspicion of iron deficiency state due to the microcytic, hypochromic changes and the wide red cell distribution width. The iron studies are confirmatory of an iron deficiency state, but are not accurate in the presence of infection, inflammation or malignancy as they are acute phase proteins and are affected in these states making the serum iron studies unreliable under these conditions. The reticulocyte haemoglobin content (CHr) indicates the iron available in the marrow for the production of Hb and are not affected by the above-mentioned situations and therefore has been recommended as a reliable marker of iron status in the body. The value for CHr given in the literature was 25pg [3]. Objectives: General objective was to evaluate the significance of CHr in the diagnosis of IDA. The Specific objectives were to compare CHr with the other conventional iron parameters including serum iron, serum ferritin, TS and TIBC and evaluate any significance of CHr with RBC indices (MCV, MCH and MCHC) and age. Methodology: A retrospective analytical study performed at the Department of Haematology of a Tertiary care hospital in Sri Lanka. Data was obtained from the patient records of those referred to the Haematology department for management of iron deficiency during the period of 9 months commencing from April 2019 to January 2020. Data from 178 adult patients both males and females (16 to 84 years) diagnosed with IDA (S. Ferritin < 20ng/ml) (Hb < 12g/dl in men and Hb

Background Visceral and renal artery aneurysms (VRAAs) are uncommon but are associated with a high mortality rate in the event of rupture. Endovascular treatment is now first line in many centres, but preservation of arterial flow may be difficult in unfavourable anatomy including wide necked aneurysms, parent artery tortuosity and proximity to arterial bifurcations. Endovascular stenting, and in particular flow-diversion, is used in neurovascular intervention to treat intracranial aneurysms but is less often utilised in the treatment of VRAAs. The CASPER stent is a low profile dual-layer braided nitinol stent designed for carotid stenting with embolic protection and flow-diversion properties. We report the novel use of the CASPER stent for the treatment of VRAAs. We present a case series describing the treatment of six patients with VRAAs using the CASPER stent. Results Six patients with unruptured VRAAs were treated electively. There were three splenic artery aneurysms and three renalartery aneurysms. Aneurysms were treated with the CASPER stent, with or without loose aneurysm coil packing or liquid embolic depending on size and morphology. All stents were successfully deployed with no immediate or periprocedural complications. Four aneurysms completely occluded after serial imaging follow up with one case requiring repeat CASPER stenting for complete occlusion. In one patient a single aneurysm remained patent at last follow up, A single case was complicated by delated splenic infarction and surgical splenectomy. Conclusion Preliminary experience with the CASPER stent suggests it is technically feasible and effective for use in the treatment of VRAAs.

The potential association between rare germline genetic variants and prostate cancer (PrCa) susceptibility has been understudied due to challenges with assessing rare variation. Furthermore, although common risk variants for PrCa have shown limited individual effect sizes, their cumulative effect may be of similar magnitude as high penetrance mutations. To identify rare variants associated with PrCa susceptibility, and better characterize the mechanisms and cumulative disease risk associated with common risk variants, we analyzed large population-based cohorts, custom genotyping microarrays, and imputation reference panels in an integrative study of PrCa genetic etiology. In particular, 11,649 men (6,196 PrCa cases, 5,453 controls) of European ancestry from the Kaiser Permanente Research Program on Genes, Environment and Health, ProHealth Study, and California Men’s Health Study were genotyped and meta-analyzed with 196,269 European-ancestry male subjects (7,917 PrCa cases, 188,352 controls) from the UK Biobank. Six novel loci were genome-wide significant in our meta-analysis, including two rare variants (minor allele frequency < 0.01, at 3p21.31 and 8p12). Gene-based rare variant tests implicated a previously discovered PrCa gene (HOXB13) as well as a novel candidate (ILDR1) highly expressed in prostate tissue. Haplotypic patterns of long-range linkage disequilibrium were observed for rare genetic variants atHOXB13and other loci, reflecting their evolutionary history. Furthermore, a polygenic risk score (PRS) of 187 known, largely common PrCa variants was strongly associated with risk in non-Hispanic whites (90thvs. 10thdecile OR = 7.66,P= 1.80*10-239). Many of the 187 variants exhibited functional signatures of gene expression regulation or transcription factor binding, including a six-fold difference in log-probability of Androgen Receptor binding at the variant rs2680708 (17q22). Our finding of two novel rare variants associated with PrCa should motivate further consideration of the role of low frequency polymorphisms in PrCa, while the considerable effect of PrCa PRS profiles should prompt discussion of their role in clinical practice.

Spinal decompression procedures require a mode of anaesthesia which should facilitate prone positioning, muscle relaxation for ease of retraction and effective, lengthy analgesia. In such cases, spinal anaesthesia is associated with numerous advantages over general anaesthesia. But precise case selection is of utmost importance. The cases presented here are single-level, unilateral decompressions in healthy young adults. The successful outcomes in these cases, both anaesthetically and surgically, suggest integration to local practice elsewhere as well.

