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IntroductionThe evolution of contraception has been crucial for public health and reproductive well-being. Over the past 60 years, combined oral contraceptives (COCs) have remained an important part of the contraceptive landscape worldwide; continued development has worked toward maintaining efficacy and improving safety.MethodsSeven global experts convened to discuss the clinical relevance of the oestrogen in COCs, focusing on the impact of the new oestrogen, oestetrol (E4). Participants then commented through an online forum on the summary content and other participants' feedback. We prepared this report to describe the experts' views, their follow-up from the open forum and the evidence supporting their views.ResultsEthinylestradiol (EE) and oestradiol (E2) affect receptors similarly whereas E4 has differential effects, especially in the liver and breast. Adequate oestrogen doses in COCs ensure regular bleeding and user acceptability. EE and E4 have longer half-lives than E2; accordingly, COCs with EE and E4 offer more predictable bleeding than those with E2. Oestrogen type and progestin influence VTE risk; E2 poses a lower risk than EE; although promising, E4/DRSP VTE risk is lacking population-based data. COCs alleviate menstrual symptoms, impact mental health, cognition, libido, skin, and bone health.ConclusionOestrogens play an important role in the contraceptive efficacy, bleeding patterns, and overall tolerability/safety of COCs. Recent studies exploring E4 combined with DRSP show promising results compared to traditional formulations, but more definitive conclusions await further research.

Ethinylestradiol and drospirenone combined oral contraceptive formulations have been marketed for >20 years. Drospirenone has antimineralocorticoid and anti-androgenic effects that may offer several health benefits. Recently, 2 new drospirenone-containing oral contraceptives entered the market, 1 as a progestin-only pill containing 4 mg drospirenone and the other as a combined oral contraceptive containing 15 mg estetrol and 3 mg drospirenone. Estetrol has a unique differential effect on nuclear and membrane estrogen α-receptors when compared with other estrogens, leading to low impact on the liver, breast, and hemostasis parameters and a beneficial effect on the endometrium, vagina, cardiovascular system, bone, and brain. Phase 3 clinical studies demonstrated that the Pearl Index (pregnancies per 100-woman-years) for drospirenone alone is 4.0 in the United States and 0.93 in the European Union and for the estetrol-drospirenone combination it is 2.65 and 0.44, respectively. Drospirenone alone demonstrates high rates of unscheduled bleeding and low rates of scheduled bleeding, whereas the estetrol-drospirenone combination demonstrates a predictable and regular bleeding profile for most users with a high stable rate of scheduled bleeding and a low rate of unscheduled bleeding, reported primarily as spotting only. The adverse event profiles and discontinuation rates owing to adverse events are comparable, and no clinically significant effects were observed on metabolic parameters with either product. Hemostatic assays for drospirenone do not fully evaluate all parameters although the testing that is available suggests negligible effects, whereas validated hemostatic assays demonstrate that the estetrol-drospirenone combination has limited impact on hemostasis. The introduction of 4 mg drospirenone and 15 mg estetrol with 3 mg drospirenone are valuable additions to the contraceptive market. Adding estetrol to 3 mg drospirenone provides advantages of contraceptive efficacy and a regular, predictable bleeding profile with minimal impact on hemostasis parameters.

This research article investigates the relationship between inflation and the performance of the financial sector within OECD countries, a group critical to global economic stability. The financial sector is a basis of sustainable economic growth, and its performance is heavily influenced by the macroeconomic environment, particularly inflation. This study analyses how inflation, alongside other significant factors such as real GDP growth, government size, trade openness, and interest rates, impacts the financial sector development. By examining data from 38 OECD countries over a 20-year period (2002-2021), this research employs a comprehensive approach using both static and dynamic panel regression models. The results consistently indicate a negative correlation between inflation and the key financial sector variables, suggesting that higher inflation levels undermine financial sector performance. These findings underscore the importance of maintaining low and stable inflation to foster an efficient and stable financial sector. This study makes a valuable contribution to the literature by focusing specifically on OECD countries, which are often seen as benchmarks for economic policies and financial systems.

