Novel associations between blood DNA methylation and body mass index in middle-aged and older adults.

BACKGROUND/OBJECTIVES: There is increasing evidence of a relationship between blood DNA methylation and body mass index (BMI). We aimed to assess associations of BMI with individual methylation measures (CpGs) through a cross-sectional genome-wide DNA methylation association study and a longitudinal analysis of repeated measurements over time. SUBJECTS/METHODS: Using the Illumina Infinium HumanMethylation450 BeadChip, DNA methylation measures were determined in baseline peripheral blood samples from 5361 adults recruited to the Melbourne Collaborative Cohort Study (MCCS) and selected for nested case-control studies, 2586 because they were subsequently diagnosed with cancer (cases) and 2775 as controls. For a subset of 1088 controls, these measures were repeated using blood samples collected at wave 2 follow-up, a median of 11 years later; weight was measured at both time points. Associations between BMI and blood DNA methylation were assessed using linear mixed-effects regression models adjusted for batch effects and potential confounders. These were applied to cases and controls separately, with results combined through fixed-effects meta-analysis. RESULTS: Cross-sectional analysis identified 310 CpGs associated with BMI with P<1.0 × 10-7, 225 of which had not been reported previously. Of these 225 novel associations, 172 were replicated (P<0.05) using the Atherosclerosis Risk in Communities (ARIC) study. We also replicated using MCCS data (P<0.05) 335 of 392 associations previously reported with P<1.0 × 10-7, including 60 that had not been replicated before. Associations between change in BMI and change in methylation were observed for 34 of the 310 strongest signals in our cross-sectional analysis, including 7 that had not been replicated using the ARIC study. CONCLUSIONS: Together, these findings suggest that BMI is associated with blood DNA methylation at a large number of CpGs across the genome, several of which are located in or near genes involved in ATP-binding cassette transportation, tumour necrosis factor signalling, insulin resistance and lipid metabolism.

The perceptions of obese school children in Hong Kong toward their weight-loss experience.

Most studies related to addressing weight management of obese children have focused on understanding the perceptions of parents and health professionals. This study identifies the factors that obese children who have tried to lose weight perceive as affecting their efforts. This descriptive qualitative study has sought to identify factors affecting obese children's weight-loss decision making and process and to explore the development of an effective weight-loss program. This study screened 603 primary school children equivalent to U.S. Grades 5 and 6 of age 10-12. Seventy-nine out of 93 obese children who had been trying on their own to lose weight for at least 1 month formed 6 focus groups. Four themes were identified: Making the decision, self-efficacy, social influences, and environmental constraints. The results suggest that the design of a weight-loss program for obese children should include the contribution of family members, school, and health professionals.

Translation, cross-cultural adaptation, and psychometric properties of the Hausa version of the Insomnia Severity Index among internally displaced persons in Africa.

BACKGROUND: Although sleep disturbances and insomnia are common among Internally Displaced Persons (IDPs), these disorders remain largely understudied among victims fleeing ethnoreligious genocide. The Insomnia Severity Index (ISI), though a widely used measure of insomnia, has not been translated, cross-culturally adapted, nor validated in common African languages. This paper aimed to translate, adapt and validate the ISI scale into Hausa, the most widely spoken non-Indo-European language in African continent. METHODS: A six-stage validation model was used for the translation and adaptation of the ISI into Hausa [(ISI-Hausa), Item-Content Validity Index (I-CVI)=0.9 to 1.0]. The tool was administered among IDPs residing in Maiduguri, North-Eastern Nigeria, from October to November 2019. A total of 281 participants from six camps were recruited via convenience sampling. The psychometric properties of the scale were assessed using an Exploratory Factor Analysis (EFA), Cronbach's alpha (α) and Intraclass Correlation Coefficients (ICC) for determining factor structure, internal consistency and test-retest reliability, respectively. RESULTS: Exploratory factor reduction resulted in a two-factor solution, with " severity of insomnia " identified as the construct for Factor 1 and " impact of insomnia " as the construct for Factor 2. Factor 1 consisted of four scale items and Factor 2 consisted of three items. Factor loadings for each item ranged from 0.535-0.812. The scale demonstrated acceptable internal consistency (α=0.72) and good test-retest reliability (ICC=0.72) (p<0.001). CONCLUSION: The ISI-Hausa scale is a psychometrically sound and culturally relevant tool for assessing the severity and impact of insomnia among Hausa speaking IDPs in Africa.

