The aim of this study was to determine the patterns and predictors of sexual activity in the Hormone Therapy (HT) Trials of the Women's Health Initiative (WHI).
Sexual activity questions were ...administered to 27,347 women ages 50 to 79 years at baseline and at year 1 and to a random 8.6% subsample at years 3 and 6. The associations with demographic and health characteristics were determined.
Sexual activity at baseline was 60.7%, 44.9%, and 28.2% in the 50- to 59-, 60- to 69-, and 70- to 79-year-old age groups, respectively. Most of the participants were satisfied with their current sexual activity (63.2%). Of those dissatisfied, 57% preferred more sexual activity. Vaginal atrophy correlated with sexual inactivity at baseline (P < 0.001). The correlates associated with stopping sexual activity at year 1 included poor/fair self-rated health, lack of satisfaction with quality of life, depression, and loss of partner (P < 0.001). The strongest predictor of sexual activity at year 1 was sexual activity at baseline (odds ratio, 96.71; 95% CI, 81.90-114.20). A subset analysis of women adherent with HT or placebo at years 3 and 6 suggested that HT was associated with a higher percentage of participants reporting sexual activity (P = 0.01).
Most women in the WHI HT Trials were satisfied with their sexual activity. Of those who were dissatisfied, the majority preferred more, rather than less, sexual activity. Vaginal atrophy at baseline correlated with sexual inactivity, and sexual activity at baseline was the strongest identified predictor of sexual activity at year 1. HT use was not predictive of ongoing sexual activity in the intent-to-treat analysis. This report further characterizes the participants in the WHI HT trials and reveals the complexity of factors related to the prevalence of sexual activity and satisfaction.
To develop a positive aging phenotype, we undertook analyses to describe multiple dimensions of positive aging and their relationships to one another in women 65 years of age and older and evaluate ...the performance of individual indicators and composite factors of this phenotype as predictors of time to death, years of healthy living, and years of independent living.
Data from Women's Health Initiative clinical trial and observational study participants ages 65 years and older at baseline, including follow-up observations up to 8 years later, were analyzed using descriptive statistics and principal components analysis to identify the factor structure of a positive aging phenotype. The factors were used to predict time to death, years of healthy living (without hospitalization or diagnosis of a serious health condition), and years of independent living (without nursing home admission or use of special services).
We identified a multidimensional phenotype of positive aging that included two factors: Physical-Social Functioning and Emotional Functioning. Both factors were predictive of each of the outcomes, but Physical-Social Functioning was the strongest predictor. Each standard deviation of increase in Physical-Social Functioning was accompanied by a 23.7% reduction in mortality risk, a 19.4% reduction in risk of major health conditions or hospitalizations, and a 26.3% reduction in risk of dependent living.
Physical-Social Functioning and Emotional Functioning constitute important components of a positive aging phenotype. Physical-Social Functioning was the strongest predictor of outcomes related to positive aging, including years of healthy living, years of independent living, and time to mortality.
We recently identified the 4-pyridinone-benzisothiazole carboxamide compound 1C8 as displaying strong anti-HIV-1 potency against a variety of clinical strains in vitro. Here we show that 1C8 ...decreases the expression of HIV-1 and alters splicing events involved in the production of HIV-1 mRNAs. Although 1C8 was designed to be a structural mimic of the fused tetracyclic indole compound IDC16 that targets SRSF1, it did not affect the splice site shifting activity of SRSF1. Instead, 1C8 altered splicing regulation mediated by SRSF10. Depleting SRSF10 by RNA interference affected viral splicing and, like 1C8, decreased expression of Tat, Gag and Env. Incubating cells with 1C8 promoted the dephosphorylation of SRSF10 and increased its interaction with hTra2β, a protein previously implicated in the control of HIV-1 RNA splicing. While 1C8 affects the alternative splicing of cellular transcripts controlled by SRSF10 and hTra2β, concentrations greater than those needed to inhibit HIV-1 replication were required to elicit significant alterations. Thus, the ability of 1C8 to alter the SRSF10-dependent splicing of HIV-1 transcripts, with minor effects on cellular splicing, supports the view that SRSF10 may be used as a target for the development of new anti-viral agents.
We aimed to test the utility of screening for depressive symptoms in the hand surgical office focusing on chances of heightened depressive symptoms in patients with no history of diagnosed depression ...and by quantifying ongoing depressive symptoms among patients diagnosed with depression accounting for antidepressant use. The clinical importance of this study was predicated on the documented negative association between depressive symptoms and hand surgical outcomes.
