Stochastic fate decisions of HSCs after transplantation: early contribution, symmetric expansion, and pool formation.

Hematopoietic stem cells (HSCs) are assumed to be rare, infrequently dividing, long-lived cells not involved in immediate recovery after transplantation. Here, we performed unprecedented high-density clonal tracking in nonhuman primates and found long-term persisting HSC clones to actively contribute during early neutrophil recovery, and to be the main source of blood production as early as 50 days after transplantation. Most surprisingly, we observed a rapid decline in the number of unique HSC clones, while persisting HSCs expanded, undergoing symmetric divisions to create identical siblings and formed clonal pools ex vivo as well as in vivo. In contrast to the currently assumed model of hematopoietic reconstitution, we provide evidence for contribution of HSCs in short-term recovery as well as symmetric expansion of individual clones into pools. These findings provide novel insights into HSC biology, informing the design of HSC transplantation and gene therapy studies.

Two-way pharmacodynamic modeling of drug combinations and its application to pairs of repurposed Ebola and SARS-CoV-2 agents.

Existing pharmacodynamic (PD) mathematical models for drug combinations discriminate antagonistic, additive, multiplicative, and synergistic effects, but fail to consider how concentration-dependent drug interaction effects may vary across an entire dose-response matrix. We developed a two-way pharmacodynamic (TWPD) model to capture the PD of two-drug combinations. TWPD captures interactions between upstream and downstream drugs that act on different stages of viral replication, by quantifying upstream drug efficacy and concentration-dependent effects on downstream drug pharmacodynamic parameters. We applied TWPD to previously published in vitro drug matrixes for repurposed potential anti-Ebola and anti-SARS-CoV-2 drug pairs. Depending on the drug pairing, the model recapitulated combined efficacies as or more accurately than existing models and can be used to infer efficacy at untested drug concentrations. TWPD fits the data slightly better in one direction for all drug pairs, meaning that we can tentatively infer the upstream drug. Based on its high accuracy, TWPD could be used in concert with PK models to estimate the therapeutic effects of drug pairs in vivo.

Genitourinary symptoms and sexual function in women with primary ovarian insufficiency.

OBJECTIVE: There are limited studies on urogenital symptoms in women who experience menopause before the age of 40 years due to primary ovarian insufficiency (POI) or bilateral oophorectomy (surgical POI). This study aimed to compare the urogenital symptoms, including sexuality, of women with POI to those without the condition. METHODS: This cross-sectional study conducted was in seven Latin American countries, in which postmenopausal women (with POI and non-POI) were surveyed with a general questionnaire, the Menopause Rating Scale (MRS) and the six-item Female Sexual Function Index (FSFI-6). The association of premature menopause with more urogenital symptoms and lower sexual function was evaluated with logistic regression analysis. RESULTS: Women with POI experience more urogenital symptoms (MRS urogenital score: 3.54 ± 3.16 vs. 3.15 ± 2.89, p < 0.05) and have lower sexual function (total FSFI-6 score: 13.71 ± 7.55 vs. 14.77 ± 7.57 p < 0.05) than women who experience menopause at a normal age range. There were no significant differences in symptoms when comparing women based on the type of POI (idiopathic or surgical). After adjusting for covariates, our logistic regression model determined that POI is associated with more urogenital symptoms (odds ratio [OR]: 1.38, 95% confidence interval [CI] 1.06-1.80) and lower sexual function (OR: 1.67, 95% CI 1.25-2.25). CONCLUSION: POI, whether idiopathic or secondary to bilateral oophorectomy, is associated with symptoms that affect vaginal and sexual health.

Large scale sampling of Mexican maize landraces for the presence of transgenes.

