Dual energy X-ray absorptiometry (DXA) is rapidly becoming more accessible and popular as a technique to monitor body composition, especially in athletic populations. Although studies in sedentary ...populations have investigated the validity of DXA assessment of body composition, few studies have examined the issues of reliability in athletic populations and most studies which involve DXA measurements of body composition provide little information on their scanning protocols. This review presents a summary of the sources of error and variability in the measurement of body composition by DXA, and develops a theoretical model of best practice to standardize the conduct and analysis of a DXA scan. Components of this protocol include standardization of subject presentation (subjects rested, overnight-fasted and in minimal clothing) and positioning on the scanning bed (centrally aligned in a standard position using custom-made positioning aids) as well as manipulation of the automatic segmentation of regional areas of the scan results. Body composition assessment implemented with such protocol ensures a high level of precision, while still being practical in an athletic setting. This ensures that any small changes in body composition are confidently detected and correctly interpreted. The reporting requirements for studies involving DXA scans of body composition include details of the DXA machine and software, subject presentation and positioning protocols, and analysis protocols.
Ubiquitination controls the stability of most cellular proteins, and its deregulation contributes to human diseases including cancer. Deubiquitinases remove ubiquitin from proteins, and their ...inhibition can induce the degradation of selected proteins, potentially including otherwise 'undruggable' targets. For example, the inhibition of ubiquitin-specific protease 7 (USP7) results in the degradation of the oncogenic E3 ligase MDM2, and leads to re-activation of the tumour suppressor p53 in various cancers. Here we report that two compounds, FT671 and FT827, inhibit USP7 with high affinity and specificity in vitro and within human cells. Co-crystal structures reveal that both compounds target a dynamic pocket near the catalytic centre of the auto-inhibited apo form of USP7, which differs from other USP deubiquitinases. Consistent with USP7 target engagement in cells, FT671 destabilizes USP7 substrates including MDM2, increases levels of p53, and results in the transcription of p53 target genes, induction of the tumour suppressor p21, and inhibition of tumour growth in mice.
Surgery for epithelial ovarian cancer (EOC) may activate stress-inflammatory responses that stimulate tumor growth and increase metastatic growth. Animal and in vitro studies have shown that ...inhibition of the catecholamine-induced inflammatory response via beta-adrenergic receptor blockade has antitumor potential in EOC. However, observational studies have reported mixed results. We assessed whether beta-blocker (BB) use at the time of primary ovarian cancer surgery was associated with improved survival in a large population-based study.
Using linked administrative data, a population-based cohort of 3,844 Australian women age 50 years or older with a history of cardiovascular conditions who underwent surgery for EOC was followed for survival outcomes. The average treatment effect of selective BB (SBB) and nonselective BB (NSBB) supply at the time of surgery on survival was estimated from a causal inference perspective using covariate-balanced inverse probability of treatment weights with flexible parametric survival models that allowed for time-varying survival effects.
Around the time of surgery, 560 (14.5%) women were supplied a SBB and 67 (1.7%) were supplied a NSBB. At 2 years postsurgery, the survival proportion was 80% (95% CI, 68 to 88) for women dispensed NSBBs at surgery compared with 69% (95% CI, 67 to 70) for women not supplied NSBBs. The survival advantage appeared to extend to at least 8 years postsurgery. No association was observed for women dispensed a SBB around the time of surgery.
Perioperative supply of NSBBs appeared to confer a survival advantage for women age over 50 years with a history of cardiovascular conditions. Long-term clinical trials are required to confirm these findings.
We performed massively parallel sequencing of paired tumor/normal samples from 203 multiple myeloma (MM) patients and identified significantly mutated genes and copy number alterations and discovered ...putative tumor suppressor genes by determining homozygous deletions and loss of heterozygosity. We observed frequent mutations in KRAS (particularly in previously treated patients), NRAS, BRAF, FAM46C, TP53, and DIS3 (particularly in nonhyperdiploid MM). Mutations were often present in subclonal populations, and multiple mutations within the same pathway (e.g., KRAS, NRAS, and BRAF) were observed in the same patient. In vitro modeling predicts only partial treatment efficacy of targeting subclonal mutations, and even growth promotion of nonmutated subclones in some cases. These results emphasize the importance of heterogeneity analysis for treatment decisions.
•Deep sequencing reveals significant genetic events in multiple myeloma•Intratumor genetic heterogeneity is common in multiple myeloma•Recurrent mutations can occur either early or late in the evolution of a tumor•Genetic heterogeneity in cancer may limit effectiveness of targeted therapy
mcr-9.1 is a newly described mobile colistin resistance gene. We have noted its presence in multiple species of carbapenem-resistant Enterobacterales (CRE) from our institution. We aimed to determine ...the clinical features, genomic context and phenotypic impact of mcr-9.1 carriage in a series of patients between 2010 and 2019.