No abstract available

Introduction Diabetic patients with peripheral arterial disease (PAD) are challenging to assess. Non-contrast magnetic resonance angiography (MRA) offers a safe alternative in patients with renal impairment. The study objective is to evaluate accuracy of lower limb quiescent-interval single-shot (QISS) MRA and pedal QISS-arterial spin-labelled (ASL) MRA for detection of significant stenosis in diabetic patients with PAD. Methods Combined QISS and QISS-ASL MRA was performed in 32 diabetic PAD patients (20 male, 12 female; mean 69 years; 8 with critical ischaemia). Two readers assessed haemodynamically significant (>50%) stenosis and diagnostic confidence on MRA, against digital subtraction angiography (DSA) as the reference standard, with subgroup analysis of patients with severe renal impairment (n = 7). Inter-reader agreement of stenosis and diagnostic confidence were evaluated. Test-retest reproducibility was evaluated in 10 subjects who underwent repeat MRA on a different day. Results At DSA, 262/645 segments (40.6%) had haemodynamically significant stenoses. MRA accuracy was 78.1% (478/612) and 75.6% (464/614), sensitivity 64.7% (161/249) and 77.5% (193/249), and specificity 87.3% (317/363) and 74.2% (271/365) for 2 readers. MRA accuracy was 80.9% and 80.7% for readers 1 and 2, respectively, in patients with severe renal impairment. QISS MRA but not pedal QISS-ASL MRA was considered of diagnostic image quality. Inter-reader agreement was moderate for stenosis (ĸ = 0.60) and diagnostic confidence (ĸ = 0.41). Test-retest reproducibility was high (ĸ = 0.87) and moderate (ĸ = 0.54) for individual readers. Conclusions Quiescent-interval single-shot MRA has reasonable accuracy in a diabetic PAD population with high burden of disease, providing a non-contrast option in patients with renal impairment. QISS-ASL MRA requires further optimisation to be clinically feasible.

Background Unplanned pregnancy is a significant public health issue in both low- and high-income countries. The burden of unplanned pregnancy is reflected in women opting for pregnancy terminations and it can be detrimental to the women and her family as well as the health system and society. Solid data on the proportion of unplanned pregnancies are using more specific tools such as the London Measure of Unplanned Pregnancy (LMUP) needed to address the issue in Sri Lankan contexts. The objective was to describe the proportion of unplanned pregnancies, their determinants and the health outcomes of women delivering at Colombo North Teaching Hospital-Ragama (CNTH). Methods A cross-sectional study was carried out among 494 consecutive pregnant women selected by non-probability consecutive sampling who were admitted for the confinement at CNTH. A pre-tested structured interviewer-administered questionnaire was used to collect data on antenatal women and intentionality measured by self-administered six-item LMUP. Maternal and newborn health outcomes were ascertained in each post-partum women before discharge. Data were analyzed with the Mann-Whitney U tests, Kruskal-Wallis tests and spearman rank correlation. We also evaluated the psychometric properties of the Sinhalese version of LMUP. Results The response rate was 97.8 and 17.2% of pregnancies ending at birth were unplanned, 12.7% were ambivalent and 70.1% were planned. Associated factor profile of women with unplanned pregnancies includes; not married women (p = 0.001), educated up to the passing of GCE ordinary level by women (p p p = 0.002) and inadequate knowledge on emergency contraceptives (p = 0.037). Less planned pregnancies were also significantly associated with anemia (p = 0.004), low mood for last 2 weeks (p p p p p Conclusions A sizeable proportion of pregnancies were unplanned. Teenage pregnancies, non-marital relationships and inadequate knowledge on emergency contraceptives, maternal anemia, low mood, and GBV were modifiable associated factors which could be prevented by evidence-based locally applicable approaches.

Background Flow diverting stents have been used safely and effectively for the treatment of intracranial aneurysms, particularly for large and wide necked aneurysms that are not amenable to conventional endovascular treatment with coiling. The Surpass Streamline device (Stryker Neurovascular, MI, USA) is a relatively new and unique flow diverting stent which maintains constant device mesh density over varying vessel diameters. This may potentially provide advantages compared to other flow diverting stents in achieving aneurysmal occlusion. Case presentation Two patients with VRAA were treated using the Surpass Streamline device. The first patient was a 65-year-old male with an incidental 2.4 cm aneurysm originating from the hepatic artery near the gastroduodenal artery (GDA). The second patient was a 56-year-old male with an incidental 1.9 cm renal aneurysm arising from an anterior inferior segmental branch of the left renal artery. A Surpass flow diverting stent was used to successfully exclude the aneurysm neck in both cases. Reduced flow was achieved in one patient (equivalent to O’Kelly-Marotta [OKM] Grade B1). Preserved flow and stagnation (equivalent to OKM Grade A3) was achieved in the other. There was preserved distal flow in the parent arteries. No immediate complications were encountered in either case. Complete occlusion of both aneurysms was seen on follow up CT angiographic imaging within 8-weeks. Conclusions The Surpass flow diverting stent can be used safely and effectively to treat VRAA. It should be considered in unruptured large and giant wide necked VRAAs aneurysms. Additional large prospective studies are required for further validation.