The presence and levels of transgenic maize in Mexico and the effect this could have on local landraces or closely related species such as teosinte has been the subject of several previous reports, some showing contrasting results. Cultural, social and political factors all affect maize cultivation in Mexico and although since 1998 there has been a moratorium on the commercial cultivation of transgenic maize, Mexico imports maize, mainly from the USA where transgenic cultivars are widely grown. Additionally extensive migration between rural areas in Mexico and the USA and customs of seed exchange between farmers may also play an unintentional role in the establishment of transgenic seed. A comprehensive study of all Mexican maize landraces throughout the country is not feasible, however this report presents data based on analysis of 3204 maize accessions obtained from the central region of Mexico (where permits have never been authorized for cultivation of transgenic maize) and the northern region (where for a short period authorization for experimental plots was granted). The results of the study confirm that transgenes are present in all the geographical areas sampled and were more common in germplasm obtained in the northern region. However, there was no evidence that regions where field trials had been authorized showed higher levels of transgene presence or that the morphology of seed lots harboring transgenic material was significantly modified in favor of expected transgenic phenotypes.

Cervicovaginal Tissue Residence Confers a Distinct Differentiation Program upon Memory CD8 T Cells.

Tissue-resident memory CD8 T cells (CD8 TRM) are critical for maintaining barrier immunity. CD8 TRM have been mainly studied in the skin, lung and gut, with recent studies suggesting that the signals that control tissue residence and phenotype are highly tissue dependent. We examined the T cell compartment in healthy human cervicovaginal tissue (CVT) and found that most CD8 T cells were granzyme B+ and TCF-1- To address if this phenotype is driven by CVT tissue residence, we used a mouse model to control for environmental factors. Using localized and systemic infection models, we found that CD8 TRM in the mouse CVT gradually acquired a granzyme B+, TCF-1- phenotype as seen in human CVT. In contrast to CD8 TRM in the gut, these CD8 TRM were not stably maintained regardless of the initial infection route, which led to reductions in local immunity. Our data show that residence in the CVT is sufficient to progressively shape the size and function of its CD8 TRM compartment.

Reliability of Self-Sampling for Accurate Assessment of Respiratory Virus Viral and Immunologic Kinetics.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic demonstrates the need for accurate and convenient approaches to diagnose and therapeutically monitor respiratory viral infections. We demonstrated that self-sampling with mid-nasal foam swabs is well-tolerated and provides quantitative viral output concordant with flocked swabs. Using longitudinal home-based self-sampling, we demonstrate that nasal cytokine levels correlate and cluster according to immune cell of origin. Periods of stable viral loads are followed by rapid elimination, which could be coupled with cytokine expansion and contraction. Nasal foam swab self-sampling at home provides a precise, mechanistic readout of respiratory virus shedding and local immune responses.

Association of bilateral oophorectomy and menopause hormone therapy with mild cognitive impairment: the REDLINC X study.

BACKGROUND: Dementia is a major public health problem. Estrogen is a regulator of the central nervous system and its deficit could be involved in cognitive decline in older women. OBJECTIVE: This study aimed to evaluate the association of bilateral oophorectomy, menopause hormone therapy (MHT) and other factors on mild cognitive impairment (MCI). METHOD: The case-control study included 941 otherwise healthy postmenopausal women aged 60 years and over from six Latin American countries. Personal and family data were recorded and MCI was assessed using the Montreal Cognitive Assessment test (MoCA). RESULTS: Average age, years of education and body mass index were 66.1 ± 5.8 years, 12.4 ± 5.0 years and 26.0 ± 4.3 kg/m2, respectively. A total of 30.2% had undergone bilateral oophorectomy and 40.3% had used MHT. A total of 232 women (24.7%) had MCI. The prevalence of MCI was higher in women with intact ovaries and non-MHT users as compared to MHT users (29.3% vs. 11.7% [odds ratio (OR) 0.32; 95% confidence interval (CI) 0.20-0.51]). Among oophorectomized women, MCI prevalence was higher among non-MHT users as compared to MHT users (45.2% vs. 12.8% [OR 0.18; 95% CI 0.10-0.32]). Logistic regression analysis determined that the variables associated with MCI were age >65 years (OR 1.69; 95% CI 1.20-2.38), parity (having >2 children; OR 1.69; 95% CI 1.21-2.37), bilateral oophorectomy (OR 1.56; 95% CI 1.09-2.24), hypertension (OR 1.41; 95% CI 1.01-1.96), being sexually active (OR 0.56; 95% CI 0.40-0.79), education >12 years (OR 0.46; 95% CI 0.32-0.65) and MHT use (OR 0.31; 95% CI 0.21-0.46). CONCLUSION: Age, parity, bilateral oophorectomy and hypertension are independent factors associated with MCI; contrary to this, higher educational level, maintaining sexual activity and using MHT are protective factors.