Anxiety, depression and stress among internally displaced persons and host community in an armed conflict region: A comparative study.

This study compares the psychological profile of Internally Displaced Persons (IDPs) and individuals living in host communities in the war-affected setting. We conducted a cross-sectional survey from October-November 2019. Subjects were recruited from six IDPs camps and the surrounding host communities within the metropolis of Maiduguri, Nigeria by convenience sampling. Data were collected using the Hausa version of Depression Anxiety Stress Scale-21, and analysed by logistic regression using adjusted odds ratio (AOR) at 95% Confidence Interval (CI). A total of 562 subjects were recruited. Living in IDP camp was the most significantly predictor of depression, anxiety, and stress. The common predictors were living in an IDP camp, and marital status (separated). Aged 18-29years was a protective factor compared to those ≥50years. Living in IDP camps, separated from partners, lack of education and pre-conflict employment were significant predictors of depression, anxiety and stress.

Effect of endorectal coils on staging of rectal cancers by magnetic resonance imaging.

OBJECTIVE: To compare the use of endorectal plus phased-array coils with use of phased-array coil alone with respect to the accuracy of magnetic resonance imaging for detecting mesorectal involvement of rectal cancer. DESIGN: Retrospective study. SETTING: A tertiary referral centre in Hong Kong. PATIENTS: Ethnic Chinese patients with rectal adenocarcinoma who underwent staging magnetic resonance imaging during the years 2003 to 2008 in our centre were selected; those who received preoperative neoadjuvant therapy were excluded. Unless otherwise contra-indicated, endorectal coils have been used since 2006. MAIN OUTCOME MEASURES: Magnetic resonance images were retrieved and reviewed by two radiologists blinded to the pathological results. The radiological findings were then correlated with the pathological reports to determine diagnostic accuracy. RESULTS: A total of 50 patients were studied; 13 of the examinations were in patients having an endorectal coil. The overall accuracy of magnetic resonance imaging in detecting mesorectal tumour involvement was 80%. Subgroup analysis showed higher accuracy in the group with endorectal coils than in those with phased-array coils alone. Over-detection of mesorectal involvement was noted in 12% of the cases, with lower rate being observed in patients with endorectal coils. Underdetection of mesorectal tumour involvement was only noted in the group without endorectal coils. With the use of endorectal coils, the sensitivity reached 100% and the specificity increased to 86%. CONCLUSION: Use of endorectal coil in staging magnetic resonance imaging of the rectum improves diagnostic accuracy. Whenever feasible, endorectal coil use is therefore recommendable to enhance diagnostic accuracy. The study results substantiate the understanding of staging by magnetic resonance imaging of rectal cancer in the local Chinese population.

Cost-consequence analysis comparing 2-octyl cyanoacrylate tissue adhesive and suture for closure of simple lacerations: a randomized controlled trial.

