To estimate the prevalence of urinary incontinence, fecal incontinence, and dual incontinence in a large cohort of older women and compare risk factors across the three conditions.
These ...cross-sectional analyses used data from the Nurses' Health Study. The 2008 questionnaire, mailed to 96,480 surviving participants aged 62-87 years, included two separate items on the prevalence of urinary and fecal incontinence. A response of leakage at least once per month defined incontinence for both urine and stool. Dual incontinence was defined by responses at this frequency for both conditions. Using a polytomous logistic regression model, we assessed each risk factor for prevalence of urinary, fecal, and dual incontinence.
The survey was completed by 64,396 women. Thirty-eight percent had urinary incontinence alone, 4% had fecal incontinence alone, and 7% had dual incontinence. Age older than 80 years compared with age younger than 70 years was associated most strongly with dual incontinence (odds ratio OR 2.49, 95% confidence interval CI 2.28-2.73) followed by depression (OR 2.28, 95% CI 2.13-2.43), neurologic disease (OR 1.84, 95% CI 1.65-2.07), functional limitations (OR 1.86, 95% CI 1.71-2.02), multiparity (OR 1.66, 95% CI 1.41-1.94), and heavier fetal birth weight (OR 1.24, 95% CI 1.10-1.41). Obesity was associated only with urinary incontinence (OR 1.99, 95% CI 1.90-2.08) and type 2 diabetes mellitus was a stronger risk factor for fecal than urinary incontinence (OR 1.43, 95% CI 1.28-1.59). Black race was associated with a reduced risk of all types of incontinence, especially dual incontinence (OR 0.30, 95% CI 0.21-0.44).
In this large cohort, dual incontinence was primarily associated with advanced age, decompensating medical conditions, depression, and multiparity.
II.
Risk factors for fecal incontinence in older women Townsend, Mary K; Matthews, Catherine A; Whitehead, William E ...
The American journal of gastroenterology,
01/2013, Letnik:
108, Številka:
1
Journal Article
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The objectives of this study were to estimate the prevalence of fecal incontinence (FI) in older women and examine associations between potential risk factors and prevalent FI.
We conducted a ...cross-sectional study of prevalent FI in 64,559 women, aged 62-87 years, in the Nurses' Health Study. Since 1976, participants provided information on health and lifestyle on mailed biennial questionnaires. Data on FI were collected in 2008. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for FI were calculated using logistic regression models.
The reported prevalence of liquid or solid stool incontinence at least monthly increased from 9% in women aged 62 to 64 years to 17% in women aged 85 to 87 years. Prevalent FI was 50% less common in black women compared with white women (6% vs. 12%, respectively). Other variables associated with increased odds of FI at least monthly were pregnancy, higher body mass index (BMI), lower physical activity, functional limitations, current cigarette smoking, type 2 diabetes, high blood pressure, and neurologic disease. Urinary incontinence (UI) was a strong correlate of FI, with 63% of women with FI reporting UI at least monthly compared with 45% of women in the whole study population.
FI is a common condition among older women, and often co-occurs with UI. Potentially modifiable risk factors include BMI, physical activity, and cigarette smoking.
Enfuvirtide (ENF), the first approved fusion inhibitor (FI) for HIV, is a 36-aa peptide that acts by binding to the heptad repeat 1 (HR1) region of gp41 and preventing the interaction of the HR1 and ...HR2 domains, which is required for virus-cell fusion. Treatment-acquired resistance to ENF highlights the need to create FI therapeutics with activity against ENF-resistant viruses and improved durability. Using rational design, we have made a series of oligomeric HR2 peptides with increased helical structure and with exceptionally high HR1/HR2 bundle stability. The engineered peptides are found to be as much as 3,600-fold more active than ENF against viruses that are resistant to the HR2 peptides ENF, T-1249, or T-651. Passaging experiments using one of these peptides could not generate virus with decreased sensitivity, even after >70 days in culture, suggesting superior durability as compared with ENF. In addition, the pharmacokinetic properties of the engineered peptides were improved up to 100-fold. The potent antiviral activity against resistant viruses, the difficulty in generating resistant virus, and the extended half-life in vivo make this class of fusion inhibitor peptide attractive for further development.
COVID-19 mRNA vaccines induce protective adaptive immunity against SARS-CoV-2 in most individuals, but there is wide variation in levels of vaccine-induced antibody and T-cell responses. However, the ...mechanisms underlying this inter-individual variation remain unclear. Here, using a systems biology approach based on multi-omics analyses of human blood and stool samples, we identified several factors that are associated with COVID-19 vaccine-induced adaptive immune responses. BNT162b2-induced T cell response is positively associated with late monocyte responses and inversely associated with baseline mRNA expression of activation protein 1 (AP-1) transcription factors. Interestingly, the gut microbial fucose/rhamnose degradation pathway is positively correlated with mRNA expression of AP-1, as well as a gene encoding an enzyme producing prostaglandin E2 (PGE2), which promotes AP-1 expression, and inversely correlated with BNT162b2-induced T-cell responses. These results suggest that baseline AP-1 expression, which is affected by commensal microbial activity, is a negative correlate of BNT162b2-induced T-cell responses.