Purpose To report the technical success, complications and long-term outcomes of patients with intrahepatic cholelithiasis not amenable to endoscopic retrograde cholangiopancreatography (ERCP) who were treated with percutaneous transhepatic biliary Laser lithotripsy (PTBLL). Patients and methods A retrospective review of 12 patients who underwent PTBLL for intrahepatic cholelithiasis was performed. There were 5 men and 7 women with a mean age of 46 ± 18 (SD) years (range: 23–75 years). PTBLL was performed when stone clearance using ERCP had previously failed or was not appropriate due to unfavourable anatomy or the presence of multiple stones or a large stone. Percutaneous biliary access into intrahepatic ducts was obtained if not already present and lithotripsy was performed using a HolmiumYAG 2100 nM Laser. Patients files were analyzed to determine the technical success, complications and long-term outcomes. Results Eleven patients (11/12; 92%) had a history of previous hepatobiliary surgery and nine (9/12; 75%) had multiple stones confirmed on preprocedure imaging. A 100% success rate in fragmenting the target stone(s) was achieved and 11/12 patients (92%) had successful first pass extraction of target stone fragments. Two patients (2/12; 17%) required repeat lithotripsy. One patient (1/12; 8%) experienced a major complication in the form of cholangitis. Of patients with long-term follow-up, 4/10 (40%) had recurrence of intrahepatic calculi with a mean time interval of 31 months (range 3–84 months). Conclusion For patients with intrahepatic biliary calculi not amenable to ERCP, PTBLL provides an effective and safe alternate treatment.

Vertebral compression fractures (VCFs) are a common cause of back pain and disability and are usually osteoporotic in nature. Therapy aims to adequately control pain and allow early mobilisation and return of function while preventing additional fractures. A proportion of patients do not achieve adequate pain relief using conservative measures alone. Unwanted adverse effects from medications may also ensue. Vertebroplasty represents an alternative treatment option for VCFs. Patients with acute VCFs (≤6 weeks old) may gain the most benefit from vertebroplasty as healed fractures are not as amenable to cement injection. High-quality studies have reported conflicting results regarding the use of vertebroplasty in the treatment of acute VCFs. Despite high-quality evidence, varying study designs and heterogenous patient cohorts make interpretation of this data difficult. Only one sham-controlled randomised controlled trial (RCT) has evaluated vertebroplasty exclusively in patients with acute VCFs, reporting favourable results. Pooled data from RCTs also suggest vertebroplasty to be safe. This article provides a concise and critical review of the current literature regarding vertebroplasty for the treatment of acute VCFs.

Goldenhar Syndrome is a rare congenital entity which comprises of facial dysmorphism, oral cavity malformations and vertebral anomalies any of which could lead to difficult airway during anaesthesia. Here, we report a case of a 5-month-old infant who underwent a congenital talipes equino varies (CTEV) correction under general anaesthesia with caudal block. We experienced difficulty in mask ventilation, failed endotracheal intubation and transient desaturation which was anticipated thus managed successfully without serious morbidity to the patient.

Introduction: ‘Preterm or Premature Birth’ is defined as birth occurring before completion of 37 weeks or 259 days since the first day of the last menstrual period of the mother. Every year, an estimated 15 million babies (more than one in ten births) are born preterm worldwide, and this number is rising. In Sri Lanka, approximately 24,500 babies are born prematurely each year. Efforts by obstetricians and neonatologists have led to significant advances in reducing preterm birth and improving outcomes.

In this paper we study the use of human robot interaction as a mean to objectively evaluate imitation deficits in children with autism. Robot control and data analysis methods were combined to assess the quality of interaction between the robot and the subjects. Humanoid robot Zeno was used to execute upper body gestures which the subjects were asked to imitate. The resulting motion of the subject was acquired through a motion capture system and compared with the intended motion performed by Zeno using the dynamic time warping (DTW) algorithm. During this study, the clinical hypothesis was that the resulting DTW cost can serve as a quantitative measure for the similarity between the motions, and thus can be used to objectively assess the severity of imitation deficits exhibited by the child. To validate this hypothesis, we present two sets of experiments, one with a set of healthy adults and the other with a group of children, some with autism spectrum disorder. The experiment with adult subjects serves as a statistically significant test to demonstrate the viability of the DTW cost as a similarity measure for the gesture analysis, whereas the experiment with child subjects is a pilot study to differentiate imitation performance for children with autism.

