Markers of ovarian reserve in women living with HIV: A systematic review.

BACKGROUND: Anti-Mullerian hormone (AMH) levels indicate ovarian reserve and are predictive of reproductive aging. Studies evaluating AMH levels in women with HIV have produced conflicting results, and reasons for inter-study differences have not been assessed. To understand reproductive aging in HIV, we conducted a systematic review of ovarian reserve among women with HIV. METHODS: We searched Ovid MEDLINE, Ovid EMBASE, and CAB Direct for studies including AMH in reproductive-aged women with HIV. Two reviewers used the Newcastle-Ottawa scale to assess the quality of extracted data. RESULTS: Of the 315 reports screened, ten met the inclusion criteria. Studies were conducted across seven countries and included 3673 women with HIV and 2342 HIV-negative women in the comparison group. Ethnic distribution, combination antiretroviral therapy coverage, and viral load suppression varied considerably across studies. Nine of the ten reviewed studies reported lower unadjusted AMH levels in women with HIV than in those without HIV; however, in studies that adjusted for confounders (n = 4), only two showed an association between HIV and AMH. Low CD4 count and high viral load correlated with low AMH in the two largest studies. Other studies found that opioid use and elevated inflammatory markers were associated with low AMH. Study quality varied considerably, and many were of low quality (n = 6). CONCLUSION: Current evidence is inconclusive about the relationship between HIV and AMH, although studies suggest a trend toward lower AMH among women with HIV. Future studies that adjust for HIV-related factors, inflammatory markers, and substance use are needed in the era of contemporary HIV care to confirm the association between HIV and reduced ovarian reserve and establish its underlying cause.

Vitamin D intakes among women living with and without HIV in Canada.

BACKGROUND: Patterns of vitamin D intake are relatively unexplored among women living with HIV, despite its importance for women's health. We compared vitamin D dietary and supplement intakes in women with HIV and population-based national controls and investigated barriers to intake. METHODS: In this case-control study, women with HIV in the Children and Women: AntiRetrovirals and Markers of Aging (CARMA) cohort were matched with Canadian Multicentre Osteoporosis Study (CaMos) controls. Participants were queried for vitamin D in dairy consumption, supplementation/dosage, and sociodemographic variables. We assessed barriers to supplementation and factors associated with dietary intake by regression modelling. RESULTS: Ninety-five women living with HIV were age-matched to 284 controls. Women with HIV had lower income and bone mineral density and were more likely to smoke, take multiple medications and be non-white. Vitamin D dietary intake was lower in women living with HIV versus controls [0.76 vs. 1.79 µg/day; adjusted odds ratio (aOR) for greater than or equal to median intake 0.29 (0.12-0.61), p = 0.002], but any supplementation was higher [62.2% vs. 44.7%; aOR = 3.44 (95% CI: 1.16-11.00), p = 0.03]. Total vitamin D intake was similar between groups. Smoking was associated with no supplementation; non-white ethnicity and low income were related to lower dietary intake. CONCLUSIONS: Women living with HIV showed lower dietary vitamin D intake but higher supplementation rates, suggesting that care providers are promoting supplementation. Women living with HIV who smoke, have low incomes and are non-white may particularly benefit from targeted efforts to improve vitamin D intake.

Stressing the need for validated measures of cortisol in HIV research: A scoping review.

OBJECTIVES: People living with HIV experience numerous endocrine abnormalities and psychosocial stressors. However, interactions between HIV, cortisol levels, and health outcomes have not been well described among people living with HIV on effective therapy. Furthermore, methods for measuring cortisol are disparate across studies. We describe the literature reporting cortisol levels in people living with HIV, describe methods to measure cortisol, and explore how this relates to health outcomes. METHODS: We searched the PubMed database for articles published in the past 20 years regarding HIV and cortisol with ≥50% of participants on antiretroviral therapies. Articles included observational, case-control, cross-sectional, and randomized controlled trials analyzing cortisol by any method. Studies were excluded if abnormal cortisol was due to medications or other infections. Variables were extracted from selected studies and their quality was assessed using the Newcastle-Ottawa Scale. RESULTS: In total, 19 articles were selected and included, covering the prevalence of abnormal cortisol (n = 4), exercise (n = 4), metabolic syndrome and/or cardiovascular disease (n = 2), mental health and cognition (n = 9), and sex/gender (n = 6). Cortisol was measured in serum (n = 7), saliva (n = 8), urine (n = 2), and hair (n = 3) specimens. Comparisons between people with and without HIV were inconsistent, with some evidence that people with HIV have increased rates of hypocortisolism. Depression and cognitive decline may be associated with cortisol excess, whereas anxiety and metabolic disease may be related to low cortisol; more data are needed to confirm these relationships. CONCLUSIONS: Data on cortisol levels in the era of antiretroviral therapy remain sparse. Future studies should include controls without HIV, appropriately timed sample collection, and consideration of sex/gender and psychosocial factors.

