Vosaroxin in combination with decitabine in newly diagnosed older patients with acute myeloid leukemia or high-risk myelodysplastic syndrome.

Vosaroxin is an anti-cancer quinolone-derived DNA topoisomerase II inhibitor. We investigated vosaroxin with decitabine in patients ≥60 years of age with newly diagnosed acute myeloid leukemia (n=58) or myelodysplastic syndrome (≥10% blasts) (n=7) in a phase II non-randomized trial. The initial 22 patients received vosaroxin 90 mg/m2 on days 1 and 4 with decitabine 20 mg/m2 on days 1-5 every 4-6 weeks for up to seven cycles. Due to a high incidence of mucositis the subsequent 43 patients were given vosaroxin 70 mg/m2 on days 1 and 4. These 65 patients, with a median age of 69 years (range, 60-78), some of whom with secondary leukemia (22%), adverse karyotype (35%), or TP53 mutation (20%), are evaluable. The overall response rate was 74% including complete remission in 31 (48%), complete remission with incomplete platelet recovery in 11 (17%), and complete remission with incomplete count recovery in six (9%). The median number of cycles to response was one (range, 1-4). Grade 3/4 mucositis was noted in 17% of all patients. The 70 mg/m2 induction dose of vosaroxin was associated with similar rates of overall response (74% versus 73%) and complete remission (51% versus 41%, P=0.44), reduced incidence of mucositis (30% versus 59%, P=0.02), reduced 8-week mortality (9% versus 23%; P=0.14), and improved median overall survival (14.6 months versus 5.5 months, P=0.007). Minimal residual disease-negative status by multiparametric flow-cytometry at response (± 3 months) was achieved in 21 of 39 (54%) evaluable responders and was associated with better median overall survival (34.0 months versus 8.3 months, P=0.023). In conclusion, the combination of vosaroxin with decitabine is effective and well tolerated at a dose of 70 mg/m2 and warrants randomized prospective evaluation. ClinicalTrials.gov: NCT01893320.

Variables affecting maximum urethral closure pressure (MUCP) and abdominal leak point pressure (ALPP) measurements.

INTRODUCTION AND HYPOTHESIS: The relationship between pelvic floor muscles and measurements of urethral function is not well studied. It is not known whether adjusting for clinical, demographic and urodynamic parameters would improve the association between MUCP and ALPP. Our hypothesis was that pelvic floor muscle strength (PFMS) influences the relationship between MUCP and ALPP. METHODS: This was a retrospective study of women who underwent a complex urodynamic study with evaluation of MUCP and ALPP using ICD-9 codes with documentation of PFMS. RESULTS: Urodynamic stress incontinence was confirmed in 478 patients, of whom 323 had MUCP recorded and 263 had both MUCP and ALPP recorded. Women with higher PFMS had a higher MUCP. In regression analysis ALPP at 150 mL and MUCP were weakly associated (coefficient 0.43, 95% CI 0.08-0.78; p = 0.02), whereas ALPP at capacity and MUCP were moderately associated (coefficient 0.60, 95% CI 0.25-0.95; p < 0.001). CONCLUSIONS: This study showed that MUCP and ALPP at 150 mL were weakly associated and that this improved to a moderate association for ALPP at capacity. MUCP increased with increasing PFMS among women with stress urinary incontinence and decreased with increasing age. There was no evidence that ALPP was associated with PFMS or age. The relationship between MUCP and ALPP was unchanged when accounting for covariates of PFMS (age, parity, BMI, prior procedure, urethral mobility, bladder capacity, stage of cystocele, or stage of uterine or apical prolapse).

Vosaroxin plus cytarabine versus placebo plus cytarabine in patients with first relapsed or refractory acute myeloid leukaemia (VALOR): a randomised, controlled, double-blind, multinational, phase 3 study.

