Abstract
Background
Sarcopenia is associated with increased morbidity and mortality in oncologic and transplant surgery. It has a high incidence in chronic inflammatory states including inflammatory ...bowel disease (IBD). The validity of existing data in IBD and of sarcopenia's correlation with surgical outcomes is limited.
Methods
We performed a systematic review to assess the correlation of sarcopenia with the requirement for surgery and surgical outcomes in patients with IBD. Observational studies of patients with IBD in whom an assessment of sarcopenic status/skeletal muscle index was undertaken, a proportion of whom proceeded to surgical management, were selected.
Results
A total of 5 studies with a combined 658 IBD patients met the inclusion criteria. The majority (70%) had a diagnosis of Crohn's disease. Median (range) body mass index and skeletal muscle index were reported in 4 studies and were 16.58 (13.66-22.50) kg/m2 and 44.52 (42.90-50.64) cm2/m2, respectively. Forty-two percent of IBD patients had sarcopenia. Notably, none of the studies assessed both the anatomical and functional component required for a correct assessment of sarcopenia. Three studies noted that sarcopenic IBD patients had a higher probability of requiring surgery. The rate of major complications (Clavien-Dindo grade ≥IIIa) was significantly higher in patients with sarcopenia. Improved perioperative nutrition management may mitigate the risk of complications.
Conclusion
Many IBD patients are young, may be malnourished, and commonly require emergent surgery. There is considerable heterogeneity in the assessment of sarcopenia. Sarcopenia is common in the IBD population and can predict the need for surgical intervention. Sarcopenia correlates with an increased rate of major postoperative complications. Improved perioperative intervention may diminish this risk. A formal assessment, screening by a dedicated IBD dietician, and preoperative physical therapy may facilitate early intervention.
In response to environmental and human-imposed selective pressures, agroecosystem pests frequently undergo rapid evolution, with some species having a remarkable capacity to rapidly develop pesticide ...resistance. Temporal sampling of genomic data can comprehensively capture such adaptive changes over time, for example, by elucidating allele frequency shifts in pesticide resistance loci in response to different pesticides. Here, we leveraged museum specimens spanning over a century of collections to generate temporal contrasts between pre- and post-insecticide populations of an agricultural pest moth, Helicoverpa armigera. We used targeted exon sequencing of 254 samples collected across Australia from the pre-1950s (prior to insecticide introduction) to the 1990s, encompassing decades of changing insecticide use. Our sequencing approach focused on genes that are known to be involved in insecticide resistance, environmental sensation, and stress tolerance. We found an overall lack of spatial and temporal population structure change across Australia. In some decades (e.g., 1960s and 1970s), we found a moderate reduction of genetic diversity, implying stochasticity in evolutionary trajectories due to genetic drift. Temporal genome scans showed extensive evidence of selection following insecticide use, although the majority of selected variants were low impact, and alternating trajectories of allele frequency change were suggestive of potential antagonistic pleiotropy. Our results provide new insights into recent evolutionary responses in an agricultural pest and show how temporal contrasts using museum specimens can improve mechanistic understanding of rapid evolution.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Obesity and musculoskeletal pain are strongly related, but there is emerging evidence that body fat, not body weight, may be a better indicator of risk. There is, therefore, a need to determine if ...body fat is associated with musculoskeletal pain as it may improve management strategies. The aim of this systematic review was to investigate the association between body fat and musculoskeletal pain.
Seven electronic databases were searched from inception to 8th January 2018. Cross-sectional and longitudinal studies investigating the association between measures of body fat and musculoskeletal pain were included. All included articles were assessed for methodological rigour using the Epidemiology Appraisal Instrument. Standardised mean differences (SMDs) and effect estimates were pooled for meta-analysis.
A total of 10,221 citations were identified through the database searching, which after abstract and full-text review, yielded 28 unique articles. Fourteen studies were included in the meta-analyses, which found significant cross-sectional associations between total body fat mass and widespread pain (SMD 0.49, 95% CI 0.37-0.61, p < 0.001). Individuals with low-back pain and knee pain had a higher body fat percentage than asymptomatic controls (SMD 0.34, 95% CI 0.17-0.52, p < 0.001 and SMD 0.18, 95% CI 0.05-0.32, p = 0.009, respectively). Fat mass index was significantly, albeit weakly, associated with foot pain (SMD 0.05, 95% CI 0.03-0.06, p < 0.001). Longitudinal studies (n = 8) were unsuitable for meta-analysis, but were largely indicative of elevated body fat increasing the risk of incident and worsening joint pain. There was conflicting evidence for an association between body fat percentage and incident low-back pain (3 studies, follow-up 4-20 years). Increasing knee pain (1 study) and incident foot pain (2 studies) were positively associated with body fat percentage and fat mass index. The percentage of items in the EAI graded as 'yes' for each study ranged from 23 to 85%, indicating variable methodological quality of the included studies.