Mathematical modeling to reveal breakthrough mechanisms in the HIV Antibody Mediated Prevention (AMP) trials.

The ongoing Antibody Mediated Prevention (AMP) trials will uncover whether passive infusion of the broadly neutralizing antibody (bNAb) VRC01 can protect against HIV acquisition. Previous statistical simulations indicate these trials may be partially protective. In that case, it will be crucial to identify the mechanism of breakthrough infections. To that end, we developed a mathematical modeling framework to simulate the AMP trials and infer the breakthrough mechanisms using measurable trial outcomes. This framework combines viral dynamics with antibody pharmacokinetics and pharmacodynamics, and will be generally applicable to forthcoming bNAb prevention trials. We fit our model to human viral load data (RV217). Then, we incorporated VRC01 neutralization using serum pharmacokinetics (HVTN 104) and in vitro pharmacodynamics (LANL CATNAP database). We systematically explored trial outcomes by reducing in vivo potency and varying the distribution of sensitivity to VRC01 in circulating strains. We found trial outcomes could be used in a clinical trial regression model (CTRM) to reveal whether partially protective trials were caused by large fractions of VRC01-resistant (IC50>50 µg/mL) circulating strains or rather a global reduction in VRC01 potency against all strains. The former mechanism suggests the need to enhance neutralizing antibody breadth; the latter suggests the need to enhance VRC01 delivery and/or in vivo binding. We will apply the clinical trial regression model to data from the completed trials to help optimize future approaches for passive delivery of anti-HIV neutralizing antibodies.

Muscle health in Hispanic women. REDLINC VIII.

Objectives: This study aimed to evaluate muscle strength and related factors in Hispanic women.Methods: We studied 593 women between 40 and 89 years old. The women were asked about personal and clinical information. The following instruments were applied: dynamometer (strength), Short Physical Performance Battery (physical performance), SARC-F (sarcopenia), International Physical Activity Questionnaire (physical activity), Menopause Rating Scale (quality of life), 36-item Short Form (general health), and Frailty (Fried's criteria).Results: Low muscle strength rises from 7.1% of women in their 40s to 79.4% in their 80s. Physical performance is low in 0.5% of the first group and rises to 60.5% in the second. The risk of sarcopenia increases significantly from 6.7% in younger women to 58.1% in older women. Frailty, which affects less than 1% of women under age 60 years, increases to 39.5% in their 80s. Sedentary lifestyle rises from 26% to 68.3%. Fragility impairs the quality of life and the perception of health (p < 0.0001). The deterioration of different tests of muscle function is significantly associated with age >70 years (OR 5-20) and with osteoarthritis (OR 4-9). Menopause before the age of 45 years increases the risk of sarcopenia (odds ratio 2.2; 95% confidence interval 1.2-4.0).Conclusion: With aging there is a decrease in muscle strength and an increase in frailty. This entails a decrease in the quality of life.

Clinical and nerve conduction features in Guillain-Barré syndrome associated with Zika virus infection in Cúcuta, Colombia.