Endoplasmic reticulum (ER) stress responses through the IRE-1/XBP-1 pathway are required for the function of STING (TMEM173), an ER-resident transmembrane protein critical for cytoplasmic DNA sensing, IFN production, and cancer control. Here we show that the IRE-1/XBP-1 pathway functions downstream of STING and that STING agonists selectively trigger mitochondria-mediated apoptosis in normal and malignant B cells. Upon stimulation, STING was degraded less efficiently in B cells, implying that prolonged activation of STING can lead to apoptosis. Transient activation of the IRE-1/XBP-1 pathway partially protected agonist-stimulated malignant B cells from undergoing apoptosis. In Eμ-TCL1 mice with chronic lymphocytic leukemia, injection of the STING agonist 3′3′-cGAMP induced apoptosis and tumor regression. Similarly efficacious effects were elicited by 3′3′-cGAMP injection in syngeneic or immunodeficient mice grafted with multiple myeloma. Thus, in addition to their established ability to boost antitumoral immune responses, STING agonists can also directly eradicate malignant B cells. Cancer Res; 76(8); 2137–52. ©2016 AACR.

The Government of Sri Lanka realised the possibility of COVID-19 becoming a pandemic and its probability of reaching Sri Lanka, even before the World Health Organisation declared COVID-19 as a pandemic. GOSL adopted a strategy focusing on minimising the risk of entry, containment, flattening the curve and minimising fatalities. To ensure social distancing for persons with chronic illnesses, a guideline was issued to deliver the medications to the doorstep of the care recipients who attend the government sector hospital clinics for Non-Communicable Diseases. To facilitate the delivery of medications, National Hospital, Kandy decided to use Patient Information Management systems available at the hospital. The care recipients were contacted over the phone, and their data was taken and fed into the electronic systems. Medical officers entered relevant prescriptions to the system, and then electronic prescriptions were used by the pharmacy for dispensing medications. Insulin was delivered to care recipients through primary and secondary hospitals of the Department of Health Services of Central Province with the help of Regional Director of Health Services Kandy. All other medications were seal packed and delivered via the Department of Posts – Sri Lanka. There were several challenges, including staff training, process flow issues, the inadequacy of resources and change management concerns regarding the procedure. Despite the challenges, 90% of care recipients of Non-Communicable Diseases clinics were registered to the system, electronic prescriptions were issued, and medications were delivered to them through the government postal service. This demonstrated that during COVID-19 pandemic, institutions under three different government sector organisations in the Central Province were able to collaborate and efficiently adapt to the urgent, unexpected situations.