The role of primary care Nurse Practitioners in reducing barriers to cervical cancer screening: A literature review.

Nearly all cases of cervical cancer (CC) are caused by persistent infection by human papillomavirus (HPV). CC remains the second most prevalent carcinoma among women and, in 2017, Canada's screening rates were off target by 19%. For example, screening rates as low as 57.6% were observed in low-income neighbourhoods in Ontario, compared to 70% in highest-income neighbourhoods. Complex, multifactorial barriers affect women's participation in cervical cancer screening (CCS). The most common barriers to screening are directly linked to disparities within determinants of health, including belonging to a minority ethnic group, low socioeconomic status, lack of education, and lack of access to healthcare. Nurse Practitioners (NPs) can reduce these barriers by providing innovative, evidence-based, culturally competent women-friendly care while building trusting relationships with patients and, thus, play a greater role in preventing the disease. The objective of this literature review is to summarize barriers to CCS and the role Canadian NPs can have in reducing them.

Demographic, health, and economic transitions and the future care burden.

The COVID-19 pandemic has caused millions of infections and deaths worldwide, forced schools to suspend classes, workers to work from home, many to lose their livelihoods, and countless businesses to close. Throughout this crisis, families have had to protect, comfort and care for their children, their elderly and other members. While the pandemic has greatly intensified family care responsibilities for families, unpaid care work has been a primary activity of families even in normal times. This paper estimates the future global need for caregiving, and the burden of that need that typically falls on families, especially women. It takes into account projected demographic shifts, health transitions, and economic changes in order to obtain an aggregate picture of the care need relative to the potential supply of caregiving in low-, middle- and high-income countries. This extensive margin of the future care burden, however, does not capture the weight of that burden unless the quantity and quality of care time per caregiver are taken into account. Adjusting for care time given per caregiver, the paper incorporates data from time-use surveys, illustrating this intensive margin of the care burden in three countries that have very different family and economic contexts-Ghana, Mongolia, and South Korea. Time-use surveys typically do not provide time data for paid care services, so the estimates depend only on the time intensity of family care. With this caveat, the paper estimates that the care need in 2030 would require the equivalent of one-fifth to two-fifths of the paid labor force, assuming 40 weekly workhours. Using the projected 2030 mean wage for care and social service workers to estimate the hypothetical wage bill for these unpaid caregivers if they were paid, we obtain a value equivalent to 16 to 32 percent of GDP in the three countries.

The Efficacy of Plasma Rich in Growth Factors for the Treatment of Alveolar Osteitis: A Randomized Controlled Trial.

PURPOSE: To investigate the efficacy of plasma rich in growth factors (PRGF; BTI Biotechnology Institute, San Antonio, Spain) for the treatment of alveolar osteitis compared with a positive control (Alvogyl; Septodont, Maidstone, Kent, UK). MATERIALS AND METHODS: This single-center, single-blinded, randomized, 2-treatment, parallel study was conducted in a UK dental hospital. All healthy adults who presented with alveolar osteitis after tooth extraction over a 3-month period were invited to participate. Each socket was randomized and treated with 1 of 2 treatment modalities, a test treatment (PRGF) or a positive control (Alvogyl). After treatment, patients were reviewed at 3 and 7 days by a second clinician blinded to the treatment given. Outcome measures included pain, exposed bone, inflammation, halitosis, dysgeusia, and quality-of-life assessment. RESULTS: Thirty-eight patients with data from 44 sockets (22 in the PRGF group and 22 in the Alvogyl group) were analyzed. The PRGF group showed significantly faster bone coverage and significantly decreased inflammation and halitosis (P < .05) compared with the control group receiving Alvogyl. There was no significant difference for pain, quality-of-life measures, or dysgeusia between groups. CONCLUSION: PRGF predictably treated alveolar osteitis after tooth extraction compared with the conventional standard treatment of Alvogyl, which has been used for many years. PRGF could be considered an alternative treatment for alveolar osteitis and indeed appears to have considerable advantages over Alvogyl.