STUDY OBJECTIVE: We investigate the cost difference between conventional suture and tissue adhesive methods in simple wound closure. METHODS: A cost-consequence analysis was conducted alongside a nonblinded randomized controlled trial comparing 2-octyl cyanoacrylate tissue adhesive with conventional suture in simple lacerations closure in emergency departments (EDs) of a university teaching hospital and a major regional hospital in Hong Kong. One hundred eighty-six adult patients with simple lacerations of length within 8 cm were randomized to receive tissue adhesive (93 patients) or conventional suture (93 patients) for wound closure. The primary outcome measures were the costs to the Hospital Authority and the charges on participants incurred in each treatment method. The secondary outcome measures included the cosmetic visual analog scale, visual analog scale, Wound Evaluation Score, total time spent in each closure method, and the overall patients' satisfaction on the whole process of wound management. RESULTS: The 2 groups had similar baseline characteristics. The tissue adhesive method incurred a higher cost to the Hospital Authority (216.12 [US $27.70] versus 171.33 [US $21.96]; absolute difference 44.79 [US $5.74] [95% confidence interval (CI) 32.76 to 55.95 [US $4.20 to 7.14]]) but a lower charge to patients (109.68 [US $14.06] versus 156.96 [US $20.12]; absolute difference 47.28 [US $6.06] [95% CI, 35.58 to 58.98 [US $4.56 to 7.56]) than the conventional suture method. The mean cosmetic visual analog scale score, visual analog scale score, and Wound Evaluation Score of the 2 groups were similar at various intervals within 3 months after wound closure. Compared with the suture group, the tissue adhesive group had a shorter median procedure time, fewer patients had wound erythema or swelling after wound closure, fewer patients required analgesics on discharge at ED, and there was a higher overall patient satisfaction score. CONCLUSION: Simple wounds closed by tissue adhesives incur a higher cost to the Hospital Authority than the conventional suture but may be favored by patients because of lower personal charge.

Genetic, functional, and histopathological evaluation of two C-terminal BRCA1 missense variants.

BACKGROUND: The vast majority of BRCA1 missense sequence variants remain uncharacterized for their possible effect on protein expression and function, and therefore are unclassified in terms of their pathogenicity. BRCA1 plays diverse cellular roles and it is unlikely that any single functional assay will accurately reflect the total cellular implications of missense mutations in this gene. OBJECTIVE: To elucidate the effect of two BRCA1 variants, 5236G>C (G1706A) and 5242C>A (A1708E) on BRCA1 function, and to survey the relative usefulness of several assays to direct the characterisation of other unclassified variants in BRCA genes. METHODS AND RESULTS: Data from a range of bioinformatic, genetic, and histopathological analyses, and in vitro functional assays indicated that the 1708E variant was associated with the disruption of different cellular functions of BRCA1. In transient transfection experiments in T47D and 293T cells, the 1708E product was mislocalised to the cytoplasm and induced centrosome amplification in 293T cells. The 1708E variant also failed to transactivate transcription of reporter constructs in mammalian transcriptional transactivation assays. In contrast, the 1706A variant displayed a phenotype comparable to wildtype BRCA1 in these assays. Consistent with functional data, tumours from 1708E carriers showed typical BRCA1 pathology, while tumour material from 1706A carriers displayed few histopathological features associated with BRCA1 related tumours. CONCLUSIONS: A comprehensive range of genetic, bioinformatic, and functional analyses have been combined for the characterisation of BRCA1 unclassified sequence variants. Consistent with the functional analyses, the combined odds of causality calculated for the 1706A variant after multifactorial likelihood analysis (1:142) indicates a definitive classification of this variant as "benign". In contrast, functional assays of the 1708E variant indicate that it is pathogenic, possibly through subcellular mislocalisation. However, the combined odds of 262:1 in favour of causality of this variant does not meet the minimal ratio of 1000:1 for classification as pathogenic, and A1708E remains formally designated as unclassified. Our findings highlight the importance of comprehensive genetic information, together with detailed functional analysis for the definitive categorisation of unclassified sequence variants. This combination of analyses may have direct application to the characterisation of other unclassified variants in BRCA1 and BRCA2.

Molecular characterization and cancer risk associated with BRCA1 and BRCA2 splice site variants identified in multiple-case breast cancer families.