BACKGROUND: Safe and effective treatments are urgently needed for patients with relapsed or refractory acute myeloid leukaemia. We investigated the efficacy and safety of vosaroxin, a first-in-class anticancer quinolone derivative, plus cytarabine in patients with relapsed or refractory acute myeloid leukaemia. METHODS: This phase 3, double-blind, placebo-controlled trial was undertaken at 101 international sites. Eligible patients with acute myeloid leukaemia were aged 18 years of age or older and had refractory disease or were in first relapse after one or two cycles of previous induction chemotherapy, including at least one cycle of anthracycline (or anthracenedione) plus cytarabine. Patients were randomly assigned 1:1 to vosaroxin (90 mg/m(2) intravenously on days 1 and 4 in a first cycle; 70 mg/m(2) in subsequent cycles) plus cytarabine (1 g/m(2) intravenously on days 1-5) or placebo plus cytarabine through a central interactive voice system with a permuted block procedure stratified by disease status, age, and geographical location. All participants were masked to treatment assignment. The primary efficacy endpoint was overall survival and the primary safety endpoint was 30-day and 60-day all-cause mortality. Efficacy analyses were done by intention to treat; safety analyses included all treated patients. This study is registered with ClinicalTrials.gov, number NCT01191801. FINDINGS: Between Dec 17, 2010, and Sept 25, 2013, 711 patients were randomly assigned to vosaroxin plus cytarabine (n=356) or placebo plus cytarabine (n=355). At the final analysis, median overall survival was 7·5 months (95% CI 6·4-8·5) in the vosaroxin plus cytarabine group and 6·1 months (5·2-7·1) in the placebo plus cytarabine group (hazard ratio 0·87, 95% CI 0·73-1·02; unstratified log-rank p=0·061; stratified p=0·024). A higher proportion of patients achieved complete remission in the vosaroxin plus cytarabine group than in the placebo plus cytarabine group (107 [30%] of 356 patients vs 58 [16%] of 355 patients, p<0·0001). Early mortality was similar between treatment groups (30-day: 28 [8%] of 355 patients in the vosaroxin plus cytarabine group vs 23 [7%] of 350 in the placebo plus cytarabine group; 60-day: 70 [20%] vs 68 [19%]). Treatment-related deaths occurred at any time in 20 (6%) of 355 patients given vosaroxin plus cytarabine and in eight (2%) of 350 patients given placebo plus cytarabine. Treatment-related serious adverse events occurred in 116 (33%) and 58 (17%) patients in each group, respectively. Grade 3 or worse adverse events that were more frequent in the vosaroxin plus cytarabine group than in the placebo plus cytarabine group included febrile neutropenia (167 [47%] vs 117 [33%]), neutropenia (66 [19%] vs 49 [14%]), stomatitis (54 [15%] vs 10 [3%]), hypokalaemia (52 [15%] vs 21 [6%]), bacteraemia (43 [12%] vs 16 [5%]), sepsis (42 [12%] vs 18 [5%]), and pneumonia (39 [11%] vs 26 [7%]). INTERPRETATION: Although there was no significant difference in the primary endpoint between groups, the prespecified secondary analysis stratified by randomisation factors suggests that the addition of vosaroxin to cytarabine might be of clinical benefit to some patients with relapsed or refractory acute myeloid leukaemia. FUNDING: Sunesis Pharmaceuticals.

Vaginal estrogen use in postmenopausal women with pelvic floor disorders: systematic review and practice guidelines.