DUSP1 Maintains IRF1 and Leads to Increased Expression of IRF1-dependent Genes: A MECHANISM PROMOTING GLUCOCORTICOID INSENSITIVITY.

Although the mitogen-activated protein kinase (MAPK) phosphatase, DUSP1, mediates dexamethasone-induced repression of MAPKs, 14 of 46 interleukin-1ß (IL1B)-induced mRNAs were significantly enhanced by DUSP1 overexpression in pulmonary A549 cells. These include the interferon regulatory factor, IRF1, and the chemokine, CXCL10. Of these, DUSP1-enhanced mRNAs, 10 including CXCL10, were IRF1-dependent. MAPK inhibitors and DUSP1 overexpression prolonged IRF1 expression by elevating transcription and increasing IRF1 mRNA and protein stability. Conversely, DUSP1 silencing increased IL1B-induced MAPK phosphorylation while significantly reducing IRF1 protein expression at 4 h. This confirms a regulatory network whereby DUSP1 switches off MAPKs to maintain IRF1 expression. There was no repression of IRF1 expression by dexamethasone in primary human bronchial epithelial cells, and in A549 cells IL1B-induced IRF1 protein was only modestly and transiently repressed. Although dexamethasone did not repress IL1B-induced IRF1 protein expression at 4-6 h, silencing of IL1B plus dexamethasone-induced DUSP1 significantly reduced IRF1 expression. IL1B-induced expression of CXCL10 was largely insensitive to dexamethasone, whereas other DUSP1-enhanced, IRF1-dependent mRNAs showed various degrees of repression. With IL1B plus dexamethasone, CXCL10 expression was also IRF1-dependent, and expression was reduced by DUSP1 silencing. Thus, IL1B plus dexamethasone-induced DUSP1 maintains expression of IRF1 and the IRF1-dependent gene, CXCL10. This is supported by chromatin immunoprecipitation showing IRF1 recruitment to be essentially unaffected by dexamethasone at the CXCL10 promoter or at the promoters of more highly repressed IRF1-dependent genes. Since IRF1-dependent genes, such as CXCL10, are central to host defense, these data may help explain the reduced effectiveness of glucocorticoids during asthma exacerbations.

Roles for the mitogen-activated protein kinase (MAPK) phosphatase, DUSP1, in feedback control of inflammatory gene expression and repression by dexamethasone.

Glucocorticoids act on the glucocorticoid receptor (NR3C1) to repress inflammatory gene expression. This is central to their anti-inflammatory effectiveness and rational improvements in therapeutic index depend on understanding the mechanism. Human pulmonary epithelial A549 cells were used to study the role of the mitogen-activated protein kinase (MAPK) phosphatase, dual-specificity phosphatase 1 (DUSP1), in the dexamethasone repression of 11 inflammatory genes induced, in a MAPK-dependent manner, by interleukin-1ß (IL1B). Adenoviral over-expression of DUSP1 inactivated MAPK pathways and reduced expression of all 11 inflammatory genes. IL1B rapidly induced DUSP1 expression and RNA silencing revealed a transient role in feedback inhibition of MAPKs and inflammatory gene expression. With dexamethasone, which induced DUSP1 expression, plus IL1B (co-treatment), DUSP1 expression was further enhanced. At 1 h, this was responsible for the dexamethasone inhibition of IL1B-induced MAPK activation and CXCL1 and CXCL2 mRNA expression, with a similar trend for CSF2. Whereas, CCL20 mRNA was not repressed by dexamethasone at 1 h, repression of CCL2, CXCL3, IL6, and IL8 was unaffected, and PTGS2 repression was partially affected by DUSP1 knockdown. At later times, dexamethasone repression of MAPKs was unaffected by DUSP1 silencing. Likewise, 6 h post-IL1B, dexamethasone repression of all 11 mRNAs was essentially unaffected by DUSP1 knockdown. Qualitatively similar data were obtained for CSF2, CXCL1, IL6, and IL8 release. Thus, despite general roles in feedback inhibition, DUSP1 plays a transient, often partial, role in the dexamethasone-dependent repression of certain inflammatory genes. Therefore this also illustrates key roles for DUSP1-independent effectors in mediating glucocorticoid-dependent repression.