Genetic screening of women from multiple-case breast cancer families and other research-based endeavors have identified an extensive collection of germline variations of BRCA1 and BRCA2 that can be classified as deleterious and have clinical relevance. For some variants, such as those in the conserved intronic splice site regions which are highly likely to alter splicing, it is not possible to classify them based on the identified DNA sequence variation alone. We studied 11 multiple-case breast cancer families carrying seven distinct splice site region genetic alterations in BRCA1 or BRCA2 (BRCA1, c.IVS6-2delA, c.IVS9-2A>C, c.IVS4-1G>T, c.IVS20+1G>A and BRCA2, c.IVS17-1G>C, c.IVS20+1G>A, c.IVS7-1G>A) and applied SpliceSiteFinder to predict possible changes in efficiency of splice donor and acceptor sites, characterized the transcripts, and estimated the average age-specific cumulative risk (penetrance) using a modified segregation analysis. SpliceSiteFinder predicted and we identified transcipts that illustrated that all variants caused exon skipping, and all but two led to frameshifts. The risks of breast cancer to age 70 yrs, averaged over all variants, over BRCA1 variants alone, and over BRCA2 variants alone, were 73% (95% confidence interval 47-93), 64% (95%CI 28-96) and 79% (95%CI 48-98) respectively (all P<0.0001). Therefore five of these seven consensus splice site variants of BRCA1 and BRCA2 produce a transcript similar to that of other previously described deleterious exonic variants and are associated with similar high lifetime risks.

Antihypertensive pyrrolo[1,2-c]quinazolines and pyrrolo[1,2-c]quinazolinones.

The synthesis of a variety of pyrrolo[1,2-c]quinazolines and pyrrolo[1,2-c]quinazolinones is described. Several of these compounds have exhibited antihypertensive properties in the spontaneously hypertensive rat (SHR). Structure-activity comparisons have indicated that optimal activity is obtained in both the 2-carbethoxydihydroquinazoline series (C) and 2-carbethoxyquinazolinone series (D) when there is either a carbethoxy or cyanoethyl group at position 6 and no substitution in the benzene ring, while optimal activity is obtained in the 2-methyl-quinazolinone series (D) when both position 6 and the benzene ring are unsubstituted.

Derivation of a prediction rule for post-traumatic acute lung injury.

The purpose of this study was to derive an early, highly sensitive and specific prediction rule for the development of post-traumatic acute lung injury (ALI). In a prospective, non-interventional study a convenience sample of 92 adults admitted to the resuscitation room following blunt trauma was studied in order to derive this prediction rule. The study was conducted in the emergency department of a university hospital in the New Territories of Hong Kong. One emergency physician assessed each patient for 25 variables, which might predict post-traumatic ALI, and the primary outcome measure was the presence or absence of ALI 48 h post-injury. Eleven variables associated with ALI were entered into a classification and regression tree (CART) in order to derive models predictive of ALI. Two models were developed and used to derive the decision rule. Acute lung injury was likely if either: (1) the patient had an ISS > 27 and a haematocrit < 0.37, or (2) the patient had a haematocrit < 0.36 and a total leucocyte count > 15. The first guideline had a classification rate of 96.7% (95% confidence interval (CI), 90.8-99.3%), a sensitivity of 100% (CI 65.2-100%) and a specificity of 96.5% (CI 90.0-99.3%). The second guideline had a classification rate of 96.7% (CI 90.8-99.3%), a sensitivity of 85.7% (CI 42.1-99.6%) and a specificity of 97.7% (CI 91.8-99.7%). Practical highly sensitive and specific prediction guidelines for post-traumatic acute lung injury have been derived and now require prospective validation.

Clinical determinants of the outcome of manual stretching in the treatment of congenital muscular torticollis in infants. A prospective study of eight hundred and twenty-one cases.