INTRODUCTION AND HYPOTHESIS: Risk of pelvic floor disorders increases after menopause and may be linked to estrogen deficiency. We aimed to systematically and critically assess the literature on vaginal estrogen in the management of pelvic floor disorders in postmenopausal women and provide evidence-based clinical practice guidelines. METHODS: MEDLINE and Cochrane databases were searched from inception to July 2014 for randomized controlled trials of commercially available vaginal estrogen products compared with placebo, no treatment, or any medication for overactive bladder or urinary incontinence. We double-screened 1,805 abstracts and identified 12 eligible papers. Studies were extracted for participant information, intervention, comparator, efficacy outcomes, and adverse events, and they were individually and collectively assessed for methodological quality and strength of evidence. RESULTS: Evidence was generally of poor to moderate quality. Vaginal estrogen application before pelvic organ prolapse surgery improved the vaginal maturation index and increased vaginal epithelial thickness. Postoperative vaginal estrogen use after a midurethral sling resulted in decreased urinary frequency and urgency. Vaginal estrogen and immediate-release oxybutynin were similar in improvement of urinary urgency, frequency, and urgency urinary incontinence in women with overactive bladder, but oxybutynin had higher rates of side effects and discontinuation. Conversely, the addition of vaginal estrogen to immediate or extended-release tolterodine did not improve urinary symptoms more than tolterodine alone. One study reported an improvement in stress urinary incontinence with use of vaginal estrogen. CONCLUSION: Vaginal estrogen application may play a useful role as an adjunct in the management of common pelvic floor disorders in postmenopausal women.

The fellowship effect: how the establishment of a fellowship in female pelvic medicine and reconstructive surgery affected resident vaginal hysterectomy training.

OBJECTIVE: We report on trends in resident-performed vaginal hysterectomies before and after the establishment of a female pelvic medicine and reconstructive surgery fellowship at Vanderbilt University Medical Center. STUDY DESIGN: We examined medical records and resident self-reports concerning all hysterectomies at our institution in an 8-year period: 4 years before fellowship and 4 years after. Route of hysterectomy, resident and fellow involvement, and division of attending surgeon were recorded from the electronic medical record. Resident Accreditation Council for Graduate Medical Education (ACGME) case log data were used to estimate the number of hysterectomies where residents reported themselves as the primary surgeon. RESULTS: During the 8-year period of this study, 3317 hysterectomies were performed at our institution, 41% (1371) before and 59% (1946) after fellowship. Prior to fellowship, 29% (393) were vaginal, 56% (766) were abdominal, and 15% (212) were laparoscopic/robotic. After addition of fellowship, 23% (449) were vaginal, 31% (597) were abdominal, and 46% (900) were laparoscopic/robotic. Of the total vaginal hysterectomies (TVH), there was resident involvement in 98.0% (385) cases before fellowship and 98.2% (441) cases after fellowship. From the ACGME case log data, the resident identified himself/herself as the primary surgeon in 388 cases before and 393 cases after fellowship. During this time period, medical records indicate a fellow was involved in 42% (189) of TVH, with resident involvement in all but 5 of these procedures. CONCLUSION: Frequency of resident involvement in TVH cases, either as primary surgeon or team member, remained constant after the addition of the female pelvic medicine and reconstructive surgery fellowship.

Genetic epidemiology of pelvic organ prolapse: a systematic review.

Given current evidence supporting a genetic predisposition for pelvic organ prolapse, we conducted a systematic review of published literature on the genetic epidemiology of pelvic organ prolapse. Inclusion criteria were linkage studies, candidate gene association and genome-wide association studies in adult women published in English and indexed in PubMed through Dec. 2012, with no limit on date of publication. Methodology adhered to the PRISMA guidelines. Data were systematically extracted by 2 reviewers and graded by the Venice criteria for studies of genetic associations. A metaanalysis was performed on all single nucleotide polymorphisms evaluated by 2 or more studies with similar methodology. The metaanalysis suggests that collagen type 3 alpha 1 (COL3A1) rs1800255 genotype AA is associated with pelvic organ prolapse (odds ratio, 4.79; 95% confidence interval, 1.91-11.98; P = .001) compared with the reference genotype GG in populations of Asian and Dutch women. There was little evidence of heterogeneity for rs1800255 (P value for heterogeneity = .94; proportion of variance because of heterogeneity, I(2) = 0.00%). There was insufficient evidence to determine whether other single nucleotide polymorphisms evaluated by 2 or more papers were associated with pelvic organ prolapse. An association with pelvic organ prolapse was seen in individual studies for estrogen receptor alpha (ER-α) rs2228480 GA, COL3A1 exon 31, chromosome 9q21 (heterogeneity logarithm of the odds score 3.41) as well as 6 single nucleotide polymorphisms identified by a genome-wide association study. Overall, individual studies were of small sample size and often of poor quality. Future studies would benefit from more rigorous study design as outlined in the Venice recommendations.