BACKGROUND AND PURPOSE: Zika virus (ZIKV) infection has been associated with an increased incidence of Guillain-Barré syndrome (GBS) but the relative frequency of acute inflammatory demyelinating polyradiculoneuropathy (AIDP) and axonal GBS subtypes is controversial. METHODS: Twenty GBS patients diagnosed according to the Brighton criteria during the ZIKV outbreak in Cúcuta, Colombia, were evaluated clinically and electrophysiologically. The electrodiagnosis of GBS subtypes was made according to a recently described criteria set that demonstrated a high diagnostic accuracy on the basis of a single test. The electrophysiological features of 34 Italian AIDP patients were used as control. RESULTS: All patients had symptoms compatible with ZIKV infection before the onset of GBS and ZIKV infection was laboratory confirmed through a plaque reduction neutralization test (PRNT90 ) in 100% of patients. The median time from onset of ZIKV infection symptoms to GBS was 5 days (interquartile range 1-6 days). Cranial nerve palsy was present in 85% of patients (facial palsy in 75%, bulbar nerve involvement in 60%), autonomic dysfunction in 85%, and 50% of patients required invasive mechanical ventilation. AIDP was diagnosed in 70% of patients. 40% of nerves of AIDP patients showed a prevalent distal demyelinating involvement but this pattern was not different from the Italian AIDP patients without ZIKV infection. CONCLUSIONS: Guillain-Barré syndrome associated with ZIKV infection in Cúcuta is characterized by a high frequency of cranial nerve involvement, autonomic dysfunction and requirement of mechanical ventilation indicating an aggressive and severe course. AIDP is the most frequent electrophysiological subtype. Demyelination is prevalent distally but this pattern is not specific for ZIKV infection.

Does the menopausal status of female gynecologists affect their prescription of menopausal hormone therapy?

OBJECTIVE: To evaluate whether menopausal status and symptoms among female gynecologists would influence their clinical behavior related to menopausal hormone therapy (MHT). METHODS: Female gynecologists of 11 Latin American countries were requested to fill out the Menopause Rating Scale and a questionnaire containing personal information and that related to MHT use. RESULTS: A total of 818 gynecologists accepted to participate (86.4%). Overall, the mean age was 45.0 ± 10.7 years, 32.2% were postmenopausal, and 17.6% worked in an academic position; 81.8% reported that they would use MHT if they have symptoms, regardless of menopausal status. Academic gynecologists favor personal MHT use at a higher rate (p = 0.04) and have a higher MHT prescription rate as compared to non-academic ones (p = 0.0001). The same trend was observed among post- as compared to premenopausal ones (p = 0.01) and among those who had hysterectomy alone as compared to those experiencing natural menopause (p = 0.002). The presence of menopausal symptoms did not influence their MHT prescription. Current use of MHT and alternative therapy was higher among post- than premenopausal gynecologists (both, p = 0.0001) and among those who had undergone hysterectomy than those experiencing natural menopause. A 38.5% perceived breast cancer as the main risk related to MHT, and a high proportion prescribed non-hormonal drugs (86.4%) or alternative therapies (84.5%). CONCLUSION: Most female gynecologists in this survey would use MHT if menopausal symptoms were present. Postmenopausal physicians use MHT and prescribe it to their symptomatic patients at a higher rate than premenopausal physicians.

Sequential antimicrobial treatment with linezolid for neurosurgical infections: efficacy, safety and cost study.

BACKGROUND: Evidence for the effectiveness of linezolid in neurosurgical infections (NSIs) is growing. The comfortable oral dosage and tolerance of linezolid opens the possibility for sequential antimicrobial treatment (SAT) in stable patients after a period of intravenous treatment. METHODS: To evaluate the efficacy and safety of SAT with oral linezolid in patients with NSI and to analyse the cost implications, an observational, non-comparative, prospective cohort study was conducted on clinically stable consecutive adult patients at the Neurosurgical Service. Following intravenous treatment, patients were discharged with SAT with oral linezolid. RESULTS: A total of 77 patients were included. The most common NSIs were: 41 surgical wound infections, 20 subdural empyemas, 18 epidural abscesses, and 16 brain abscesses. Forty-four percent of patients presented two or more concomitant NSIs. Aetiological agents commonly isolated were: Propionibacterium acnes (36 %), Staphylococcus aureus (23 %), Staphylococcus epidermidis (21 %) and Streptococcus spp. (13 %). The median duration of the SAT was 15 days (range, 3-42). The SAT was interrupted in five cases due to adverse events. The remainder of the patients were cured at the end of the SAT. A total of 1,163 days of hospitalisation were saved. An overall cost reduction of €516,188 was attributed to the SAT. Eight patients with device infections did not require removal of the device, with an additional cost reduction of €190,595. The mean cost saving per patient was €9,179. CONCLUSIONS: SAT with linezolid was safe and effective for the treatment of NSI. SAT reduces hospitalisation times, which means significant savings of health and economic resources.