This cross-sectional study analyzed 351 patients presenting to a tertiary hand center between April 21, 2016, and November 22, 2017. Adult patients completed self-administered Patient-Reported Outcomes Measurement Information System (PROMIS) Depression computer adaptive tests at registration. Health records were examined for a past medical history of diagnosed depression and whether patients reported current use of prescription antidepressants. Mean PROMIS Depression scores were compared by analysis of variance (groups: no diagnosed depression, depression without medication, depression with medication). Four points represented a clinically relevant difference in PROMIS Depression scores between groups and Depression scores greater than 59.9 were categorized as having heightened depressive symptoms.
Sixty-two patients (18%) had been diagnosed with depression. Thirty-four of these patients (55%) reported taking antidepressant medications. The PROMIS Depression scores indicated greater current depressive symptoms among patients with a history of diagnosed depression when not taking antidepressants (11 points worse than unaffected) and also among patients taking antidepressants (7 points worse than unaffected). Heightened depressive symptoms were detected in all groups but were more prevalent among those diagnosed with depression (36% with no medication, 29% with antidepressant medication) compared with unaffected patients (7%).
Depression screening for heightened depressive symptoms identifies 1 in 14 patients without diagnosed depression and 1 in 3 patients diagnosed with depression as having currently heightened depressive symptoms. Hand surgeons can use PROMIS Depression screening in all patients and using this to guide referrals for depression treatment to ameliorate one confounder of hand surgical outcomes.
Symptom prevalence study II.
HIV-1 replication is critically dependent upon controlled processing of its RNA and the activities provided by its encoded regulatory factors Tat and Rev. A screen of small molecule modulators of RNA ...processing identified several which inhibited virus gene expression, affecting both relative abundance of specific HIV-1 RNAs and the levels of Tat and Rev proteins.
The screen for small molecules modulators of HIV-1 gene expression at the post-transcriptional level identified three (a pyrimidin-7-amine, biphenylcarboxamide, and benzohydrazide, designated 791, 833, and 892, respectively) that not only reduce expression of HIV-1 Gag and Env and alter the accumulation of viral RNAs, but also dramatically decrease Tat and Rev levels. Analyses of viral RNA levels by qRTPCR and RTPCR indicated that the loss of either protein could not be attributed to changes in abundance of the mRNAs encoding these factors. However, addition of the proteasome inhibitor MG132 did result in significant restoration of Tat expression, indicating that the compounds are affecting Tat synthesis and/or degradation. Tests in the context of replicating HIV-1 in PBMCs confirmed that 791 significantly reduced virus replication. Parallel analyses of the effect of the compounds on host gene expression revealed only minor changes in either mRNA abundance or alternative splicing. Subsequent tests suggest that 791 may function by reducing levels of the Tat/Rev chaperone Nap1.
The three compounds examined (791, 833, 892), despite their lack of structural similarity, all suppressed HIV-1 gene expression by preventing accumulation of two key HIV-1 regulatory factors, Tat and Rev. These findings demonstrate that selective disruption of HIV-1 gene expression can be achieved.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A pulse electrodeposition method for preparing stress-free CoFeB thin films is described. The method was optimized to produce amorphous films with soft magnetic properties and the best composition ...was found to be Co
94Fe
5B
1. The optimized conditions were used to obtain arrays of ordered nanowires, using nanoporous alumina membranes as templates. While magnetization measurements demonstrate that the microstructure of the array influences the detailed characteristics of the hysteresis loops, the general pattern of the magnetization curves, characterized by high saturation fields and low squareness, is the same as for crystalline Co arrays obtained in similar conditions. This observation, as well as data obtained from variable temperature measurements, shows that the overall magnetic behavior is determined mainly by the competition of the shape anisotropy and magnetostatic interactions. Whether the wire axis is easy or hard for the array depends upon the array geometry: wire diameter, length and the packing density of the wires. In order to explain these effects, a micromagnetic model was used to calculate the saturation fields for in-plane and out-of-plane magnetized array, as a function of the geometrical parameters. These agree well with the experimental results.