Sling surgery for stress urinary incontinence in women: a systematic review and metaanalysis.

OBJECTIVE: Understanding the long-term comparative effectiveness of competing surgical repairs is essential as failures after primary interventions for stress urinary incontinence (SUI) may result in a third of women requiring repeat surgery. STUDY DESIGN: We conducted a systematic review including English-language randomized controlled trials from 1990 through April 2013 with a minimum 12 months of follow-up comparing a sling procedure for SUI to another sling or Burch urethropexy. When at least 3 randomized controlled trials compared the same surgeries for the same outcome, we performed random effects model metaanalyses to estimate pooled odds ratios (ORs). RESULTS: For midurethral slings (MUS) vs Burch, metaanalysis of objective cure showed no significant difference (OR, 1.18; 95% confidence interval [CI], 0.73-1.89). Therefore, we suggest either intervention; the decision should balance potential adverse events (AEs) and concomitant surgeries. For women considering pubovaginal sling vs Burch, the evidence favored slings for both subjective and objective cure. We recommend pubovaginal sling to maximize cure outcomes. For pubovaginal slings vs MUS, metaanalysis of subjective cure favored MUS (OR, 0.40; 95% CI, 0.18-0.85). Therefore, we recommend MUS. For obturator slings vs retropubic MUS, metaanalyses for both objective (OR, 1.16; 95% CI, 0.93-1.45) and subjective cure (OR, 1.17; 95% CI, 0.91-1.51) favored retropubic slings but were not significant. Metaanalysis of satisfaction outcomes favored obturator slings but was not significant (OR, 0.77; 95% CI, 0.52-1.13). AEs were variable between slings; metaanalysis showed overactive bladder symptoms were more common following retropubic slings (OR, 1.413; 95% CI, 1.01-1.98, P = .046). We recommend either retropubic or obturator slings for cure outcomes; the decision should balance AEs. For minislings vs full-length MUS, metaanalyses of objective (OR, 4.16; 95% CI, 2.15-8.05) and subjective (OR, 2.65; 95% CI, 1.36-5.17) cure both significantly favored full-length slings. Therefore, we recommend a full-length MUS. CONCLUSION: Surgical procedures for SUI differ for success rates and complications, and both should be incorporated into surgical decision-making. Low- to high-quality evidence permitted mostly level-1 recommendations when guidelines were possible.

Formerly used defense sites on Unalaska Island, Alaska: Mapping a legacy of environmental pollution.

Unalaska Island, Alaska, served as a US military base during World War II. The military installed bases on Unalaska and nearby islands, many of which were built adjacent to Unangan communities. The military used toxic compounds in its operations and left a legacy of pollution that may pose health risks to residents and local wildlife. The goals of this study were to identify hotspots of contamination remaining at Unalaska formerly used defense (FUD) sites, evaluate the risk posed by arsenic, and examine "no US Department of Defense action indicated" (NDAI) status determinations for FUD sites near communities. We compiled soil chemistry data from remediation reports prepared by the US Army Corps of Engineers at 18 FUD sites on and near Unalaska. Nine had past and/or active remediation projects and on-site sampling data. Eight sites did not have sampling data and were characterized as NDAI. One site was listed as closed. For the nine sites with sampling data, we compiled data for 22 contaminants of concern (COC) and compared concentrations to soil cleanup levels for human health (18 AAC 75.341). We mapped contaminant concentrations exceeding these levels to identify hotspots of contamination. We found that concentrations of some of the 22 COC exceeded Alaska cleanup levels despite remediation efforts, including diesel range organics, arsenic, and lead. The highest COC concentrations were at the FUD site adjacent to the City of Unalaska. A quantitative risk assessment for arsenic found that the risk of exposure through drinking water is low. We highlight concerns with NDAI designations and current remedial practices at remote FUD sites located adjacent to communities. Our data suggest the need for further remediation and monitoring efforts on Unalaska for certain contaminants and research to examine potential threats to human and animal health associated with these sites. Integr Environ Assess Manag 2024;00:1-12. © 2024 SETAC.