Protamine/DNA/Niosome Ternary Nonviral Vectors for Gene Delivery to the Retina: The Role of Protamine.

The present study aimed to evaluate the incorporation of protamine into niosome/DNA vectors to analyze the potential application of this novel ternary formulation to deliver the pCMS-EGFP plasmid into the rat retina. Binary vectors based on niosome/DNA and ternary vectors based on protamine/DNA/niosomes were prepared and physicochemically characterized. In vitro experiments were performed in ARPE-19 cells. At 1:1:5 protamine/DNA/niosome mass ratio, the resulted ternary vectors had 150 nm size, positive charge, spherical morphology, and condensed, released, and protected the DNA against enzymatic digestion. The presence of protamine in the ternary vectors improved transfection efficiency, cell viability, and DNA condensation. After ocular administration, the EGFP expression was detected in different cell layers of the retina depending on the administration route without any sign of toxicity associated with the formulations. While subretinal administration transfected mainly photoreceptors and retinal pigment epithelial cells at the site of injection, intravitreal administration produced a more uniform distribution of the protein expression through the inner layers of the retina. The protein expression in the retina persisted for at least one month after both administrations. Our study highlights the flattering properties of protamine/DNA/niosome ternary vectors for efficient and safe gene delivery to the rat retina.

Niosomes based on synthetic cationic lipids for gene delivery: the influence of polar head-groups on the transfection efficiency in HEK-293, ARPE-19 and MSC-D1 cells.

We designed niosomes based on three lipids that differed only in the polar-head group to analyze their influence on the transfection efficiency. These lipids were characterized by small-angle X-ray scattering before being incorporated into the niosomes which were characterized in terms of pKa, size, zeta potential, morphology and physical stability. Nioplexes were obtained upon the addition of a plasmid. Different ratios (w/w) were selected to analyze the influence of this parameter on size, charge and the ability to condense, release and protect the DNA. In vitro transfection experiments were performed in HEK-293, ARPE-19 and MSC-D1 cells. Our results show that the chemical composition of the cationic head-group clearly affects the physicochemical parameters of the niosomes and especially the transfection efficiency. Only niosomes based on cationic lipids with a dimethyl amino head group (lipid 3) showed a transfection capacity when compared with their counterparts amino (lipid 1) and tripeptide head-groups (lipid 2). Regarding cell viability, we clearly observed that nioplexes based on the cationic lipid 3 had a more deleterious effect than their counterparts, especially in ARPE-19 cells at 20/1 and 30/1 ratios. Similar studies could be extended to other series of cationic lipids in order to progress in the research on safe and efficient non-viral vectors for gene delivery purposes.

Comparison of gas exchange after lung resection with a Boussignac CPAP or Venturi mask.