Publisher's version (útgefin grein), Importance: Aortic stenosis (AS) has no approved medical treatment. Identifying etiological pathways for AS could identify pharmacological targets. Objective: To identify novel genetic loci and pathways associated with AS. Design, Setting, and Participants: This genome-wide association study used a case-control design to evaluate 44703 participants (3469 cases of AS) of self-reported European ancestry from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort (from January 1, 1996, to December 31, 2015). Replication was performed in 7 other cohorts totaling 256926 participants (5926 cases of AS), with additional analyses performed in 6942 participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Follow-up biomarker analyses with aortic valve calcium (AVC) were also performed. Data were analyzed from May 1, 2017, to December 5, 2019. Exposures: Genetic variants (615643 variants) and polyunsaturated fatty acids (ω-6 and ω-3) measured in blood samples. Main Outcomes and Measures: Aortic stenosis and aortic valve replacement defined by electronic health records, surgical records, or echocardiography and the presence of AVC measured by computed tomography. Results: The mean (SD) age of the 44703 GERA participants was 69.7 (8.4) years, and 22019 (49.3%) were men. The rs174547 variant at the FADS1/2 locus was associated with AS (odds ratio [OR] per C allele, 0.88; 95% CI, 0.83-0.93; P = 3.0 × 10-6), with genome-wide significance after meta-analysis with 7 replication cohorts totaling 312118 individuals (9395 cases of AS) (OR, 0.91; 95% CI, 0.88-0.94; P = 2.5 × 10-8). A consistent association with AVC was also observed (OR, 0.91; 95% CI, 0.83-0.99; P =.03). A higher ratio of arachidonic acid to linoleic acid was associated with AVC (OR per SD of the natural logarithm, 1.19; 95% CI, 1.09-1.30; P = 6.6 × 10-5). In mendelian randomization, increased FADS1 liver expression and arachidonic acid were associated with AS (OR per unit of normalized expression, 1.31 [95% CI, 1.17-1.48; P = 7.4 × 10-6]; OR per 5-percentage point increase in arachidonic acid for AVC, 1.23 [95% CI, 1.01-1.49; P =.04]; OR per 5-percentage point increase in arachidonic acid for AS, 1.08 [95% CI, 1.04-1.13; P = 4.1 × 10-4]). Conclusions and Relevance: Variation at the FADS1/2 locus was associated with AS and AVC. Findings from biomarker measurements and mendelian randomization appear to link ω-6 fatty acid biosynthesis to AS, which may represent a therapeutic target., This study was supported by grant R01 HL128550 from the NHLBI of the NIH (Dr Thanassoulis); the Ellison Medical Foundation, Robert Wood Johnson Foundation, Wayne and Gladys Valley Foundation, Kaiser Permanente Northern California, and the Kaiser Permanente National and Regional Community Benefit Programs (The Kaiser Permanente Research Program on Genes, Environment and Health); a grant from the NIH (The Genetic Epidemiology Research on Adult Health and Aging cohort); a strategic partnership between the MRC and the University of Oxford (University of Oxford MRC Population Health Research Unit); application 24281 from the UK Biobank Resource; contracts NO1-HC-25195 and HHSN268201500001I, R01 HL 089590, and the SHARe project from the NHLBI (Framingham Heart Study); the NHLBI in collaboration with Multi-Ethnic Study of Atherosclerosis (MESA) investigators (MESA and the MESA SHARe project); contracts HHSN268201500003I from the NIH, contracts N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, and N01-HC-95169 from the NHLBI, contracts UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, and UL1-TR-001881 from the National Center for Advancing Translational Sciences, and contract DK063491 from the National Institute of Diabetes and Digestive and Kidney Diseases (MESA); contract N02-HL-64278 from the NHLBI (SHARe genotyping); shared instrumentation grant s10rr025141 from the NIH, awards UL1TR002243 and UL1TR000445 from the National Center for Clinical and Translational Science, and award UL1RR024975 from the National Center for Research Resources (Vanderbilt University Medical Center’s Vanderbilt DNA Biobank projects); and investigator-led projects U01HG004798, R01NS032830, RC2GM092618, P50GM115305, U01HG006378, U19HL065962, and R01HD07471 from the NIH (genomic data).

Spinal metastases are the most commonly encountered tumour of the spine, occurring in up to 40% of patients with cancer. Each year, approximately 5% of cancer patients will develop spinal metastases. This number is expected to increase as the life expectancy of cancer patients increases. Patients with spinal metastases experience severe and frequently debilitating pain, which often decreases their remaining quality of life. With a median survival of less than 1 year, the goals of treatment in spinal metastases are reducing pain, improving or maintaining level of function and providing mechanical stability. Currently, conventional treatment strategies involve a combination of analgesics, bisphosphonates, radiotherapy and/or relatively extensive surgery. Despite these measures, pain management in patients with spinal metastases is often suboptimal. In the last two decades, minimally invasive percutaneous interventional radiology techniques such as vertebral augmentation and radiofrequency ablation (RFA) have shown progressive success in reducing pain and improving function in many patients with symptomatic spinal metastases. Both vertebral augmentation and RFA are increasingly being recognised as excellent alternative to medical and surgical management in carefully selected patients with spinal metastases, namely those with severe refractory pain limiting daily activities and stable pathological vertebral compression fractures. In addition, for more complicated lesions such as spinal metastasis with soft tissue extension, combined treatments such as vertebral augmentation in conjunction with RFA may be helpful. While combined RFA and vertebral augmentation have theoretical benefits, comparative trials have not been performed to establish superiority of combined therapy. We believe that a multidisciplinary approach as well as careful pre-procedure evaluation and imaging will be necessary for effective and safe management of spinal metastases. RFA and vertebral augmentation should be considered during early stages of the disease so as to maintain the remaining quality of life in this patient population group.

A genome-wide association study (GWAS) of prostate cancer in Kaiser Permanente health plan members (7,783 cases, 38,595 controls; 80.3% non-Hispanic white, 4.9% African-American, 7.0% East Asian, and 7.8% Latino) revealed a new independent risk indel rs4646284 at the previously identified locus 6q25.3 that replicated in PEGASUS (N = 7,539) and the Multiethnic Cohort (N = 4,679) with an overall P = 1.0 × 10−19 (OR, 1.18). Across the 6q25.3 locus, rs4646284 exhibited the strongest association with expression of SLC22A1 (P = 1.3 × 10−23) and SLC22A3 (P = 3.2 × 10−52). At the known 19q13.33 locus, rs2659124 (P = 1.3 × 10−13; OR, 1.18) nominally replicated in PEGASUS. A risk score of 105 known risk SNPs was strongly associated with prostate cancer (P < 1.0 × 10−8). Comparing the highest to lowest risk score deciles, the OR was 6.22 for non-Hispanic whites, 5.82 for Latinos, 3.77 for African-Americans, and 3.38 for East Asians. In non-Hispanic whites, the 105 risk SNPs explained approximately 7.6% of disease heritability. The entire GWAS array explained approximately 33.4% of heritability, with a 4.3-fold enrichment within DNaseI hypersensitivity sites (P = 0.004). Significance: Taken together, our findings of independent risk variants, ethnic variation in existing SNP replication, and remaining unexplained heritability have important implications for further clarifying the genetic risk of prostate cancer. Our findings also suggest that there may be much promise in evaluating understudied variation, such as indels and ethnically diverse populations. Cancer Discov; 5(8); 878–91. ©2015 AACR. This article is highlighted in the In This Issue feature, p. 783