Infection and lymphopenia are established bendamustine-related complications. The relationship between lymphopenia severity and infection risk, and the role of antimicrobial prophylaxis, is not well ...described. This multicentre retrospective study analysed infection characteristics and antimicrobial prophylaxis in 302 bendamustine-treated indolent non-Hodgkin lymphoma patients. Lymphopenia (<1 × 10
/L) was near universal and time to lymphocyte recovery correlated with cumulative bendamustine dose. No association between lymphopenia severity and duration with infection was observed. Infections occurred in 44% of patients (50% bacterial) with 27% hospitalised; 32% of infections occurred ≥3 months post bendamustine completion. Infection was associated with obinutuzumab and/or maintenance anti-CD20 therapy, prior therapy and advanced stage. Twenty-four opportunistic infections occurred in 21 patients: ten varicella zoster virus (VZV), seven herpes simplex virus (HSV), one cytomegalovirus, one progressive multifocal leucoencephalopathy, one nocardiosis, one Pneumocystis jiroveci pneumonia (PJP) and three other fungal infections. VZV/HSV and PJP prophylaxis were prescribed to 42% and 54% respectively. Fewer VZV/HSV infections occurred in patients receiving prophylaxis (HR 0.14, p = 0.061) while PJP prophylaxis was associated with reduced risk of bacterial infection (HR 0.48, p = 0.004). Our study demonstrates a significant infection risk regardless of lymphopenia severity and supports prophylaxis to mitigate the risk of early and delayed infections.
Endometrioid (ENOC) and clear cell ovarian carcinoma (CCOC) share a common precursor lesion, endometriosis, hence the designation endometriosis associated ovarian cancers (EAOC). Long interspersed ...nuclear element 1 (LINE-1 or L1), is a family of mobile genetic elements activated in many cancers capable of moving neighboring DNA through 3′ transductions. Here we investigated the involvement of specific L1-mediated transductions in EAOCs.
Through whole genome sequencing, we identified active L1-mediated transductions originating within the TTC28 gene in 34% (10/29) of ENOC and 31% (11/35) of CCOC cases. We used PCR and capillary sequencing to assess the presence of specific TTC28-L1 transductions in formalin-fixed paraffin-embedded (FFPE) blocks from six different anatomical sites (five tumors and one normal control) for four ENOC and three CCOC cases, and compared the results to the presence of single nucleotide variations (SNVs)/frame shift (fs) mutations detected using multiplex PCR and next generation sequencing.
TTC28-L1 mediated transductions were identified in at least three tumor samplings in all cases, and were present in all five tumor samplings in 5/7 (71%) cases. In these cases, KRAS, PIK3CA, CTNNB1, ARID1A, and PTEN mutations were found across all tumor sites while other selected SNV/fs mutations of unknown significance were present at varying allelic frequencies.
The TTC28-L1 transductions along with classical driver mutations were near ubiquitous across the tumors, suggesting that L1 activation likely occurred early in the development of EAOCs. TTC28-L1 transductions could potentially be used to determine clonal relationships and to track ovarian cancer progression.
•An active LINE-1 retrotransposon from TTC28 gene is present in 32% of EAOCs.•TTC28 LINE-1 events are near ubiquitous across multiple EAOC tumor samplings.•TTC28 LINE-1 is likely activated early during EAOC development.•TTC28 LINE-1 may be used to track EAOC development.
Introduction
The combination of rituximab & lenalidomide (R 2) is an established regimen for treatment of follicular lymphoma (FL), with efficacy reported in the first line and relapsed setting ...(Morchhauser NEJM 2018, Leonard JCO 2019). The inferior OS of patients who remain post-induction PET-CT positive (PET+ve) has also been demonstrated in both settings (Trotman Lancet Haem 2014, Lancet Oncol 2018, Ysebaert, ASH 2011). We sought to study the effect of R 2 in relapsed FL by examining its ability to convert to PET-negative (PET-ve) those patients who remain PET+ve after reinduction rituximab-chemotherapy.
Methods
This was a prospective, multicentre, Phase 2 study of patients with bulky Stage II, or Stage III-IV relapsed FL. Eligibility criteria were: at least stable disease on CT within 4-6 weeks of last cycle of re-induction rituximab-chemotherapy; ECOG ≤2; CrCL ³30mL/min; haemoglobin >80g/L, neutrophils >1.0 & platelets >75 x 10 9/L. Exclusion criteria were: histological transformation ≤12 months (mo); any interim-PET that was negative, and other malignancy ≤5 years. After enrolment pts underwent a centrally-reviewed PET within 8 weeks of D1 last cycle of re-induction rituximab-chemotherapy. Given the higher probability of further progression in the relapsed setting PET+ve was defined as a Deauville score (DS) 3-5. PET-ve patients were assigned rituximab maintenance q2mo for 2 years, and those remaining PET+ve were assigned R 2 to commence within 12 weeks. Lenalidomide schedule for R 2 pts was 10mg/d x 21 q28d, with dose modifications for tolerance, over a planned 2 years. Repeat PET scans were scheduled at 6 & 12 mo after starting R 2.