BACKGROUND: Postoperative continuous positive airway pressure (CPAP) can improve lung function. The aim of our study was to assess the efficacy of prophylactic CPAP on the Pa(O2)/FI(O2) ratio measured the day after surgery in patients undergoing lung resection surgery (LRS). METHODS: The study population comprised 110 patients undergoing LRS. On arrival in the postanaesthesia care unit (PACU), patients were randomized to receive CPAP at 5-7 cm H2O during the first 6 h after surgery (CPAP group) or supplemental oxygen through a Venturi mask (Venturi group). The Pa(O2)/FI(O2) ratio was measured on arrival in the PACU, 7 h after admission, and the day after surgery. The Pa(O2)/FI(O2) ratio is the primary endpoint of our study. We also analysed the chest radiograph and assessed the postoperative course. We then analysed the impact of ventilatory management in the PACU depending on the respiratory risk of the patient. RESULTS: Baseline characteristics were similar in both groups. Patients who received CPAP had significantly higher Pa(O2)/FI(O2) at 24 h after surgery compared with patients managed conventionally (Venturi group) (48.6±14 vs 42.3±12, P=0.031), but there were no differences at 7 h. On subgroup analysis, we found that the benefits of CPAP were greater in higher risk patients. The incidence of postoperative pulmonary complications and stay in the PACU and hospital were similar in both groups. CONCLUSIONS: In patients undergoing LRS, prophylactic CPAP during the first 6 h after surgery with a pressure of 5-7 cm H2O improved the Pa(O2)/FI(O2) ratio at 24 h. This effect was more evident in patients with increased risk of postoperative pulmonary complications.

A multicentric study regarding the use of hormone therapy during female mid-age (REDLINC VI).

BACKGROUND: Menopausal hormone therapy (HT) has shown benefits for women; however, associated drawbacks (i.e. risks, costs, fears) have currently determined its low use. OBJECTIVE: To determine the prevalence of current HT use among mid-aged women and describe the characteristics of those who have never used, have abandoned or are currently using HT. In addition, reasons for not using HT were analyzed. METHOD: This was a cross-sectional study that analyzed a total of 6731 otherwise healthy women (45-59 years old) of 15 cities in 11 Latin American countries. Participants were requested to fill out the Menopause Rating Scale (MRS) and a questionnaire containing sociodemographic data and items regarding the menopause and HT use. RESULTS: The prevalence of current HT use was 12.5%. Oral HT (43.7%) was the most frequently used type of HT, followed by transdermal types (17.7%). The main factors related to the current use of HT included: positive perceptions regarding HT (odds ratio (OR) 11.53, 95% confidence interval (CI) 9.41-14.13), being postmenopausal (OR 3.47, 95% CI 2.75-4.36) and having a better socioeconomic level. A total of 48.8% of surveyed women had used HT in the past, but abandoned it due to symptom improvement or being unconcerned; fear of cancer or any other secondary effects were also reported but in less than 10%. Among women who had never used HT, 28% reported the lack of medical prescription as the main reason, followed by the absence of symptoms (27.8%). Among those reporting lack of prescription as the main reason for not using HT, 30.6% currently had severe menopausal symptoms (total MRS score > 16); 19.5% of women were using alternative 'natural' therapies, with 35.1% of them displaying severe menopausal symptoms as compared to a 22.5% observed among current HT users. CONCLUSION: The use of HT has not regained the rates observed a decade ago. Positive perceptions regarding HT were related to a higher use. Lack of medical prescription was the main reason for not using HT among non-users, many of whom were currently displaying severe menopausal symptoms.

Dynamics of virological and immunological markers of HIV persistence after allogeneic haematopoietic stem-cell transplantation in the IciStem cohort: a prospective observational cohort study.