We identified 32 patients with mcr-9.1-carrying CRE isolates (mCRE) and collected demographic, antimicrobial exposure and infection data. Whole-genome sequencing (including short and long reads) was performed on 32 isolates. We assessed sequence similarity of mcr-9.1-harbouring plasmids, then compared our findings with plasmids for which sequence data were publicly available.
There was no colistin exposure in patients prior to isolation of mCRE. mcr-9.1 was identified on IncHI2 plasmids across four different bacterial species and was co-located with blaIMP-4 in 23/30 plasmids studied. mCRE isolates did not demonstrate phenotypic colistin resistance, either at baseline or following sublethal colistin exposure, thus showing that mcr-9.1 alone is not sufficient for resistance. Publicly available sequence data indicated the presence of carbapenemase genes in 236/619 mcr-9.1-carrying genomes (38%). IncHI2 plasmids carrying mcr-9.1 and carbapenemase genes were detected in genomes from North America, Europe, North Africa, Asia and Oceania.
Spread of mcr-9.1 in CRE from our institution was driven by IncHI2 ‘superplasmids’, so termed because of their large size and their prolific carriage of resistance determinants. These were also detected in global CRE genomes. Phenotypic colistin resistance was not detected in our isolates but remains to be determined from global mCRE.
Hysterectomy is one of the most commonly performed gynecologic surgeries, with an estimated 30% of women in Australia undergoing the procedure by age of 70 years. In the United States, about 45% of ...women undergo hysterectomy in their lifetime. Some studies have suggested that this procedure increases the risk of premature mortality. With many women making the decision to undergo hysterectomy for a benign indication each year, additional research is needed to clarify whether there are long-term health consequences of hysterectomy.
This study aimed to examine the association between hysterectomy for benign indications, with or without removal of the ovaries, and cause-specific and all-cause mortality.
Our cohort of 666,588 women comprised the female population of Western Australia with linked hospital and health records from 1970 to 2015. Cox regression models were used to assess the association between hysterectomy and all-cause, cardiovascular disease, cancer, and other mortality by oophorectomy type (categorized as none, unilateral, and bilateral), with no hysterectomy or oophorectomy as the reference group. We repeated these analyses using hysterectomy without oophorectomy as the reference group. We also investigated whether associations varied by age at the time of surgery, although small sample size precluded this analysis in women who underwent hysterectomy with unilateral salpingo-oophorectomy.
In our main analysis, women who underwent hysterectomy or oophorectomy as part of cancer treatment were retained in the analysis and considered unexposed to that surgery. For a sensitivity analysis, we censored procedures performed for cancer.
Compared with no surgery, hysterectomy without oophorectomy before 35 years was associated with an increase in all-cause mortality (hazard ratio, 1.29; 95% confidence interval, 1.19–1.40); for surgery after 35 years of age, there was an inverse association (35–44 years: hazard ratio, 0.93; 95% confidence interval, 0.89–0.97). Similarly, hysterectomy with bilateral salpingo-oophorectomy before 45 years of age was associated with increased all-cause mortality (35–44 years: hazard ratio, 1.15; 95% confidence interval, 1.04–1.27), but decreased mortality rates after 45 years of age. In our sensitivity analysis, censoring gynecologic surgeries for cancer resulted in many cancer-related deaths being excluded for women who did not have surgery for benign indications and thus increased the hazard ratios for the associations between both hysterectomy without oophorectomy and hysterectomy with bilateral salpingo-oophorectomy and risk of all-cause and cancer-specific mortality. The sensitivity analysis therefore potentially biased the results in favor of no surgery.
Among women having surgery for benign indications, hysterectomy without oophorectomy performed before 35 years of age and hysterectomy with bilateral salpingo-oophorectomy performed before 45 years of age were associated with an increase in all-cause mortality. These procedures are not associated with poorer long-term survival when performed at older ages.
Infections caused by Klebsiella oxytoca are the second most common cause of Klebsiella infections in humans. Most studies have focused on K. oxytoca outbreaks and few have examined the broader ...clinical context of K. oxytoca.
Here, we collected all clinical isolates identified as K. oxytoca in a hospital microbiological diagnostic lab across a 15-month period (n = 239). Whole genome sequencing was performed on a subset of 92 isolates (all invasive, third-generation cephalosporin resistant (3GCR) and non-urinary isolates collected > 48 h after admission), including long-read sequencing on a further six isolates with extended-spectrum beta-lactamase or carbapenemase genes.