Background & Aims Low estrogen levels can contribute to development of fecal incontinence (FI) in women after menopause by altering neuromuscular continence mechanisms. However, studies have produced ...conflicting results on the association between menopausal hormone therapy (MHT) and risk of FI. Methods We studied the association between MHT and risk of FI among 55,828 postmenopausal women (mean age, 73 years) who participated in the Nurses’ Health Study, were enrolled since 2008, and with no report of FI. We defined incident FI as a report of at least 1 liquid or solid FI episode per month during 4 years of follow-up from self-administered, biennial questionnaires administered in 2010 and 2012. We used Cox proportional hazard models to calculate multivariate-adjusted hazard ratios and 95% confidence intervals (CIs) for FI risk in women receiving MHT, adjusting for potential confounding factors. Results During more than 185,000 person-years of follow-up, there were 6834 cases of incident FI. Compared with women who never used MHT, the multivariate hazard ratio for FI was 1.26 (95% CI, 1.18−1.34) for past users of MHT and 1.32 (95% CI, 1.20−1.45) for current users. The risk of FI increased with longer duration of MHT use ( P trend ≤ .0001) and decreased with time since discontinuation. There was an increased risk of FI among women receiving MHT that contained a combination of estrogen and progestin (hazard ratio, 1.37; 95% CI, 1.10–1.70) compared with estrogen monotherapy. Conclusions Current or past use of MHT was associated with a modestly increased risk of FI among postmenopausal women in the Nurses’ Health Study. These results support a potential role for exogenous estrogens in the impairment of the fecal continence mechanism.
Higher body mass index (BMI) and low physical activity have been associated with increased prevalence of fecal incontinence (FI) in cross-sectional studies, but prospective studies examining the role ...of these factors are lacking. We sought to determine whether BMI and/or physical activity are associated with risk of FI among older women.
We prospectively examined the association between BMI and physical activity and risk of FI in the Nurses' Health Study among 51,708 women who were free of FI in 2008. We defined FI as at ≥1 liquid or solid FI episode/month during the past year reported in 2010 or 2012. We used Cox proportional hazards models to calculate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for FI according to physical activity and BMI, adjusting for potential confounding factors.
During more than 175,000 person-years of follow-up, we documented 5954 cases of incident FI. Compared with women in the lowest activity category (<3 metabolic equivalent of task (MET)-hrs/week), multivariable-adjusted HRs for FI were 0.86 (95% CI 0.80-0.93) for women doing 3-8 MET-hrs/week, 0.78 (95% CI 0.72-0.84) for 9-17 MET-hrs/week, 0.76 (95% CI 0.69-0.83) for 18-26 MET-hrs/week, and 0.75 (95% CI 0.70-0.81) for 27 + MET-hrs/week (P
= <0.0001). There was no association between BMI and risk of FI.
Higher levels of physical activity were associated with a modest reduction (25%) in risk of incident FI among older women. These results support a potential role of ongoing physical activity in the neuromuscular health of the anorectal continence mechanism with aging.
These results support a potential role of ongoing physical activity in the neuromuscular health of the anorectal continence mechanism with aging.
In models of HIV fusion, the glycoprotein gp41 is thought to form a six-helix bundle during viral fusion with the target cell. This bundle is comprised of three helical regions (from the heptad ...repeat 2, or HR2, region of gp41) bound to an inner, trimeric, coiled-coil core (from the HR1 region). Although much has been learned about the structure and thermodynamics of this complex, the energetics of the isolated HR1 self-associated oligomer remain largely unknown. By systematically studying self-association through a series of truncations based on a 51-mer HR1 peptide (T865), we have identified amino acid segments which contribute significantly to the stability of the oligomeric HR1 complex. Biophysical characterization of C-terminal truncations of T865 identifies a 10−15-amino acid region that is essential for HR1 oligomerization. This region coincides with a hydrophobic pocket that provides important contacts for the interaction of HR2 helices. Complete removal of this pocket abolishes HR1 oligomerization. Despite the dramatic reduction in stability, the monomeric HR1 peptides are still able to form stable six-helix bundles in the presence of HR2 peptides. Truncations on the N-terminal side of T865 have little effect on oligomerization but significantly reduce the stability of the HR1−HR2 six-helix bundle. Unlike the HR2 binding site, which extends along a hydrophobic groove on the HR1 oligomer, the residues that are critical for HR1 oligomerization are concentrated in a 10−15-amino acid region. These results demonstrate that there are localizations of binding energy, or “hot spots”, in the self-association of peptides derived from the HR1 region of gp41.
HIV fusion is mediated by a conformational transition in which the C‐terminal region (HR2) of gp41 interacts with the N‐terminal region (HR1) to form a six‐helix bundle. Peptides derived from the HR1 ...form a well‐characterized, trimeric coiled‐coil bundle in the presence of HR2 peptides, but there is little structural information on the isolated HR1 trimer. Using protein design, we have designed synthetic HR1 peptides that form soluble, thermostable HR1 trimers. In vitro binding of HR2 peptides to the engineered trimer suggests that the design strategy has not significantly impacted the ability to form the six‐helix bundle. The peptides have enhanced antiviral activity compared to wild type, with up to 30‐fold greater potency against certain viral isolates. In vitro passaging was used to generate HR1‐resistant virus and the observed resistance mutations map to the HR2 region of gp41, demonstrating that the peptides block the fusion process by binding to the viral HR2 domain. Interestingly, the activity of the HR2 fusion inhibitor, enfuvirtide (ENF), against these resistant viruses is maintained or improved up to fivefold. The 1.5 Å crystal structure of one of these designs has been determined, and we show that the isolated HR1 is very similar to the conformation of the HR1 in the six‐helix bundle. These results provide an initial model of the pre‐fusogenic state, are attractive starting points for identifying novel fusion inhibitors, and offer new opportunities for developing HIV therapeutics based on HR1 peptides.
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