Soybean is a broadly popular and extensively cultivated crop, however, many high-yield and high-quality varieties require specific growth conditions, restricting their widespread adoption. The appropriate light conditions and photoperiod must be attained for these varieties to thrive in new environments. In this study, we employed CRISPR/Cas9 to design two sgRNAs aimed at knocking out the maturity-related gene E4 in a major American soybean variety called ''Jack'', which belongs to maturity group MGII. E4 gene is primarily involved in the photoperiodic flowering and maturity in soybean, making it an ideal candidate for genetic manipulation. We successfully obtained 1 homozygous E4-SG1 mutant type with 1-bp insertion, and 4 homozygous E4-SG2 mutants type with 2-bp deletion, 7-bp deletion, 61-bp deletion, and 1-bp insertion, respectively. The homozygous e4 mutant plants contained early termination codons devoid of transgenic elements. Additionally, no potential off-target sites of the E4 gene were detected. A comparative analysis revealed that, unlike the wild-type, the maturity time of homozygous e4 mutants was early under both short-day and long-day conditions. These mutants offer novel germplasm resources that may be used to modify the photoperiod sensitivity and maturity of soybean, enhancing its adaptability to high-latitude regions.

Several policymakers and academic works have been discussing the nature of Central Bank Digital Currency (CBDC) as well as its debated relationship with crypto-assets. CBDC would allow the private (non-financial) sector to access the central bank’s reserves. Given its superior hierarchy in the money spectrum, CBDC adoption could trigger a strong or mild conversion from deposits, depending on its design, with strong impacts on the assets and liabilities composition and magnitude of different actors. The aim of this paper is to study the dynamics related to the transmigration process from deposits to CBDC as well as the process of money creation through a detailed step-by-step analysis, tracking the transactions between the institutions involved in its adoption. It underlines the validity of the endogenous money theory (EMT) in describing those transactions while clarifying the maintenance of the commercial banks’ vital role in the process of money creation, in a world with the emergence of CBDC. [ABSTRACT FROM AUTHOR]

ObjectiveTo evaluate overall and subgroup efficacy of an estetrol (E4) 15 mg drospirenone (DRSP) 3 mg oral contraceptive in a 24/4-day regimen.Study designWe pooled efficacy outcomes from 2 pivotal phase 3 contraceptive trials with E4/DRSP conducted in the United States/Canada and Europe/Russia. We assessed Pearl Index (PI; pregnancies per 100 participant-years) and 13-cycle life-table pregnancy rates in at-risk cycles (confirmed intercourse and no other contraceptive use) among participants 16 to 35 years. We calculated PI by age and further subcategorization (contraceptive history and body mass index [BMI]). We performed multivariable analysis using Cox regression to assess impact of potential confounding factors.ResultsAnalyses included 3027 participants, of whom 451 (14.9%) had a BMI ≥30 kg/m2. The pooled PI was 1.52 (95% confidence interval 1.04-2.16) and the 13-cycle life-table pregnancy rate was 1.28% (0.83%-1.73%). We calculated unadjusted pooled PI in participants 16 to 25 years and 26 to 35 years of 1.61 (0.94-2.57) and 1.43 (0.78-2.40), respectively; in new starters and switchers of 1.88 (1.09-3.00) and 1.24 (0.68-2.08), respectively; and by BMI

ObjectivesTo evaluate tolerability and safety of estetrol (E4) 15 mg/drospirenone (DRSP) 3 mg oral contraceptive using pooled data from two, multicenter, phase 3 trials.Study designThe two trials enrolled participants aged 16-50 years with a body mass index ≤35.0 kg/m2 to use E4/DRSP in a 24/4-day regimen for up to 13 cycles. We pooled data from participants who used at least one E4/DRSP dose and had a follow-up assessment to analyze adverse events (AEs), vital signs, and laboratory parameters, including serum lipids, glucose, glycated hemoglobin, and potassium. We consolidated similar Medical Dictionary for Regulatory Activities preferred terms into groupings.ResultsOf 3725 participants enrolled, we included 3417 in the analyses of whom 1786 (52.3%) reported ≥1 AE. Most participants with reported AEs had AEs that investigators rated as mild or moderate (n = 1665, 93.2%); of participants reporting AEs, 1105 (61.9%) did so during cycles 1 to 3. In total, 981 (28.7%) participants experienced ≥1 treatment-related AE, most frequently related to bleeding complaints (n = 323, 9.5%), breast pain or tenderness (n = 136, 4.0%), acne (n = 113, 3.3%), and mood disturbance (n = 111, 3.2%). Discontinuation due to treatment-related AEs occurred in 272 participants (8.0%), with only bleeding complaints (n = 97, 2.8%) and mood disturbance (n = 38, 1.1%) at rates exceeding 1%. Three participants experienced serious AEs, which the site investigators considered treatment-related: one venous thromboembolism, one worsening of depression, and one ectopic pregnancy. We found no clinically relevant changes in weight, blood pressure, heart rate, or laboratory parameters during treatment.ConclusionsE4/DRSP is associated with a favorable tolerability and safety profile.Implications statementPooling data allowed for a robust assessment of tolerability and safety, including relatively infrequent events. Other than bleeding complaints and mood disturbance, no adverse event resulted in E4/DRSP discontinuation at rates >1%. Post-marketing surveillance studies are needed to evaluate long-term safety of the E4/DRSP COC and population-based venous thromboembolism risks.