BACKGROUND: Allogeneic haematopoietic stem-cell transplantation (allo-HSCT) markedly reduces HIV reservoirs, but the mechanisms by which this occurs are only partly understood. In this study, we aimed to describe the dynamics of virological and immunological markers of HIV persistence after allo-HSCT. METHODS: In this prospective observational cohort study, we analysed the viral reservoir and serological dynamics in IciStem cohort participants with HIV who had undergone allo-HSCT and were receiving antiretroviral therapy, ten of whom had received cells from donors with the CCR5Δ32 mutation. Participants from Belgium, Canada, Germany, Italy, the Netherlands, Spain, Switzerland, and the UK were included in the cohort both prospectively and retrospectively between June 1, 2014 and April 30, 2019. In the first 6 months after allo-HSCT, participants had monthly assessments, with annual assessments thereafter, with the protocol tailored to accommodate for the individual health status of each participant. HIV reservoirs were measured in blood and tissues and HIV-specific antibodies were measured in plasma. We used the Wilcoxon signed-rank test to compare data collected before and after allo-HSCT in participants for whom longitudinal data were available. When the paired test was not possible, we used the Mann-Whitney U test. We developed a mathematical model to study the factors influencing HIV reservoir reduction in people with HIV after allo-HSCT. FINDINGS: We included 30 people with HIV with haematological malignancies who received a transplant between Sept 1, 2009 and April 30, 2019 and were enrolled within the IciStem cohort and included in this analysis. HIV reservoirs in peripheral blood were reduced immediately after full donor chimerism was achieved, generally accompanied by undetectable HIV-DNA in bone marrow, ileum, lymph nodes, and cerebrospinal fluid, regardless of donor CCR5 genotype. HIV-specific antibody levels and functionality values declined more slowly than direct HIV reservoir values, decaying significantly only months after full donor chimerism. Mathematical modelling suggests that allogeneic immunity mediated by donor cells is the main viral reservoir depletion mechanism after massive reservoir reduction during conditioning chemotherapy before allo-HSCT (half-life of latently infected replication-competent cells decreased from 44 months to 1·5 months). INTERPRETATION: Our work provides, for the first time, data on the effects of allo-HSCT in the context of HIV infection. Additionally, we raise the question of which marker can serve as the last reporter of the residual viraemia, postulating that the absence of T-cell immune responses might be a more reliable marker than antibody decline after allo-HSCT. FUNDING: amfAR (American Foundation for AIDS Research; ARCHE Program), National Institutes of Health, National Institute of Allergy and Infectious Diseases, and Dutch Aidsfonds.

Type II diabetes mellitus and menopause: a multinational study.

BACKGROUND: Type II diabetes mellitus causes metabolic changes that may lead to early menopause and worsen climacteric symptoms. OBJECTIVES: To determine the risk factors for type II diabetes mellitus and assess the impact of this disease on the age of menopause and on climacteric symptoms. METHODS: A total of 6079 women aged between 40 and 59 years from 11 Latin American countries were requested to answer the Menopause Rating Scale and Goldberg Anxiety-Depression Scale. RESULTS: The prevalence of diabetes was 6.7%. Diabetes mellitus was associated with arterial hypertension (odds ratio (OR) 4.49; 95% confidence interval (CI) 3.47-5.31), the use of psychotropic drugs (OR 1.54; 95% CI 1.22-1.94), hormonal therapy (OR 1.46; 95% CI 1.11-1.92), ≥ 50 years of age (OR 1.48; 95% CI 1.17-1.86), overweight or obese (OR 1.47; 95% CI 1.15-1.89), and waist circumference ≥ 88 cm (OR 1.32; 95% CI 1.06-1.65). Factors associated with lower risk of diabetes were the use of hormonal contraceptives (OR 0.55; 95% CI 0.35-0.87), alcohol (OR 0.73; 95% CI 0.54-0.98) and living in cities > 2500 meters above sea level (OR 0.70; 95% CI 0.53-0.91) or with high temperatures (OR 0.67; 95% CI 0.51-0.88). In turn, diabetes tripled the risk of menopause in women under 45 years of age. Diabetes did not increase the risk of deterioration of quality of life due to climacteric symptoms. CONCLUSION: Menopause does not increase the risk of type II diabetes mellitus. Diabetes is associated with early menopause in women under 45 years of age.

Hepatitis delta virus RNA decline post-inoculation in human NTCP transgenic mice is biphasic.