ß2-Adrenoceptor agonist-induced RGS2 expression is a genomic mechanism of bronchoprotection that is enhanced by glucocorticoids.

In asthma and chronic obstructive pulmonary disease, activation of G(q)-protein-coupled receptors causes bronchoconstriction. In each case, the management of moderate-to-severe disease uses inhaled corticosteroid (glucocorticoid)/long-acting ß(2)-adrenoceptor agonist (LABA) combination therapies, which are more efficacious than either monotherapy alone. In primary human airway smooth muscle cells, glucocorticoid/LABA combinations synergistically induce the expression of regulator of G-protein signaling 2 (RGS2), a GTPase-activating protein that attenuates G(q) signaling. Functionally, RGS2 reduced intracellular free calcium flux elicited by histamine, methacholine, leukotrienes, and other spasmogens. Furthermore, protection against spasmogen-increased intracellular free calcium, following treatment for 6 h with LABA plus corticosteroid, was dependent on RGS2. Finally, Rgs2-deficient mice revealed enhanced bronchoconstriction to spasmogens and an absence of LABA-induced bronchoprotection. These data identify RGS2 gene expression as a genomic mechanism of bronchoprotection that is induced by glucocorticoids plus LABAs in human airway smooth muscle and provide a rational explanation for the clinical efficacy of inhaled corticosteroid (glucocorticoid)/LABA combinations in obstructive airways diseases.

Longitudinal Assessment of Bone Mineral Density in Women Living With and Without HIV Across Reproductive Phases.

BACKGROUND: Women living with HIV commonly experience low areal bone mineral density (BMD), but whether this is affected by low ovarian hormonal states (prolonged amenorrhea or menopause) is unknown. We compared rates of BMD loss between women living with HIV and HIV-negative control women and investigated its association with low ovarian hormonal states. SETTING: Women living with HIV were enrolled from Vancouver Canada and controls from 9 Canadian sites. METHODS: This longitudinal analysis included age-matched women living with HIV in the Children and Women: AntiRetrovirals and Markers of Aging cohort and controls in the population-based Canadian Multicentre Osteoporosis Study. Rate of change/year in BMD at the total hip and lumbar spine (L1-L4) between 3 and 5 years was compared between groups, adjusting for sociodemographic and clinical variables. RESULTS: Ninety-two women living with HIV (median [interquartile range] age: 49.5 [41.6-54.1] years and body mass index: 24.1 [20.7-30.8] kg/m 2 ) and 278 controls (age: 49.0 [43.0-55.0] years and body mass index: 25.8 [22.9-30.6] kg/m 2 ) were included. Total hip BMD loss was associated with HIV (ß: -0.003 [95% CI: -0.006 to -0.0001] g/cm 2 /yr), menopause (ß: -0.007 [-0.01 to -0.005] g/cm 2 /yr), and smoking (ß: -0.003 [-0.006 to -0.0002] g/cm 2 /yr); BMD gain was linked with higher body mass index (ß: 0.0002 [0.0007-0.0004] g/cm 2 /yr). Menopause was associated with losing L1-L4 BMD (ß: -0.01 [-0.01 to -0.006] g/cm 2 /yr). Amenorrhea was not associated with BMD loss. CONCLUSIONS: HIV and menopause negatively influenced total hip BMD. These data suggest women living with HIV require hip BMD monitoring as they age.

Restoratively driven planning for implants in the posterior maxilla - Part 2: implant planning, biomechanics and prosthodontic planning a proposed prosthodontic complexity index.

Restoratively driven implant planning in the posterior maxilla requires a comprehensive understanding of the anatomical and physiological changes of the alveolar bone following tooth extraction and sinus augmentation. As a part of restoratively driven planning, alveolar bone, inter-arch relationships, proposed crown-implant ratio and anticipated non-axial loading should be assessed pre-operatively. This helps determine the prosthodontic and surgical aspects of implant treatment, such as prosthesis design, implant number, implant angulation, implant length and the necessity for additional bone grafting procedures. However, currently no implant planning classification is restoratively driven and include these important prosthodontic considerations. Therefore, a new index - the Posterior Maxilla Prosthodontic Index - is defined to encourage restoratively driven implant planning in the posterior maxilla.

Sexual Satisfaction of Midlife Women Living With HIV in Canada: A Prospective Cohort Analysis.