The paper examines different real-monetary dynamics and policy responses during the COVID-19 pandemic (C19P) and the Global Financial Crisis (GFC) in the United States through the lens of the Sraffian Supermultiplier model and the endogenous money approach. On the one hand, the C19P triggered a relatively deeper contraction in GDP, but its recovery was relatively faster and more robust. The ‘V’ shaped recovery from the C19P significantly contrasted the ‘L’ shaped trajectory of the post-GFC period. On the other hand, the money supply (M2) grew relatively more, and the monetary base expanded relatively less during the C19P. To explain these different real-monetary dynamics, a theoretical framework is developed and analyzed empirically for the United States. The theoretical model and the empirical analysis suggest that money supply is endogenously determined by creditworthy demand derived from the multiplier-accelerator effect of non-capacity generating autonomous demand, in which government spending plays a key role. Therefore, the absence of full hysteresis after the C19P shock had nothing to do with a traditional neoclassical trend reversal mechanism but with the fiscal supermultiplier effect of the extraordinary pandemic-related government spending. [ABSTRACT FROM AUTHOR]

Banks play an essential role in the economy, therefore, their performance must be maintained. Compared to other business sectors, the banking sector has continually achieved the greatest market shares over several periods. When a bank becomes more efficient, it can raise its income and market prices as well as investor confidence. This study examines various factors that influence operational efficiency and the implication for market prices. In 2016 – 2021 years, 28 banking companies were sampled from all banking companies listed on the Indonesia Stock Exchange. Purposive sampling was used for data collection, and linear multiple regression was used for data processing by running tests such as descriptive statistics, determination, regression equations, hypotheses, and implications. The findings reveal a statistically significant relationship between a firm’s size, capital adequacy, loan-to-deposit ratio, net interest, and inflation with operational efficiency, while non-performing loans and exchange rates have no a substantial impact. Additionally, capital adequacy, loan-to-deposit ratio, inflation, and exchange rates had statistically significant effects on market prices, although operational efficiency, non-performing loans, and net interest did not. The mediating analysis reveals that there is no interaction between non-performing loans and net interest with market prices, but it is a mediator for other variables. The research is important for a variety of stakeholders, including managers, investors, and policymakers, who are interested in resolving banking business operations, increasing financial performance, and preserving market prices by establishing mitigation strategies related to specific-internal and external factors.

Polyomaviruses are widely distributed viruses of birds that may induce developmental deformities and internal organ disorders primarily in nestlings. In this study, polyomavirus sequence was detected in kidney and liver samples of a common kestrel (Falco tinnunculus) that succumbed at a rescue station in Hungary. The amplified 5025 nucleotide (nt) long genome contained the early (large and small T antigen, LTA and STA) and late (viral proteins, VP1, VP2, VP3) open reading frames (ORFs) typical for polyomaviruses. One of the additional putative ORFs (named VP4) showed identical localization with the VP4 and ORF-X of gammapolyomaviruses, but putative splicing sites could not be found in its sequence. Interestingly, the predicted 123 amino acid (aa) long protein sequence showed the highest similarity with human papillomavirus E4 early proteins in respect of the aa distribution and motif arrangement implying similar functions. The LTA of the kestrel polyomavirus shared <59.2% nt and aa pairwise identity with the LTA sequence of other polyomaviruses and formed a separated branch in the phylogenetic tree among gammapolyomaviruses. Accordingly, the kestrel polyomavirus may be the first member of a novel species within the Gammapolyomavirus genus, tentatively named Gammapolyomavirus faltin. [ABSTRACT FROM AUTHOR]

IntroductionThe evolution of contraception has been crucial for public health and reproductive well-being. Over the past 60 years, combined oral contraceptives (COCs) have remained an important part of the contraceptive landscape worldwide; continued development has worked toward maintaining efficacy and improving safety.MethodsSeven global experts convened to discuss the clinical relevance of the oestrogen in COCs, focusing on the impact of the new oestrogen, oestetrol (E4). Participants then commented through an online forum on the summary content and other participants' feedback. We prepared this report to describe the experts' views, their follow-up from the open forum and the evidence supporting their views.ResultsEthinylestradiol (EE) and oestradiol (E2) affect receptors similarly whereas E4 has differential effects, especially in the liver and breast. Adequate oestrogen doses in COCs ensure regular bleeding and user acceptability. EE and E4 have longer half-lives than E2; accordingly, COCs with EE and E4 offer more predictable bleeding than those with E2. Oestrogen type and progestin influence VTE risk; E2 poses a lower risk than EE; although promising, E4/DRSP VTE risk is lacking population-based data. COCs alleviate menstrual symptoms, impact mental health, cognition, libido, skin, and bone health.ConclusionOestrogens play an important role in the contraceptive efficacy, bleeding patterns, and overall tolerability/safety of COCs. Recent studies exploring E4 combined with DRSP show promising results compared to traditional formulations, but more definitive conclusions await further research.