This systematic review and meta-analysis identified positive cross-sectional associations between increased body fat and widespread and single-site joint pain in the low-back, knee and foot. Longitudinal studies suggest elevated body fat may infer increased risk of incident and worsening joint pain, although further high-quality studies are required.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Massively parallel sequencing of barcoded DNA samples significantly increases screening efficiency for clinically important genes. Short read aligners are well suited to single nucleotide and indel ...detection. However, methods for CNV detection from targeted enrichment are lacking. We present a method combining coverage with map information for the identification of deletions and duplications in targeted sequence data.
Sequencing data is first scanned for gains and losses using a comparison of normalized coverage data between samples. CNV calls are confirmed by testing for a signature of sequences that span the CNV breakpoint. With our method, CNVs can be identified regardless of whether breakpoints are within regions targeted for sequencing. For CNVs where at least one breakpoint is within targeted sequence, exact CNV breakpoints can be identified. In a test data set of 96 subjects sequenced across ~1 Mb genomic sequence using multiplexing technology, our method detected mutations as small as 31 bp, predicted quantitative copy count, and had a low false-positive rate.
Application of this method allows for identification of gains and losses in targeted sequence data, providing comprehensive mutation screening when combined with a short read aligner.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Within the mega-pest lineage of heliothine moths are a number of polyphagous, highly mobile species for which the exchange of adaptive traits through hybridization would affect their properties as ...pests. The recent invasion of South America by one of the most significant agricultural pests, Helicoverpa armigera, raises concerns for the formation of novel combinations of adaptive genes following hybridization with the closely related Helicoverpa zea. To investigate the propensity for hybridization within the genus Helicoverpa, we carried out whole-genome resequencing of samples from six species, focusing in particular upon H. armigera population structure and its relationship with H. zea. We show that both H. armigera subspecies have greater genetic diversity and effective population sizes than do the other species. We find no signals for gene flow among the six species, other than between H. armigera and H. zea, with nine Brazilian individuals proving to be hybrids of those two species. Eight had largely H. armigera genomes with some introgressed DNA from H. zea scattered throughout. The ninth resembled an F1 hybrid but with stretches of homozygosity for each parental species that reflect previous hybridization. Regions homozygous for H. armigera-derived DNA in this individual included one containing a gustatory receptor and esterase genes previously associated with host range, while another encoded a cytochrome P450 that confers insecticide resistance. Our data point toward the emergence of novel hybrid ecotypes and highlight the importance of monitoring H. armigera genotypes as they spread through the Americas.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Hallmarks of germline BRCA1/2-associated ovarian carcinomas include chemosensitivity and improved survival. The therapeutic impact of somatic BRCA1/2 mutations and mutations in other homologous ...recombination DNA repair genes is uncertain.
Using targeted capture and massively parallel genomic sequencing, we assessed 390 ovarian carcinomas for germline and somatic loss-of-function mutations in 30 genes, including BRCA1, BRCA2, and 11 other genes in the homologous recombination pathway.
Thirty-one percent of ovarian carcinomas had a deleterious germline (24%) and/or somatic (9%) mutation in one or more of the 13 homologous recombination genes: BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK1, CHEK2, FAM175A, MRE11A, NBN, PALB2, RAD51C, and RAD51D. Nonserous ovarian carcinomas had similar rates of homologous recombination mutations to serous carcinomas (28% vs. 31%, P = 0.6), including clear cell, endometrioid, and carcinosarcoma. The presence of germline and somatic homologous recombination mutations was highly predictive of primary platinum sensitivity (P = 0.0002) and improved overall survival (P = 0.0006), with a median overall survival of 66 months in germline homologous recombination mutation carriers, 59 months in cases with a somatic homologous recombination mutation, and 41 months for cases without a homologous recombination mutation.
Germline or somatic mutations in homologous recombination genes are present in almost one third of ovarian carcinomas, including both serous and nonserous histologies. Somatic BRCA1/2 mutations and mutations in other homologous recombination genes have a similar positive impact on overall survival and platinum responsiveness as germline BRCA1/2 mutations. The similar rate of homologous recombination mutations in nonserous carcinomas supports their inclusion in PARP inhibitor clinical trials.
Inherited loss-of-function mutations in BRCA1 and BRCA2 and other tumor suppressor genes predispose to ovarian carcinomas, but the overall burden of disease due to inherited mutations is not known. ...Using targeted capture and massively parallel genomic sequencing, we screened for germ-line mutations in 21 tumor suppressor genes in genomic DNA from women with primary ovarian, peritoneal, or fallopian tube carcinoma. Subjects were consecutively enrolled at diagnosis and not selected for age or family history. All classes of mutations, including point mutations and large genomic deletions and insertions, were detected. Of 360 subjects, 24% carried germ-line loss-of-function mutations: 18% in BRCA1 or BRCA2 and 6% in BARD1, BRIP1, CHEK2, MRE11A, MSH6, NBN, PALB2, RAD50, RAD51C, or TP53. Six of these genes were not previously implicated in inherited ovarian carcinoma. Primary carcinomas were generally characterized by genomic loss of normal alleles of the mutant genes. Of women with inherited mutations, >30% had no family history of breast or ovarian carcinoma, and >35% were 60 y or older at diagnosis. More patients with ovarian carcinoma carry cancer-predisposing mutations and in more genes than previously appreciated. Comprehensive genetic testing for inherited carcinoma is warranted for all women with ovarian, peritoneal, or fallopian tube carcinoma, regardless of age or family history. Clinical genetic testing is currently done gene by gene, with each test costing thousands of dollars. In contrast, massively parallel sequencing allows such testing for many genes simultaneously at low cost.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
•Psychopathology is significantly more prevalent in people sustaining a calcaneal fracture compared to an ankle fracture.•Suicidal ideation was the only specific condition significantly more common ...in the calcaneal fracture group.•The mechanism linking psychopathology to calcaneal fractures is unknown, but could be related to either conditions or medications (or both).