Differential gene expression and developmental pathologies associated with persistent organic pollutants in sentinel fish in Troutman Lake, Sivuqaq, Alaska.

Persistent organic pollutants (POPs) are lipophilic compounds that bioaccumulate in animals and biomagnify within food webs. Many POPs are endocrine disrupting compounds that impact vertebrate development. POPs accumulate in the Arctic via global distillation and thereby impact high trophic level vertebrates as well as people who live a subsistence lifestyle. The Arctic also contains thousands of point sources of pollution, such as formerly used defense (FUD) sites. Sivuqaq (St. Lawrence Island), Alaska was used by the U.S. military during the Cold War and FUD sites on the island remain point sources of POP contamination. We examined the effects of POP exposure on ninespine stickleback (Pungitius pungitius) collected from Troutman Lake in the village of Gambell as a model for human exposure and disease. During the Cold War, Troutman Lake was used as a dump site by the U.S. military. We found that PCB concentrations in stickleback exceeded the U.S. Environmental Protection Agency's guideline for unlimited consumption despite these fish being low trophic level organisms. We examined effects at three levels of biological organization: gene expression, endocrinology, and histomorphology. We found that ninespine stickleback from Troutman Lake exhibited suppressed gonadal development compared to threespine stickleback (Gasterosteus aculeatus) studied elsewhere. Troutman Lake stickleback also displayed two distinct hepatic phenotypes, one with lipid accumulation and one with glycogen-type vacuolation. We compared the transcriptomic profiles of these liver phenotypes using RNA sequencing and found significant upregulation of genes involved in ribosomal and metabolic pathways in the lipid accumulation group. Additionally, stickleback displaying liver lipid accumulation had significantly fewer thyroid follicles than the vacuolated phenotype. Our study and previous work highlight health concerns for people and wildlife due to pollution hotspots in the Arctic, and the need for health-protective remediation.

Transcriptomic and developmental effects of persistent organic pollutants in sentinel fishes collected near an arctic formerly used defense site.

Alaska contains over 600 formerly used defense (FUD) sites, many of which serve as point sources of pollution. These sites are often co-located with rural communities that depend upon traditional subsistence foods, especially lipid-rich animals that bioaccumulate and biomagnify persistent organic pollutants (POPs). Many POPs are carcinogenic and endocrine-disrupting compounds that are associated with adverse health outcomes. Therefore, elevated exposure to POPs from point sources of pollution may contribute to disproportionate incidence of disease in arctic communities. We investigated PCB concentrations and the health implications of POP exposure in sentinel fishes collected near the Northeast Cape FUD site on Sivuqaq (St. Lawrence Island), Alaska. Sivuqaq residents are almost exclusively Yupik and rely on subsistence foods. At the request of the Sivuqaq community, we examined differential gene expression and developmental pathologies associated with exposure to POPs originating at the Northeast Cape FUD site. We found significantly higher levels of PCBs in Alaska blackfish (Dallia pectoralis) collected from contaminated sites downstream of the FUD site compared to fish collected from upstream reference sites. We compared transcriptomic profiles and histopathologies of these same blackfish. Blackfish from contaminated sites overexpressed genes involved in ribosomal and FoxO signaling pathways compared to blackfish from reference sites. Contaminated blackfish also had significantly fewer thyroid follicles and smaller pigmented macrophage aggregates. Conversely, we found that ninespine stickleback (Pungitius pungitius) from contaminated sites exhibited thyroid follicle hyperplasia. Despite our previous research reporting transcriptomic and endocrine differences in stickleback from contaminated vs. reference sites, we did not find significant differences in kidney or gonadal histomorphologies. Our results demonstrate that contaminants from the Northeast Cape FUD site are associated with altered gene expression and thyroid development in native fishes. These results are consistent with our prior work demonstrating disruption of the thyroid hormone axis in Sivuqaq residents.