IntroductionEstrogens used in women's healthcare have been associated with increased risks of venous thromboembolism (VTE) and breast cancer. Estetrol (E4), an estrogen produced by the human fetal liver, has recently been approved for the first time as a new estrogenic component of a novel combined oral contraceptive (E4/drospirenone [DRSP]) for over a decade. In phase 3 studies, E4/DRSP showed good contraceptive efficacy, a predictable bleeding pattern, and a favorable safety and tolerability profile.Areas coveredThis narrative review discusses E4's pharmacological characteristics, mode of action, and the results of preclinical and clinical studies for contraception, as well as for menopause and oncology.Expert opinionExtensive studies have elucidated the properties of E4 that underlie its favorable safety profile. While classical estrogens (such as estradiol) exert their actions via both activation of nuclear and membrane estrogen receptor α (ERα), E4 presents a specific profile of ERα activation: E4 binds and activates nuclear ERα but does not induce the activation of membrane ERα signaling pathways in specific tissues. E4 has a small effect on normal breast tissue proliferation and minimally affects hepatic parameters. This distinct profile of ERα activation, uncoupling nuclear and membrane activation, is unique.

The adoption of inflation-targeting regimes has led central banks to devote considerable efforts to improve their transparency. Following this trend, several authors have developed tools to measure and compare the levels of transparency of central banks. This paper undertakes this task for the Central Bank of Uruguay by applying two different transparency indexes. The first one was designed in the mid-2000s and has been applied in a sample with a significant number of countries. The second index is based on a new approach that seeks to reflect the best practices of the most advanced inflation-forecast-targeting regimes.

AbstractThe paper examined the interest rate operations and processes in Nigeria and examined the role of financial development in incentivizing central bank monetary policies from the monetary policy rate to the money market rates, lending rates, and deposit rates. The analysis covered the period from 1981 to 2021 with sub-samples for 1981 to 2011 and 1991 to 2021 to test the consistency of the findings. The findings confirmed that interest rate pass-through is incomplete for Nigeria, albeit to a lower degree in the short run compared to the long run. The reasons for this may be due to interest rate stickiness, problems of asymmetric information, and bank switching costs. Also, the findings confirmed that financial development weakens the impact of monetary policy on the interest rate pass-through process, while the analysis of the asymmetric mean adjustment lags confirmed that changes in the policy rate are transmitted to the deposit and lending rates within the year it was announced. The analysis confirmed that the results across each sub-sample and the robustness tests are consistent with the main analysis. Therefore, it is imperative that policymakers should account for financial development when designing monetary policy effectiveness since it can hinder or strengthen the interest rate monetary policy channel.

Ethinylestradiol and drospirenone combined oral contraceptive formulations have been marketed for >20 years. Drospirenone has antimineralocorticoid and anti-androgenic effects that may offer several health benefits. Recently, 2 new drospirenone-containing oral contraceptives entered the market, 1 as a progestin-only pill containing 4 mg drospirenone and the other as a combined oral contraceptive containing 15 mg estetrol and 3 mg drospirenone. Estetrol has a unique differential effect on nuclear and membrane estrogen α-receptors when compared with other estrogens, leading to low impact on the liver, breast, and hemostasis parameters and a beneficial effect on the endometrium, vagina, cardiovascular system, bone, and brain. Phase 3 clinical studies demonstrated that the Pearl Index (pregnancies per 100-woman-years) for drospirenone alone is 4.0 in the United States and 0.93 in the European Union and for the estetrol-drospirenone combination it is 2.65 and 0.44, respectively. Drospirenone alone demonstrates high rates of unscheduled bleeding and low rates of scheduled bleeding, whereas the estetrol-drospirenone combination demonstrates a predictable and regular bleeding profile for most users with a high stable rate of scheduled bleeding and a low rate of unscheduled bleeding, reported primarily as spotting only. The adverse event profiles and discontinuation rates owing to adverse events are comparable, and no clinically significant effects were observed on metabolic parameters with either product. Hemostatic assays for drospirenone do not fully evaluate all parameters although the testing that is available suggests negligible effects, whereas validated hemostatic assays demonstrate that the estetrol-drospirenone combination has limited impact on hemostasis. The introduction of 4 mg drospirenone and 15 mg estetrol with 3 mg drospirenone are valuable additions to the contraceptive market. Adding estetrol to 3 mg drospirenone provides advantages of contraceptive efficacy and a regular, predictable bleeding profile with minimal impact on hemostasis parameters.