BACKGROUND: Although sexual activity and function decline in older women living with HIV, positive dimensions of sexual health, such as satisfaction, are relatively unexplored. We evaluated the prevalence of sexual satisfaction for midlife women with HIV and assessed its relation to women's physical, mental, and sociostructural experiences. SETTING: We studied women in the Canadian HIV Women's Sexual and Reproductive Health Cohort Study (CHIWOS) over 3 survey waves (2013-2018). METHODS: We included women living with HIV aged ≥45 years who reported ever having consensual sex. Sexual satisfaction was assessed using an item from the Sexual Satisfaction Scale for Women and was dichotomized into satisfactory ("completely/very/reasonably satisfactory") and not satisfactory ("not very/not at all satisfactory"). Probable depression was based on CES-D ≥10. Multivariable logistic regression and fixed effects models determined correlates of sexual satisfaction. Reasons for sexual inactivity and alternate forms of sexual expression were also explored. RESULTS: Among 508 midlife women, 61% were satisfied with their sexual lives at baseline. Women with probable depression had lower odds of sexual satisfaction than those without (aOR: 0.44; 95% CI: 0.27 to 0.71) and worsening depressive symptoms over time were associated with poorer sexual satisfaction ( P = 0.001). Increased sexual activity was associated with higher sexual satisfaction (aOR: 2.75; 95% CI: 1.54 to 4.91); however, 51% of women reporting sexual satisfaction were sexually inactive. Sexually inactive women engaged in alternate forms of sexual expression such as self-pleasure (37%) and intimate relationships without sex (13%). CONCLUSION: Midlife women with HIV have high rates of sexual satisfaction, even in the absence of sexual activity. Depressive symptoms were closely associated with sexual dissatisfaction, alerting providers to the importance of screening for depression and sexual health together.

Age at Natural Menopause in Women Living with HIV: A Cross-Sectional Study Comparing Self-Reported and Biochemical Data.

Early menopause (<45 years) has significant impacts on bone, cardiovascular, and cognitive health. Several studies have suggested earlier menopause for women living with HIV; however, the current literature is limited by reliance on self-report data. We determined age at menopause in women living with HIV and socio-demographically similar HIV-negative women based on both self-report of menopause status (no menses for ≥12 months) and biochemical confirmation (defined as above plus follicle-stimulating hormone level ≥ 25 IU/mL). Multivariable median regression models assessed factors associated with menopause age, controlling for relevant confounders. Overall, 91 women living with HIV and 98 HIV-negative women were categorized as menopausal by self-report, compared to 83 and 92 by biochemical confirmation. Age at menopause did not differ significantly between groups, whether based on self-report (median [IQR]: 49.0 [45.3 to 53.0] vs. 50.0 [46.0 to 53.0] years; p = 0.28) or biochemical confirmation (50.0 [46.0 to 53.0] vs. 51.0 [46.0 to 53.0] years; p = 0.54). In the multivariable model, no HIV-related or psychosocial variables were associated with earlier age at menopause (all p > 0.05). Overall, HIV status per se was not statistically associated with an earlier age at menopause, emphasizing the importance of comparing socio-demographically similar women in reproductive health and HIV research.

Resilience and psychosocial factors linked to symptom experience during the menopause transition for women living with HIV.

OBJECTIVE: Women living with HIV (WLWH) are commonly symptomatic during perimenopause and menopause (≥1 y without menstruation), however, little is known of risks for symptoms and their timing. We analyzed these unwanted experiences to inform care. METHODS: WLWH (≥40 y) in the Canadian HIV Women's Sexual and Reproductive Health Cohort Study rated midlife experiences for seven symptoms and a symptom composite (from 0 to 21). Timing was categorized into four phases: i) perimenopause (flow in the last year), ii) 1-2 years from final menstrual period (FMP), iii) 2-5 years post-FMP; and iv) >5 years post-FMP. Resilience (standardized out of 100) was assessed based on Wagnild's Resilience Scale. Univariable/multivariable mixed effects linear regression assessed correlates of symptom intensity by composite score. RESULTS: Among 457 peri-/menopausal women mean age 54.7 (±6.6) over two time points (703 observations), 88% experienced ≥1 mild symptom; 75% were of moderate and 55% severe intensity. The most frequently reported symptoms were joint/muscle stiffness (67%), depressed mood (67%), and hot flashes (57%). After adjusting for reproductive phase, we found that women with greater resilience had fewer/lower intensity symptoms (symptom score 1.37 [2.30 to 0.44] lower; P = 0.004); those with depressive symptoms and recreational drug use (respectively) had more/higher intensity symptoms (scores 1.71 [0.61 to 2.82] [P = 0.002]; 2.89 [2.09 to 3.77] [P<0.001] higher). Symptoms were most intense in perimenopause and declined with increasing menopausal years (P = 0.03). CONCLUSIONS: WLWH experiences a high burden of midlife symptoms, decreased by resilience and most intense during perimenopause. Unwanted experiences were linked to psychosocial and behavioral factors. These data encourage HIV providers to adopt a bio-psychosocial approach to midlife management.