Phenotyping clinical disorders: lessons learned from pelvic organ prolapse.

Genetic epidemiology, the study of genetic contributions to risk for disease, is an innovative area in medicine. Although research in this arena has advanced in other disciplines, few genetic epidemiological studies have been conducted in obstetrics and gynecology. It is crucial that we study the genetic susceptibility for issues in women's health because this information will shape the new frontier of personalized medicine. To date, preterm birth may be one of the best examples of genetic susceptibility in obstetrics and gynecology, but many areas are being evaluated including endometriosis, fibroids, polycystic ovarian syndrome, and pelvic floor disorders. An essential component to genetic epidemiological studies is to characterize, or phenotype, the disorder to identify genetic effects. Given the growing importance of genomics and genetic epidemiology, we discuss the importance of accurate phenotyping of clinical disorders and highlight critical considerations and opportunities in phenotyping, using pelvic organ prolapse as a clinical example.

Clinical findings associated with bladder trabeculations in women.

INTRODUCTION AND HYPOTHESIS: This study evaluated whether bladder trabeculations are associated with advanced prolapse, urinary urgency, or detrusor overactivity among women undergoing office cystoscopy. It is well established that bladder trabeculations are associated with bladder outlet obstruction (BOO) in men; however, the clinical significance of trabeculations in women is unclear. Whereas an analogous relationship has been proposed between prostatic obstruction in men and advanced pelvic organ prolapse (POP) in women, little data in the medical literature supports this theory. METHODS: A retrospective cohort study was conducted using Current Procedural Terminology (CPT) codes (52000, 52204) to identify all women who underwent office cystoscopy at our urogynecology center between January 2008 and May 2011. The 551 women identified were grouped by the presence or absence of bladder trabeculations. Multivariable logistic regression was used to estimate the association between trabeculations and the primary aim, increasing stage of prolapse, and the secondary aims: bladder outlet obstruction, detrusor overactivity, or urge urinary incontinence (UUI). RESULTS: Of the 551 women meeting inclusion criteria, 86 had trabeculations. Controlling for age, the odds of bladder trabeculations were eightfold greater for women with stage IV POP when compared with women with stage 0 prolapse [odds ratio (OR) 8.2, 95% confidence interval (CI) 1.6-43.1]. The odds of bladder trabeculations were twofold greater for women with detrusor overactivity (OR 2.3, 95% CI 1.3-4.0) found on urodynamic study and also as reflected subjectively by answers to Pelvic Floor Distress Inventory (PFDI) item number 16 (OR 4.2, 95% CI 1.3-14.5). CONCLUSION: In this study, bladder trabeculations were associated with stage IV prolapse in the anterior compartment as well as with detrusor overactivity and UUI.

A novel method for extraction and quantification of feather triiodothyronine (T3) and application to ecotoxicology of Purple Martin (Progne subis).