Noninvasive biomarkers that detect the activity of important oncogenic drivers could significantly improve cancer diagnosis and management of treatment. The goal of this study was to determine whether 68Ga-citrate (which avidly binds to circulating transferrin) can detect MYC-positive prostate cancer tumors, as the transferrin receptor is a direct MYC target gene. PET imaging paired with 68Ga-citrate and molecular analysis of preclinical models, human cell-free DNA (cfDNA), and clinical biopsies were conducted to determine whether 68Ga-citrate can detect MYC-positive prostate cancer. Importantly, 68Ga-citrate detected human prostate cancer models in a MYC-dependent fashion. In patients with castration-resistant prostate cancer, analysis of cfDNA revealed that all patients with 68Ga-citrate avid tumors had a gain of at least one MYC copy number. Moreover, biopsy of two PET avid metastases showed molecular or histologic features characteristic of MYC hyperactivity. These data demonstrate that 68Ga-citrate targets prostate cancer tumors with MYC hyperactivity. A larger prospective study is ongoing to demonstrate the specificity of 68Ga-citrate for tumors with hyperactive MYC. Implications: Noninvasive measurement of MYC activity with quantitative imaging modalities could substantially increase our understanding of the role of MYC signaling in clinical settings for which invasive techniques are challenging to implement or do not characterize the biology of all tumors in a patient. Moreover, measuring MYC activity noninvasively opens the opportunity to study changes in MYC signaling in patients under targeted therapeutic conditions thought to indirectly inhibit MYC. Mol Cancer Res; 15(9); 1221–9. ©2017 AACR.

Visceral and renal artery aneurysms (VRAAs) are an uncommon clinical entity but carry a risk of rupture with associated morbidity and mortality. The rupture risk is particularly high when the aneurysms are large, of unfavourable morphology or in the setting of pregnancy and perioperative period. Endovascular approaches are now first line in the treatment of VRAA, but conventional techniques may be ineffective in excluding aneurysms with unfavourable anatomy such as those with wide necks or at arterial bifurcation points. The neurovascular Comaneci neck-bridging device is used to temporarily cover the neck of intracranial aneurysms without occluding forward arterial flow during endovascular coiling. We report the novel use of the Comaneci neck-bridging device for the treatment of complex peripheral VRAAs. We describe the treatment of two patients with renal and splenic artery aneurysms demonstrating unfavourable anatomic morphology for conventional endovascular approaches. In the first patient, the renal artery aneurysm was situated at the intrarenal bifurcation of the main renal artery in the setting of a solitary kidney. In the second patient, the splenic artery aneurysm was situated close to the splenic hilum at the distal splenic arterial bifurcation. The Comaneci neck-bridging device was successfully used in both cases to assist coil embolisation with visceral preservation. The Comaneci neck-bridging device is potentially safe and effective for the treatment of peripheral VRAA with unfavourable anatomic characteristics that would have been deemed unsuitable for treatment using conventional techniques. Level 4, Technical Report.

Prostate-specific antigen (PSA) levels have been used for detection and surveillance of prostate cancer (PCa). However, factors other than PCa—such as genetics—can impact PSA. Here we present findings from a genome-wide association study (GWAS) of PSA in 28,503 Kaiser Permanente whites and 17,428 men from replication cohorts. We detect 40 genome-wide significant (P−8) single-nucleotide polymorphisms (SNPs): 19 novel, 15 previously identified for PSA (14 of which were also PCa-associated), and 6 previously identified for PCa only. Further analysis incorporating PCa cases suggests that at least half of the 40 SNPs are PSA-associated independent of PCa. The 40 SNPs explain 9.5% of PSA variation in non-Hispanic whites, and the remaining GWAS SNPs explain an additional 31.7%; this percentage is higher in younger men, supporting the genetic basis of PSA levels. These findings provide important information about genetic markers for PSA that may improve PCa screening, thereby reducing over-diagnosis and over-treatment.