BACKGROUND: The natural history of congenital muscular torticollis and the outcome of different treatment modalities have been poorly investigated, and the results of treatment have varied considerably. METHODS: The main objective of this prospective study was to evaluate the outcomes of 821 consecutive patients with congenital muscular torticollis who were first seen when they were less than one year old, were treated with a standardized program of manual stretching, and were followed for a mean of 4.5 years. Before treatment, the patients were classified into one of three clinical groups: (1) palpable sternomastoid tumor, (2) muscular torticollis (thickening and tightness of the sternocleidomastoid muscle), and (3) postural torticollis (torticollis but no tightness or tumor). RESULTS: Of the 821 patients, 452 (55%) had a sternomastoid tumor; 276 (34%), muscular torticollis; and ninety-three (11%), postural torticollis. Multivariate analysis of the outcomes showed that (1) the duration of treatment was significantly associated with the clinical group (p < 0.0001), a passive rotation deficit of the neck (p < 0.0001), involvement of the right side (p < 0.0001), difficulties with the birth (p < 0.009), and age at presentation (p < 0.0001); (2) the overall final assessment score was associated with the rotation deficit (p = 0.02), age at presentation (p = 0.014), and duration of treatment (p < 0.0001); and (3) subsequent surgical treatment was required by 8% (thirty-four) of the 452 patients in the sternomastoid tumor group compared with 3% (eight) of the 276 patients in the muscular torticollis group and 0% (none) of the ninety-three patients in the postural torticollis group. CONCLUSIONS: This large prospective study demonstrated that controlled manual stretching is safe and effective in the treatment of congenital muscular torticollis when a patient is seen before the age of one year. The most important factors that predict the outcome of manual stretching are the clinical group, the initial deficit in rotation of the neck, and the age of the patient at presentation. Surgical treatment is indicated when a patient has undergone at least six months of controlled manual stretching and has residual head tilt, deficits of passive rotation and lateral bending of the neck of >15 degrees, a tight muscular band or tumor, and a poor outcome according to our special assessment chart.

Longitudinal changes in trunkal balance after selective fusion of King II curves in adolescent idiopathic scoliosis.

STUDY DESIGN: A retrospective study was performed on the longitudinal changes of the trunkal balance in King II curves treated with selective posterior fusion of the thoracic curve. OBJECTIVES: To determine the effect of selective fusion on the coronal and sagittal plane balance in King II adolescent idiopathic scoliosis by analyzing the changes in shoulder level, pelvic tilt, trunk shift, centering of fusion mass, changes in the T11-L1 sagittal angle, and behavior of the unfused lumbar curve and its correlation with the end level of fusion. SUMMARY OF BACKGROUND DATA: It has been shown that selective fusion of the thoracic curve in a King II curve is associated with good results and arrest of lumbar curve progression in selected cases. Detailed quantitative analysis of the longitudinal changes and correlation between various clinical and radiologic parameters was not readily available in the literature. METHODS: This study investigated 24 patients with King II adolescent idiopathic scoliosis treated with Harrington rod and segmental spinous processes wiring in a 10-year period with follow-up periods of 3 to 8 years. Clinical and radiologic parameters were analyzed longitudinally during the preoperative and immediate postoperative period, then at 6 months, 1 year, 3 years, and final follow-up assessment. RESULTS: Progressive improvement in the trunk shift to within 2 cm of the center sacral line together with progressive leveling and stabilization of the shoulder and pelvic tilt was noted during the first year after surgery. Gradual movement of the Harrington rod toward the center sacral line assuming a "straight rod sign" with a rod to center line distance of less than 1 cm was found in 90% of the cases. Improvement of the sagittal alignment with no significant residual junctional kyphosis also was found. The unfused lumbar curve improved in both the coronal and sagittal plane and did not show any further progression. Patients whose lower end level of fusion was at T12 had a better percentage of lumbar curve correction than those that ended at L1. CONCLUSIONS: Selective thoracic fusion for King II idiopathic scoliosis curve can achieve acceptable coronal and sagittal plane balance of the spine. The rod to centersacral line distance is a helpful parameter in assessing the results and prognosis of surgically treated patients.

The clinical presentation and outcome of treatment of congenital muscular torticollis in infants--a study of 1,086 cases.