Brief Report: Undertreated Midlife Symptoms for Women Living With HIV Linked to Lack of Menopause Discussions With Care Providers.

BACKGROUND: Increasingly, women living with HIV are entering menopause (ie, cessation of menses for ≥1 year) and experiencing midlife symptoms. Menopausal hormone therapy (MHT) is first-line therapy for bothersome hot flashes and early menopause (ie, before age 45 years); however, its use in women living with HIV is poorly described. We conducted a cross-sectional assessment of MHT uptake and barriers to use in this group. SETTING: This study was conducted across 3 Canadian provinces from 2015 to 2017. METHODS: Perimenopausal and postmenopausal women living with HIV (35 years or older) in the Canadian HIV Women's Sexual and Reproductive Health Cohort Study who answered questions related to MHT use were included. Univariable/multivariable logistic regression evaluated factors associated with MHT use, adjusted for age and contraindications. RESULTS: Among 464 women, 47.8% (222 of 464) had a first-line indication for MHT; however, only 11.8% (55 of 464) reported ever using MHT and 5.6% (26 of 464) were current users. Only 44.8% had ever discussed menopause with their care provider despite almost all women having regular HIV care (97.8%). African/Caribbean/Black women had lower unadjusted odds of MHT treatment compared with White women [odds ratio (OR) 0.42 (0.18-0.89); P = 0.034]. Those who had discussed menopause with their care provider had higher odds of treatment [OR 3.13 (1.74-5.86); P < 0.001]. In adjusted analyses, only women having had a menopause discussion remained significantly associated with MHT use [OR 2.97 (1.62-5.61); P < 0.001]. CONCLUSION: Women living with HIV are seldom prescribed MHT despite frequent indication. MHT uptake was associated with care provider-led menopause discussions underscoring the need for care provider education on menopause management within HIV care.

Inflammatory stimuli inhibit glucocorticoid-dependent transactivation in human pulmonary epithelial cells: rescue by long-acting beta2-adrenoceptor agonists.

By repressing inflammatory gene expression, glucocorticoids are the most effective treatment for chronic inflammatory diseases such as asthma. However, in some patients with severe disease, or who smoke or suffer from chronic obstructive pulmonary disease, glucocorticoids are poorly effective. Although many investigators focus on defects in the repression of inflammatory gene expression, glucocorticoids also induce (transactivate) the expression of numerous genes to elicit anti-inflammatory effects. Using human bronchial epithelial (BEAS-2B) and pulmonary (A549) cells, we show that cytokines [tumor necrosis factor α (TNFα) and interleukin 1ß], mitogens [fetal calf serum (FCS) and phorbol ester], cigarette smoke, and a G(q)-linked G protein-coupled receptor agonist attenuate simple glucocorticoid response element (GRE)-dependent transcription. With TNFα and FCS, this effect was not overcome by increasing concentrations of dexamethasone, budesonide, or fluticasone propionate. Thus, the maximal ability of the glucocorticoid to promote GRE-dependent transcription was reduced, and this was shown additionally for the glucocorticoid-induced gene p57(KIP2). The long-acting ß(2)-adrenoceptor agonists (LABAs) formoterol fumarate and salmeterol xinafoate enhanced simple GRE-dependent transcription to a level that could not be achieved by glucocorticoid alone. In the presence of TNFα or FCS, which repressed glucocorticoid responsiveness, these LABAs restored glucocorticoid-dependent transcription to levels that were achieved by glucocorticoid alone. Given the existence of genes, such as p57(KIP2), which may mediate anti-inflammatory actions of glucocorticoids, we propose that repression of transactivation represents a mechanism for glucocorticoid resistance and for understanding the clinical benefit of LABAs as an add-on therapy in asthma and chronic obstructive pulmonary disease.