Seventy-three percent of aerial insectivore species of birds breeding in North America have declined in the past five years. This decline is even greater in migratory insectivorous species, which face stressors in both their breeding and non-breeding ranges. The Purple Martin (Progne subis) is an aerial insectivore swallow that overwinters in South America and migrates to North America to breed. Purple Martin populations have declined by an estimated 25% since 1966. The eastern subspecies (P. subis subis) has declined the most and overwinters in the Amazon Basin, a region rich in environmental mercury (Hg) contamination. Previous studies reported elevated levels of Hg in feathers of this subspecies, which correlated negatively with body mass and fat reserves. Given the propensity of Hg to disrupt the endocrine system, and the role of thyroid hormones in regulating fat metabolism, this study quantifies concentrations of Hg and the thyroid hormone triiodothyronine (T3) in the feathers of P. subis subis. To our knowledge, this is the first study to extract and quantify T3 in feathers; thus, we developed, tested, and optimized a method for extracting T3 from feather tissue and validated an enzyme immunoassay (EIA) to quantify T3 in Purple Martin feathers. The developed method yielded acceptable results for both parallelism and accuracy. The observed T3 concentrations were statistically modeled along with total Hg (THg) concentrations, but these variables were not significantly correlated. This suggests that the observed variation in THg concentration may be insufficient to cause a discernible change in T3 concentration. Furthermore, the observed effect of breeding location on feather T3 concentration might have obscured any effect of Hg.

Factors associated with exposure of transvaginally placed polypropylene mesh for pelvic organ prolapse.

INTRODUCTION AND HYPOTHESIS: This study evaluates potential risk factors for mesh exposure following transvaginal placement of polypropylene mesh for pelvic organ prolapse requiring reoperation. METHODS: We performed a case-control study. Cases had mesh exposure requiring surgical revision; controls had no mesh exposures and were chosen for similar surgical date and type of mesh. RESULTS: We identified 48 cases and 48 controls. The adjusted odds ratio of having a bleeding complication at the time of mesh implantation was 7.25 [95% confidence interval (CI) 1.47-35.66], smokers versus nonsmokers was 3.17 (95% CI 0.59-17.12), and being 1 year older was 0.96 (95% CI 0.92-1.0), among women with mesh exposure. CONCLUSIONS: We identified bleeding complications at the time of mesh implantation as a risk factor for mesh exposure requiring reoperation. Despite being one of the largest studies on this topic, our data were inconclusive regarding the impact of other possible factors on mesh exposure.

Frequent genetic abnormalities of the PI3K/AKT pathway in primary ovarian cancer predict patient outcome.

Identification and characterization of underlying genetic aberrations could facilitate diagnosis and treatment of ovarian cancer. Copy number analysis using array Comparative Genomic Hybridization (aCGH) on 93 primary ovarian tumors identified PI3K/AKT pathway as the most frequently altered cancer related pathway. Furthermore, survival analyses to correlate gene copy number and mutation data with patient outcome showed that copy number gains of PIK3CA, PIK3CB, and PIK3R4 in these tumors were associated with decreased survival. To confirm these findings at the protein level, immunohistochemistry (IHC) for PIK3CA product p110α and p-Akt was performed on tissue microarrays from 522 independent serous ovarian cancers. Overexpression of either of these two proteins was found to be associated with decreased survival. Multivariant analysis from these samples further showed that overexpression of p-AKT and/or p110α is an independent prognostic factor for these tumors. siRNAs targeting altered PI3K/AKT pathway genes inhibited proliferation and induced apoptosis in ovarian cancer cell lines. In addition, the effect of the siRNAs in different cell lines seemed to correlate with the particular genetic alterations that the cell line carries. These results strongly support the utilization of PI3K pathway inhibitors in ovarian cancer. They also suggest identifying the specific component in the PI3K pathway that is genetically altered has the potential to help select the most effective therapy. Both mutation as well as copy number changes can be used as predictive markers for this purpose.

Risks and risk mitigation in homecare for people with dementia-A two-sided matter: A systematic review.