Chronic infection with hepatitis B and delta viruses (HDV) is the most serious form of viral hepatitis due to more severe manifestations of an accelerated progression to liver fibrosis, cirrhosis, and hepatocellular carcinoma. We characterized early HDV kinetics post-inoculation and incorporated mathematical modeling to provide insights into host-HDV dynamics. We analyzed HDV RNA serum viremia in 192 immunocompetent (C57BL/6) and immunodeficient (NRG) mice that did or did not transgenically express the HDV receptor-human sodium taurocholate co-transporting polypeptide (hNTCP). Kinetic analysis indicates an unanticipated biphasic decline consisting of a sharp first-phase and slower second-phase decline regardless of immunocompetence. HDV decline after re-inoculation again followed a biphasic decline; however, a steeper second-phase HDV decline was observed in NRG-hNTCP mice compared to NRG mice. HDV-entry inhibitor bulevirtide administration and HDV re-inoculation indicated that viral entry and receptor saturation are not major contributors to clearance, respectively. The biphasic kinetics can be mathematically modeled by assuming the existence of a non-specific-binding compartment with a constant on/off-rate and the steeper second-phase decline by a loss of bound virus that cannot be returned as free virus to circulation. The model predicts that free HDV is cleared with a half-life of 35 minutes (standard error, SE: 6.3), binds to non-specific cells with a rate of 0.05 per hour (SE: 0.01), and returns as free virus with a rate of 0.11 per hour (SE: 0.02). Characterizing early HDV-host kinetics elucidates how quickly HDV is either cleared or bound depending on the immunological background and hNTCP presence. IMPORTANCE The persistence phase of HDV infection has been studied in some animal models; however, the early kinetics of HDV in vivo is incompletely understood. In this study, we characterize an unexpectedly HDV biphasic decline post-inoculation in immunocompetent and immunodeficient mouse models and use mathematical modeling to provide insights into HDV-host dynamics.

Hepatitis delta virus RNA decline post inoculation in human NTCP transgenic mice is biphasic.

Background and Aims: Chronic infection with hepatitis B and hepatitis delta viruses (HDV) is considered the most serious form of viral hepatitis due to more severe manifestations of and accelerated progression to liver fibrosis, cirrhosis, and hepatocellular carcinoma. There is no FDA-approved treatment for HDV and current interferon-alpha treatment is suboptimal. We characterized early HDV kinetics post inoculation and incorporated mathematical modeling to provide insights into host-HDV dynamics. Methods: We analyzed HDV RNA serum viremia in 192 immunocompetent (C57BL/6) and immunodeficient (NRG) mice that did or did not transgenically express the HDV receptor - human sodium taurocholate co-transporting peptide (hNTCP). Results: Kinetic analysis indicates an unanticipated biphasic decline consisting of a sharp first-phase and slower second-phase decline regardless of immunocompetence. HDV decline after re-inoculation again followed a biphasic decline; however, a steeper second-phase HDV decline was observed in NRG-hNTCP mice compared to NRG mice. HDV-entry inhibitor bulevirtide administration and HDV re-inoculation indicated that viral entry and receptor saturation are not major contributors to clearance, respectively. The biphasic kinetics can be mathematically modeled by assuming the existence of a non-specific binding compartment with a constant on/off-rate and the steeper second-phase decline by a loss of bound virus that cannot be returned as free virus to circulation. The model predicts that free HDV is cleared with a half-life of 18 minutes (standard error, SE: 2.4), binds to non-specific cells with a rate of 0.06 hour -1 (SE: 0.03), and returns as free virus with a rate of 0.23 hour -1 (SE: 0.03). Conclusions: Understanding early HDV-host kinetics will inform pre-clinical therapeutic kinetic studies on how the efficacy of anti-HDV therapeutics can be affected by early kinetics of viral decline. LAY SUMMARY: The persistence phase of HDV infection has been studied in some animal models, however, the early kinetics of HDV in vivo is incompletely understood. In this study, we characterize an unexpectedly HDV biphasic decline post inoculation in immunocompetent and immunodeficient mouse models and use mathematical modeling to provide insights into HDV-host dynamics. Understanding the kinetics of viral clearance in the blood can aid pre-clinical development and testing models for anti-HDV therapeutics.