Glucocorticoids inhibit IL-1beta-induced GM-CSF expression at multiple levels: roles for the ERK pathway and repression by MKP-1.

In the present study, IL (interleukin)-1beta increased GM-CSF (granulocyte/macrophage colony-stimulating factor) expression from pulmonary A549 cells and primary HBE (human bronchial epithelial) cells. These responses were repressed by the glucocorticoid dexamethasone, allowing the use of A549 cells as a relevant model. IL-1beta induced GM-CSF release into the culture medium by 6 h and in cell lysates (cytosolic) at 2 h. These effects were profoundly inhibited by dexamethasone, yet IL-1beta-induced GM-CSF mRNA and unspliced nRNA (nuclear RNA; a surrogate of transcription rate) were modestly inhibited by dexamethasone at times up to 2 h. Although this indicates an effect on protein synthesis, actinomycin D chase experiments also indicated post-transcriptional repression by dexamethasone. Dexamethasone-dependent mRNA repression increased with time and was prevented by translational blockade. In addition, dexamethasone and the dissociated steroid RU24858 repressed GM-CSF release in an actinomycin D-sensitive manner, thereby implicating glucocorticoid-induced gene expression. At 2 h, IL-1beta-induced expression of GM-CSF protein, but not mRNA, was sensitive to the MEK [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase] inhibitors PD098059 and U0126. Although this indicates a role for the MEK/ERK pathway in GM-CSF translation, PD098059 subsequently destabilized GM-CSF mRNA. Dexamethasone and RU24858 both reduced IL-1beta-induced ERK phosphorylation and increased MKP-1 (MAPK phosphatase-1) expression. Inhibition of ERK phosphorylation was reproduced by MKP-1 overexpression and prevented by MKP-1-targeting siRNA (small interfering RNA). Since MKP-1 prevented GM-CSF expression by transcriptional, post-transcriptional and translational processes, we propose that glucocorticoids induce MKP-1 expression to reduce both MEK/ERK activation and GM-CSF protein synthesis. Thus de novo gene expression, particularly of MKP-1, is involved in the repressive effects of glucocorticoids.

Treatment Dilemmas in Disseminated Nontuberculous Mycobacterial Infections With Interferon-gamma Autoantibodies.

Disseminated Mycobacterium avium complex (dMAC) is typically seen in individuals with impaired cell-mediated immunity and is best described in those with HIV. Recently, cases have been described in otherwise healthy individuals with neutralizing antibodies to interferon-gamma (nIFNγ-autoAb), especially in patients of Southeast Asian descent. Treatment is often refractory to mycobacterial therapies, and the use of rituximab and other immunomodulatory agents has been explored. We report 3 cases of dMAC with nIFN-γ-autoAb and review the available literature on treatment strategies to provide a framework for the management of patients with refractory infections in the context of neutralizing antibodies to interferon-gamma.

Age at menopause in women living with HIV: a systematic review.

IMPORTANCE: With improved HIV care, more women living with HIV (WLWH) are aging and entering menopause. Understanding any increased risk conferred by a potentially earlier menopause transition is important for the care of these women. OBJECTIVE: There is conflicting literature regarding the association between HIV and an earlier onset of menopause. We conducted a systematic review to summarize the literature on the association between HIV and age at menopause. EVIDENCE REVIEW: A search of Ovid MEDLINE, EMBASE, and Web of Science identified 894 articles. We included cohort studies that assessed age at menopause, primary ovarian insufficiency (POI), or early menopause among WLWH and used the World Health Organization definition of menopause as ≥12 months of amenorrhea. FINDINGS: Nine studies were included and eight reported on age at menopause. Across studies, the age at menopause for WLWH fell between 46 and 50 years. Five of seven studies reported that WLWH had an earlier menopausal transition than HIV negative controls/the general population. Six studies reported on the prevalence of POI or early menopause among WLWH, with all studies demonstrating an increased prevalence of both among WLWH. CONCLUSIONS: Our systematic review summarizes the literature around HIV and age at menopause. Many studies reported a high prevalence of POI and early menopause among WLWH; a factor that may partially account for the observed lower age at menopause. As only one study included biochemical confirmation of menopause, it remains unclear whether individuals with early menopause or POI were truly menopausal or had prolonged amenorrhea due to other causes. Overall, our findings highlight the need for further investigation with studies that include an HIV negative control group and biochemical confirmation of menopause to better understand whether menopause truly is occurring earlier among WLWH.