BACKGROUND/PURPOSE: The main objectives of this study were to define the clinical patterns and characteristics of congenital muscular torticollis (CMT) presented in the first year of life and to study the outcome of different treatment methods. METHODS: This is a prospective study of all CMT patients seen in 1 center over a 12-year period with uniform recording system, assessment methods, and treatment protocol. RESULTS: From a total of 1,086 CMT infants, 3 clinical subgroups of sternomastoid tumor (SMT; 42.7%), muscular torticollis (MT; 30.6%), and postural torticollis (POST; 22.1%) were identified. The SMT group was found to present earlier within the first 3 months and was associated with higher incidence of breech presentation (19.5%), difficult labor (56%), and hip dysplasia (6.81%). Severity of limitation of passive neck rotation range (ROTGp) was found to correlate significantly with the presence of SMT, bigger tumor size, hip dysplasia, degree of head tilt, and craniofacial asymmetry. CONCLUSIONS: A total of 24.5% of the patients with initial deficits of passive rotation of less than 10 degrees showed excellent and good outcome with active home positioning and stimulation program. The remaining cases with rotation deficits of over 10 degrees and treated with manual stretching program showed an overall excellent to good results in 91.1% with 5.1% requiring subsequent surgical treatment. The most important prognostic factors for the necessity of surgical treatment were the clinical subgroup, the ROTGp, and the age at presentation (P < .001).

Using tumour pathology to identify people at high genetic risk of breast and colorectal cancers.

Genes have been identified for which germline mutations are associated with high lifetime risks of breast, colorectal and other cancers. Identification of mutation carriers through genetic testing is important as it could help lower cancer incidence and mortality. The translation of genetic information into better health outcomes is expensive because of the costs of genetic counselling as well as laboratory testing. Approaches to triage for mutation screening of known genes which rely on cancer family history are not necessarily sensitive and specific or the most cost-effective. Recent population-based research has shown that the cancers and precancerous lesions arising in mutation carriers have specific molecular and morphological characteristics. People with colorectal cancer, especially those diagnosed at a young age, whose tumours exhibit microsatellite instability and some specific pathology and immunohistochemically-defined features are more likely to carry a germline mutation in one of four mismatch repair genes. Some morphological and immunohistochemically-defined features are associated with breast cancers arising in women who carry BRCA1 or BRCA2 germline mutations, especially if at a young age. Screening paradigms based on molecular and morphological features that predict mutation status, especially if focused on early-onset disease, have the potential to identify mutation carriers with greater sensitivity and specificity, and in a more cost-effective way, than those based on family history alone. Genetic testing results could help inform treatment if those affected are tested soon after diagnosis using pathology-led selection strategies to identify cases most likely to carry germline mutations. We propose how this new approach could be undertaken by having genetic testing and counselling prioritised to those with the greatest probability of carrying a germline mutation in these known cancer predisposition genes.

Development of a validated quality of life tool specific to children with bladder dysfunction.

AIMS: To date there have not been any generic or continence-specific measurement tools that allow clinicians to investigate quality of life in children with bladder dysfunction. The aim of this research was to create a cross-cultural tool to assess and measure the wider psychosocial impact of current and new interventions for bladder dysfunction in children. MATERIALS AND METHODS: The study was conducted in three parts: expert consultation with continence clinicians; design and administration of a child-completed international questionnaire; item analysis, validity and reliability testing, and design of a new tool. RESULTS: The need for a pediatric incontinence QoL measure evaluation was strongly endorsed by clinicians. Data from 156 child-completed questionnaires collected in 10 countries was analyzed for item characteristics and found to be free of item correlation and ceiling and floor effects. Factor analysis revealed 2 factors, which were labeled intrinsic and extrinsic. Rasch analyses showed the internal validity of both subscales was reasonable good. Cronbach's alpha for each factor was 0.91 and 0.72. After analysis, items were selected for the new tool, PinQ, and evaluated for ambiguity, clarity, comprehension level required, choice of words and phrases, and age-appropriate concepts. Twenty-one items were finally selected and randomly positioned within the tool. CONCLUSIONS: A cross-cultural tool that quantifies the holistic effect of bladder dysfunction in children has been designed and tested for validity.