The calcaneus is the most commonly fractured hindfoot bone, accounting for over 60% of all tarsal fractures. The aim of this study was to compare the mechanism of injury and psychological health status in patients presenting with calcaneal fractures to an age- and sex-matched control group with ankle fractures.
This retrospective study was undertaken within an orthopaedic unit at a tertiary hospital. An electronic medical record chart review was performed to identify eligible patients. Descriptive statistics were used to summarise the demographic and clinical characteristics of the patients. Between-group differences were analysed with the Mann-Whitney U test and Fisher's exact test for continuous and categorical variables, respectively. Multivariable binary logistic regression was used to determine the relationship between fracture type and underlying psychopathology, adjusting for mechanism of injury.
Two-hundred and fifteen patients met the eligibility criteria for calcaneal fractures and these patients were subsequently matched to 215 ankle fracture patients. Men accounted for 154 (71.6%) of the patients in each group. Over half (51.2%) of all calcaneal fractures were due to an uncontrolled fall above one-metre, as opposed to 26.0% of ankle fractures, p < 0.001. Falling from a standing height was more common in the ankle fracture group, 37 (17.2%) versus 10 (4.7%), p < 0.001. Patients with calcaneal fractures were more likely to have a diagnosed psychological health complaint, 63 (29.3%) versus 32 (14.9%), p < 0.001. Suicidal ideation was significantly more common in the calcaneal fracture group 14 (6.5%) versus 3 (1.4%), p = 0.011. The presence of premorbid psychopathology was associated with calcaneal fracture, after adjusting for mechanism of injury (odds ratio 2.20, 95% confidence interval 1.32 to 3.65, p = 0.003).
Calcaneal and ankle fractures display differences in both the mechanism of injury and the history of psychological health conditions. However, after adjusting for the mechanism of injury, diagnosed premorbid psychopathology remains twice as likely in someone with a calcaneal fracture as opposed to an ankle fracture. It may be prudent for orthopaedic surgeons to consider further investigations of psychological health when managing patients with a calcaneal fracture.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
We hypothesized that mutations in homologous recombination repair (HRR) genes beyond
and
improve outcomes for ovarian carcinoma patients treated with platinum therapy and would impact the relative ...benefit of adding prolonged bevacizumab.
We sequenced DNA from blood and/or neoplasm from 1,195 women enrolled in GOG-0218, a randomized phase III trial in advanced ovarian carcinoma of bevacizumab added to carboplatin and paclitaxel. Defects in HRR were defined as damaging mutations in 16 genes. Proportional hazards models were used to estimate relative hazards for progression-free survival (PFS) and overall survival (OS).
Of 1,195 women with ovarian carcinoma, HRR mutations were identified in 307 (25.7%). Adjusted hazards for progression and death compared with those without mutations were lower for women with non-
HRR mutations HR = 0.73; 95% confidence interval (CI), 0.57-0.94;
= 0.01 for PFS; HR = 0.67; 95% CI, 0.50-0.90;
= 0.007 for OS and
mutations (HR = 0.80; 95% CI, 0.66-0.97;
= 0.02 for PFS; HR = 0.74; 95% CI, 0.59-0.94;
= 0.01 for OS) and were lowest for
mutations (HR = 0.52; 95% CI, 0.40-0.67;
< 0.0001 for PFS; HR = 0.36; 95% CI, 0.25-0.53;
< 0.0001 for OS). A test of interaction showed no difference in the effect of bevacizumab on PFS between cases with and without mutations.
HRR mutations, including non-
genes, significantly prolong PFS and OS in ovarian carcinoma and should be stratified for in clinical trials. The benefit of adding bevacizumab was not significantly modified by mutation status.
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We report germline missense mutations in ETV6 segregating with the dominant transmission of thrombocytopenia and hematologic malignancy in three unrelated kindreds, defining a new hereditary syndrome ...featuring thrombocytopenia with susceptibility to diverse hematologic neoplasms. Two variants, p.Arg369Gln and p.Arg399Cys, reside in the highly conserved ETS DNA-binding domain. The third variant, p.Pro214Leu, lies within the internal linker domain, which regulates DNA binding. These three amino acid sites correspond to hotspots for recurrent somatic mutation in malignancies. Functional studies show that the mutations abrogate DNA binding, alter subcellular localization, decrease transcriptional repression in a dominant-negative fashion and impair hematopoiesis. These familial genetic studies identify a central role for ETV6 in hematopoiesis and malignant transformation. The identification of germline predisposition to cytopenias and cancer informs the diagnosis and medical management of at-risk individuals.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
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