The primary endpoint was the rate of conversion from postinduction PET+ve to PET-ve in evaluable patients 6 mo after commencing lenalidomide. Evaluable patients were defined as those receiving >63 days of Lenalidomide. Sample size calculations used a one-sided exact test for proportions, assuming a conversion rate of ³50% as worthy of further evaluation and ≤20% as unacceptable. Thus 16 evaluable patients were required to have 80% power with type I error of 5%. Secondary endpoints were PET conversion rates by baseline DS in the PET+ve, the toxicity & deliverability of R 2, and PFS & OS in both the PET+ve & PET-ve populations.
Results
Thirty-seven patients (pts) were recruited from Nov 2013 to Jan 2021 when the study was closed due to poor recruitment attributed to competing studies. Median (med) age was 67yrs (36-83); 58% male, med 2 (range 2-11) prior therapies incl. the recent rituximab-chemotherapy; FLIPI low risk (21%), intermediate risk (12%) high risk (67%). Eighteen of 37 (48.6%) pts were postinduction PET+ve. Med follow-up was 38 mo (0.8 - 76.4): 32 mo (0.8 - 76.4) in PET+ve and 42 mo (6.7 - 73.8) in PET-neg. Of the 18 PET+ve pts one was ineligible for R 2 due to reactivation of hepatitis B; 3 were not evaluable having not received >63 doses of lenalidomide due to progressive disease (PD). Thus 14/18 (78%) PET+ve pts were evaluable, of whom 5/14 (36%; 95% CI 11% - 61%) became PET-ve at 6-mo, thus not excluding a PET conversion rate of <20%, (p=0.14). If we had obtained full recruitment both additional pts would have had to convert to PET-neg to meet the primary endpoint. PET conversion occurred in 4/6 evaluable pts with DS 3 and 1/8 with DS 5. PD occurred in 14 pts: 11/17 PET+ve and 3/19 PET-ve. Med PFS was 30.8 mo (5.7-37.6) in the PET+ve and NR (95% CI 42.3-NR) in the PET-ve, p = 0.0001. Death occurred in 11/37 (30%): 7 from lymphoma (5 PET+ve), 1 other malignancy, 2 pneumonia, 1 aspergillosis. Med OS was 68.1 mo (9.6 - NR) in PET+ve and NR (95% CI 42.3 - NR) in PET-ve (p 0.059).
Of the 17 PET+ve pts starting lenalidomide, deliverability was limited by both disease progression and AEs: 3 failed to receive 3 cycles, 6 pts received 4-6, and 8 pts 7-24 cycles. Mean number of lenalidomide doses was 213 (SD 188). At least one AE was reported in 16/17 (94%), most commonly neutropenia (n=10, 59%, Gd4 24%). At least one SAE occurred in 9/17 (53%): infections 2, malignancy 2, cardiac disorders 2, musculoskeletal 2, other causes 3 pts.
Conclusion
The high PET+ve rate of 49% (DS 3-5) after rituximab-chemotherapy for relapsed FL suggests the need for consolidation therapy. However, R 2 did not achieve a sufficiently high PET-conversion rate to justify further study. The inferior outcome of patients who remain PET+ve after treatment of relapse highlights the importance of investigating novel approaches in this setting.
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Trotman: TAKEDA: Research Funding; beigene: Research Funding; roche: Research Funding; BMS: Research Funding; PCYC: Research Funding; JANSSEN: Research Funding. Gandhi: janssen: Research Funding; novartis: Honoraria. Butcher: WriteSource: Current Employment, Other: Medical writing for Pharma companies. Not pertinent to this abstract for which author is study Statisticiam.
To establish the incidence of nontraumatic lower-extremity amputation (LEA) in people with diabetes in Scotland.
This cohort study linked national morbidity records and diabetes datasets to establish ...the number of people with diabetes who underwent nontraumatic major and minor LEA in Scotland from 2004 to 2008.
Two thousand three hundred eighty-two individuals with diabetes underwent a nontraumatic LEA between 2004 and 2008; 57.1% (n = 1,359) underwent major LEAs. The incidence of any LEA among persons with diabetes fell over the 5-year study period by 29.8% (3.04 per 1,000 in 2004 to 2.13 per 1,000 in 2008, P < 0.001). Major LEA rates decreased by 40.7% from 1.87 per 1,000 in 2004 to 1.11 per 1,000 in 2008 (P < 0.001).
There has been a significant reduction in the incidence of LEA in persons with diabetes in Scotland between 2004 and 2008, principally explained by a reduction in major amputation.
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