The majority of isolates were sensitive to antimicrobials, however 22 isolates were 3GCR, of which five were also carbapenem resistant. Genomic analyses showed those identified as K. oxytoca by the clinical laboratory actually encompassed four distinct species (K. oxytoca, Klebsiella michiganensis, Klebsiella grimontii and Klebsiella pasteurii), referred to as the K. oxytoca species complex (KoSC). There was significant diversity within the population, with only 10/67 multi-locus sequence types (STs) represented by more than one isolate. Strain transmission was rare, with only one likely event identified. Six isolates had extended spectrum beta-lactamase (bla
and/or bla
) or carbapenemase (bla
) genes. One pair of K. michiganensis and K. pasteurii genomes carried identical bla
IncL/M plasmids, indicative of plasmid transmission.
Whilst antimicrobial resistance was rare, the resistance plasmids were similar to those found in other Enterobacterales, demonstrating that KoSC has access to the same plasmid reservoir and thus there is potential for multi-drug resistance. Further genomic studies are required to improve our understanding of the KoSC population and facilitate investigation into the attributes of successful nosocomial isolates.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This study aimed to investigate the associations between hysterectomy for benign indications and risk of breast, colorectal, kidney, and thyroid cancer, and to explore whether these associations are ...modified by removal of ovaries at the time of surgery or by age at surgery.
We conducted a retrospective cohort study of the female population of Western Australia (
= 839,332) linking data from electoral, hospital, births, deaths, and cancer records. We used Cox regression to estimate HRs and 95% confidence intervals (CI) for the associations between hysterectomy and diagnosis of breast, colorectal, kidney, and thyroid cancers.
Compared with no surgery, hysterectomy without oophorectomy (hysterectomy) and hysterectomy with bilateral salpingo-oophorectomy (hysterectomy-BSO) were associated with higher risk of kidney cancer (HR, 1.32; 95% CI, 1.11-1.56 and HR, 1.29; 95% CI, 0.96-1.73, respectively). Hysterectomy, but not hysterectomy-BSO, was related to higher risk of thyroid cancer (HR, 1.38; 95% CI, 1.19-1.60). In contrast, hysterectomy (HR, 0.94; 95% CI, 0.90-0.98) and hysterectomy-BSO (HR, 0.92; 95% CI, 0.85-1.00) were associated with lower risk of breast cancer. We found no association between hysterectomy status and colorectal cancer.
The associations between hysterectomy and cancer varied by cancer type with increased risks for thyroid and kidney cancer, decreased risk for breast cancer, and no association for colorectal cancer.
As breast, colorectal, and gynecologic cancers comprise a sizeable proportion of all cancers in women, our results suggest that hysterectomy is unlikely to increase overall cancer risk; however, further research to understand the higher risk of thyroid and kidney cancer is warranted.
Relapse of serious mental illness (psychotic and bipolar disorders; SMI) in the postpartum period is potentially devastating for mother and baby. There is limited evidence on whether medication in ...the perinatal period is protective against postpartum relapse for women with SMI particularly non-affective psychoses. We aimed to investigate risk factors for postpartum relapse, particularly the potential prophylactic effects of medication.
Using an anonymised resource of comprehensive electronic secondary mental health care records linked with maternity data, women with history of SMI who gave birth from 2007 to 2011 were identified.
Relapse was defined as admission to acute care in the first 3 months postpartum. Women who were exposed to regular medication were compared with women who were unexposed. Data were analysed by pregnancy using random effects models to account for repeated measures in women who had more than one pregnancy in the study period.
There were 452 full term pregnancies, of which 128 (28.3%) were associated with relapse in the first 3 months postpartum, with recent relapse an independent predictor (aOR; 95% CI:1.30–2.27). There was no evidence of a prophylactic effect of medication (crude OR = 0.65; 0.34–1.25) (aOR = 0.99; 0.54–1.83), in women with non-affective or affective psychoses (interaction test p = 0.453).
Recent relapse increases the risk of relapse in the postpartum period so women with severe illnesses with a recent history of relapse should be warned pre-conception about the high risk of relapse.
The lack of evidence of a protective impact of medication prophylaxis may reflect confounding by indication.
Multiple myeloma is an incurable malignancy of plasma cells, and its pathogenesis is poorly understood. Here we report the massively parallel sequencing of 38 tumour genomes and their comparison to ...matched normal DNAs. Several new and unexpected oncogenic mechanisms were suggested by the pattern of somatic mutation across the data set. These include the mutation of genes involved in protein translation (seen in nearly half of the patients), genes involved in histone methylation, and genes involved in blood coagulation. In addition, a broader than anticipated role of NF-κB signalling was indicated by mutations in 11 members of the NF-κB pathway. Of potential immediate clinical relevance, activating mutations of the kinase BRAF were observed in 4% of patients, suggesting the evaluation of BRAF inhibitors in multiple myeloma clinical trials. These results indicate that cancer genome sequencing of large collections of samples will yield new insights into cancer not anticipated by existing knowledge.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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