Activation of the ER stress response is associated with malignant progression of B cell chronic lymphocytic leukemia (CLL). We developed a murine CLL model that lacks the ER stress-associated transcription factor XBP-1 in B cells and found that XBP-1 deficiency decelerates malignant progression of CLL-associated disease. XBP-1 deficiency resulted in acquisition of phenotypes that are disadvantageous for leukemic cell survival, including compromised BCR signaling capability and increased surface expression of sphingosine-1-phosphate receptor 1 (S1P1). Because XBP-1 expression requires the RNase activity of the ER transmembrane receptor IRE-1, we developed a potent IRE-1 RNase inhibitor through chemical synthesis and modified the structure to facilitate entry into cells to target the IRE-1/XBP-1 pathway. Treatment of CLL cells with this inhibitor (B-I09) mimicked XBP-1 deficiency, including upregulation of IRE-1 expression and compromised BCR signaling. Moreover, B-I09 treatment did not affect the transport of secretory and integral membrane-bound proteins. Administration of B-I09 to CLL tumor-bearing mice suppressed leukemic progression by inducing apoptosis and did not cause systemic toxicity. Additionally, B-I09 and ibrutinib, an FDA-approved BTK inhibitor, synergized to induce apoptosis in B cell leukemia, lymphoma, and multiple myeloma. These data indicate that targeting XBP-1 has potential as a treatment strategy, not only for multiple myeloma, but also for mature B cell leukemia and lymphoma.

To describe the natural history of liver adenomatosis (LA), including complications and changes in lesion size over time. Eighteen patients with clinical diagnosis of LA were included. Clinical and biochemical information were collected. The initial and follow-up MR studies were reviewed retrospectively to determine change in lesion size and imaging features. Seventeen patients were women (94.4%). The mean age of the initial MR study was 37.0 years (18–52 years). The median size of the largest lesion was 6.7 cm (range 3.0–13.5 cm). Intratumoral bleeding was detected on MRI in 9 lesions, in 7 patients (38.8%). The median size for hemorrhagic lesions was 7.6 cm (range 4.1–13.5 cm). During the mean follow-up period of 29.4 (range 4–98) months, 10 patients had stable disease (55.6%), and 8 patients had tumor regression (44.4%). Of 8 patients who were followed without intervention, 3 patients (37.5%) had spontaneous regression. No malignant transformation or lesion progression was occurred. During an over 2-year follow-up period, the majority of lesions of LA appeared to remain stable or showed tumor regression. Spontaneous tumor regression can be observed in approximately 37% of individuals in the age range of 28–53 years.

We examined whether cross-bridge cycle models with one or two tension-generating steps can account for the force-velocity relation of and tension response to length steps of frog skeletal muscle. Transition-state theory defined the strain dependence of the rate constants. The filament stiffness was non-Hookean. Models were refined against experimental data by simulated annealing and downhill simplex runs. Models with one tension-generating step were rejected, as they had a low efficiency and fitted the experimental data relatively poorly. The best model with two tension-generating steps (stroke distances 5.6 and 4.6 nm) and a cross-bridge stiffness of 1.7 pN/nm gave a good account of the experimental data. The two tensing steps allow an efficiency of up to 38% during shortening. In an isometric contraction, 54.7% of the attached heads were in a pre-tension-generating state, 44.5% of the attached heads had undergone the first tension-generating step, and only 0.8% had undergone both tension-generating steps; they bore 34%, 64%, and 2%, respectively, of the isometric tension. During slow shortening, the second tensing step made a greater contribution. During lengthening, up to 93% of the attached heads were in a pre-tension-generating state yet bore elevated tension by being dragged to high strains before detaching.

OBJECTIVE The aim of this study was to evaluate image quality and accuracy of 64+ detector multidetector computed tomography angiography (MDCTA) for hemodynamically significant (≥50%) stenosis in patients with symptomatic peripheral arterial disease (PAD) using digital subtraction angiography as the reference standard. METHODS This is a retrospective study of 29 patients with PAD (19 men, 10 women) who underwent lower limb MDCTA (64- or 80-detector) and digital subtraction angiography. Image quality and accuracy of MDCTA for hemodynamically significant stenosis were assessed in the infrarenal aorta and 15 lower extremity segments. RESULTS Four hundred fifty-three segments were adequately visualized at both modalities. Multidetector CTA had 84.8% sensitivity, 87.7% specificity, and 86.3% accuracy for significant stenosis. Accuracy was decreased in the calf when compromising arterial wall calcifications were present versus absent (55.9% vs 82.4%, P < 0.0001). CONCLUSIONS 64+ MDCTA is accurate in patients with symptomatic PAD. However, diagnostic accuracy in below-knee vessels remains relatively poorer. Alternative imaging modalities should be considered where below-knee disease is suspected.