Policy guidance promotes supporting people to live in their own homes for as long as possible with support from homecare services. People living with dementia who need such support can experience a range of physical and cognitive difficulties, which can increase the risks associated with homecare for this group. We aimed to examine risk and safety issues for people with dementia and their homecare workers and risk mitigation practices adopted by homecare workers to address identified risks. We searched MEDLINE, EMBASE, AMED, CINAHL, PsycINFO, ASSIA and Cochrane Central Register of Controlled Trials databases 5 March 2021. Included studies focussed on homecare for people with dementia and had a risk or safety feature reported. Risk of bias was assessed with the Joanna Briggs Institute Critical Appraisal tools. Two authors assessed articles for potential eligibility and quality. A narrative synthesis combines the findings. The search identified 2259 records; 27 articles, relating to 21 studies, met the eligibility criteria. The review identified first-order risks that homecare workers in the studies sought to address. Two types of risk mitigation actions were reported: harmful interventions and beneficial interventions. Actions adopted to reduce risks produced intended benefits but also unintended consequences, creating second-order risks to both clients with dementia and homecare workers, placing them at greater risk. Risk mitigation interventions should be person-centred, the responsibility of all relevant professions, and planned to minimise the creation of unintended risks.

Elevated mercury and PCB concentrations in Dolly Varden (Salvelinus malma) collected near a formerly used defense site on Sivuqaq, Alaska.

Environmental pollution causes adverse health effects in many organisms and contributes to health disparities for Arctic communities that depend on subsistence foods, including the Yupik residents of Sivuqaq (St. Lawrence Island), Alaska. Sivuqaq's proximity to Russia made it a strategic location for U.S. military defense sites during the Cold War. Two radar surveillance stations were installed on Sivuqaq, including at the Northeast Cape. High levels of persistent organic pollutants and toxic metals continue to leach from the Northeast Cape formerly used defense (FUD) site despite remediation efforts. We quantified total mercury (Hg) and polychlorinated biphenyl (PCB) concentrations, and carbon and nitrogen stable isotope signatures, in skin and muscle samples from Dolly Varden (Salvelinus malma), an important subsistence species. We found that Hg and PCB concentrations significantly differed across locations, with the highest concentrations found in fish collected near the FUD site. We found that 89% of fish collected from near the FUD site had Hg concentrations that exceeded the U.S. Environmental Protection Agency's (EPA) unlimited Hg-contaminated fish consumption screening level for subsistence fishers (0.049 µg/g). All fish sampled near the FUD site exceeded the EPA's PCB guidelines for cancer risk for unrestricted human consumption (0.0015 µg/g ww). Both Hg and PCB concentrations had a significant negative correlation with δ13C when sites receiving input from the FUD site were included in the analysis, but these relationships were insignificant when input sites were excluded. δ15N had a significant negative correlation with Hg concentration, but not with PCB concentration. These results suggest that the Northeast Cape FUD site remains a point source of Hg and PCB pollution and contributes to higher concentrations in resident fish, including subsistence species. Moreover, elevated Hg and PCB levels in fish near the FUD site may pose a health risk for Sivuqaq residents.

Case studies on longitudinal mercury content in humpback whale (Megaptera novaeangliae) baleen.

Quantification of contaminant concentrations in baleen whales is important for individual and population level health assessments but is difficult due to large migrations and infrequent resighings. The use of baleen allows for a multiyear retrospective analysis of contaminant concentrations without having to collect repeated samples from the same individual. Here we provide case studies of mercury analysis using cold vapor atomic absorption spectroscopy in three individual humpback whales (Megaptera novaeangliae), a 44.5-year-old female and two males aged ≥35 and 66 years, over approximately three years of baleen growth. Mercury concentrations in the female's baleen were consistently 2-3 times higher than in either male. Age did not affect mercury concentrations in baleen; the younger male had comparable levels to the older male. In the female, mercury concentrations in the baleen did not change markedly during pregnancy but mercury did spike during the first half of lactation. Stable isotope profiles suggest that diet likely drove the female's high mercury concentrations. In conclusion, variations in baleen mercury content can be highly individualistic. Future studies should compare sexes as well as different populations and species to determine how the concentrations of mercury and other contaminants vary by life history parameters and geography.