RESULTS: We collected data for 131 patients who had varicocele embolization treatment. Of these, we were able to gather complete follow up data for 83 patients. We found an abandonment rate of 4.8%, and a complication rate of 6.1% although all of these complications were minor and did not result in abandonment. In terms of follow up data, we found recurrences in five patients (6.0%). These results were comparable to similar studies published in the literature, although we demonstrated a smaller recurrence rate, possibly due to the lack of a learning curve with our interventional radiology unit. A summary of our patient demographics is presented in the table attached. CONCLUSIONS: Our study demonstrates that radiological embolization is an effective modality for the treatment of varicoceles. We were able to demonstrate comparable results in terms of completion rate, complication rate and recurrence rate versus surgical treatment options. Furthermore, the fact that embolization is a day procedure that can be completed under local anaesthesia make it an effective option comparable to surgery for the treatment of varicoceles.

Venous thromboembolism (VTE) encompasses a range of clinical presentations, with pulmonary embolism (PE) being the most significant due to its potential to cause fatal cardiopulmonary compromise. An estimated 25,000 to 200,000 fatalities per year are attributable to PE with rates of nonfatal PE thought to reach 630,000 cases per year. 1 , 2 , 3 Although systemic anticoagulation remains the gold-standard therapy for all forms of VTE, inferior vena cava (IVC) interruption with an implantable filter is advocated in a small subgroup of patients in whom anticoagulation is contraindicated or ineffective. This chapter provides an overview on the use of IVC filters in select patient groups (including those utilized in trauma patients), highlighting different filter types, indications, techniques, and potential associated complications.

IL-10 is an immunoregulatory cytokine expressed by numerous cell types. Studies in mice confirm that different IL-10–expressing cell subsets contribute differentially to disease phenotypes. However, little is known about the relationship between cell- or tissue-specific IL-10 expression and disease susceptibility in humans. In this study, we used the previously described human (h)IL10BAC transgenic model to examine the role of hIL-10 in maintaining intestinal homeostasis. Genomically controlled hIL-10 expression rescued Il10−/− mice from Helicobacter-induced colitis and was associated with control of proinflammatory cytokine expression and Th17 cell accumulation in gut tissues. Resistance to colitis was associated with an accumulation of hIL-10–expressing CD4+Foxp3+ regulatory T cells specifically within the lamina propria but not other secondary lymphoid tissues. Cotransfer of CD4+CD45RBlo cells from Il10−/−/hIL10BAC mice rescued Rag1−/− mice from colitis, further suggesting that CD4+ T cells represent a protective source of hIL-10 in the colon. In concordance with an enhanced capacity to express IL-10, CD4+CD44+ T cells isolated from the lamina propria exhibited lower levels of the repressive histone mark H3K27Me3 and higher levels of the permissive histone mark acetylated histone H3 in both the human and mouse IL10 locus compared with the spleen. These results provide experimental evidence verifying the importance of T cell-derived hIL-10 expression in controlling inflammation within the colonic mucosa. We also provide molecular evidence suggesting the tissue microenvironment influences IL-10 expression patterns and chromatin structure in the human (and mouse) IL10 locus.

Sri Lanka has an exemplary record in maternal and child health care. Provision of free education for over 60 years has helped to empower women. Medical care is accessible and provided free of charge. The maternal mortality ratio and the other indices of maternal and neonatal health have shown uninterrupted improvement since 1930. Midwives and the policy to increase their presence has been the key to success. Public health midwives provide care at the doorstep. Institutional midwives carry out the vast majority of deliveries, of which 99% occur in hospitals. Although on target with the Millennium Development Goals, some challenges that still remain are maternal death from postpartum haemorrhage and unsafe abortion, and perinatal deaths due to congenital abnormalities and prematurity.

Background: Matrix metalloproteinase-9 (MMP-9) shows significant involvement with cancer invasion and therefore has prognostic significance. Tumor tissues from nasopharyngeal carcinoma (NPC) patients are not easy to access, and peripheral blood mononuclear cells (PBMC) are a valuable alternative. This study compared the expression levels of MMP-9 in PBMCs from NPC patients and healthy controls and evaluated the potential as a prognostic biomarker for NPC patients. Methods: MMP-9 mRNA concentrations in PBMCs from 146 NPC patients and 110 healthy controls were measured using quantitative real-time PCR. Differences in MMP-9 expression between NPC patients and controls were evaluated using non-parametric tests, and the effects of different clinical characteristics on MMP-9 expression were also analyzed. The Kaplan-Meier test and Cox regression model were used to explore the association between MMP-9 expression and overall survival of NPC patients. Results: MMP-9 mRNA levels in PBMCs were significantly higher in NPC patients than in healthy controls (pMMP-9 expression was associated with the following clinical characteristics: advanced clinical stage (p Conclusions: MMP-9 mRNA expression in PBMCs from NPC patients is increased and associated with the clinical characteristics and overall survival. It supports the belief that MMP-9 may contribute to the progression of NPC.