Epidemiological data suggest that the severe acute respiratory syndrome coronavirus 2 infection rate is higher in women than in men, but the death rate is lower, while women (>50 years) on menopausal hormone therapy (MHT) have a higher survival rate than those not on MHT. Classical oral estrogen enhances the synthesis of coagulation markers and may increase the risk of thromboembolic events that are common in coronavirus disease 2019 (COVID-19). The favorable hemostatic profile of estetrol (E4) might be suitable for use in women who are receiving estrogen treatment and contract COVID-19. A multicenter, randomized, double-blind, placebo-controlled, phase 2 study (NCT04801836) investigated the efficacy, safety, and tolerability of E4 versus placebo in hospitalized patients with moderate COVID-19. Eligible postmenopausal women and men (aged ≥ 18 years old) were randomized to E4 15 mg or placebo, once daily for 21 days, in addition to the standard of care (SoC). The primary efficacy endpoint of improvement in COVID-19 (percentage of patients recovered at day 28) between the placebo and E4 arms was not met. E4 was well tolerated, with no safety signals or thromboembolic events, suggesting that postmenopausal women can safely continue E4-based therapy in cases of moderate COVID-19 managed with SoC. [ABSTRACT FROM AUTHOR]

Abstract Background APOE variants are strongly associated with abnormal amyloid aggregation and additional direct effects of APOE on tau aggregation are reported in animal and human cell models. The degree to which these effects are present in humans when individuals are clinically unimpaired (CU) but have abnormal amyloid (Aβ+) remains unclear. Methods We analyzed data from CU individuals in the Anti-Amyloid Treatment in Asymptomatic AD (A4) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies. Amyloid PET data were available for 4486 participants (3163 Aβ-, 1323 Aβ+) and tau PET data were available for a subset of 447 participants (55 Aβ-, 392 Aβ+). Linear models examined APOE (number of e2 and e4 alleles) associations with global amyloid and regional tau burden in medial temporal lobe (entorhinal, amygdala) and early neocortical regions (inferior temporal, inferior parietal, precuneus). Consistency of APOE4 effects on regional tau were examined in 220 Aβ + CU and mild cognitive impairment (MCI) participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Results APOE2 and APOE4 were associated with lower and higher amyloid positivity rates, respectively. Among Aβ+ CU, e2 and e4 were associated with reduced (−12 centiloids per allele) and greater (+15 centiloids per allele) continuous amyloid burden, respectively. APOE2 was associated with reduced regional tau in all regions (-0.05 to -0.09 SUVR per allele), whereas APOE4 was associated with greater regional tau (+0.02 to +0.07 SUVR per allele). APOE differences were confirmed by contrasting e3/e3 with e2/e3 and e3/e4. Mediation analyses among Aβ+ s showed that direct effects of e2 on regional tau were present in medial temporal lobe and early neocortical regions, beyond an indirect pathway mediated by continuous amyloid burden. For e4, direct effects on regional tau were only significant in medial temporal lobe. The magnitude of protective e2 effects on regional tau was consistent across brain regions, whereas detrimental e4 effects were greatest in medial temporal lobe. APOE4 patterns were confirmed in Aβ+ ADNI participants. Conclusions APOE influences early regional tau PET burden, above and beyond effects related to cross-sectional amyloid PET burden. Therapeutic strategies targeting underlying mechanisms related to APOE may modify tau accumulation among Aβ+ individuals.

This article revisits the Portfolio Theory of Inflation (PTI) proposed in my original work published earlier (Bossone, B. (2019, 4 June). The portfolio theory of inflation and policy (in)effectiveness. Economics Journal, 1–25. Article No. 2019-33.), with a view to further articulate its findings and implications. The article adds to the micro- and macro-foundations of the PTI model of the economy, framing the portfolio choices of global investors more rigorously, providing richer analysis of their macroeconomic effects, and in the process also correcting errors contained in the original PTI formulation. The article explores additional dimensions of how capital allocation choices by global investors interact with government macro-policies, and further studies how such choices shape the space available to country authorities for active macro-policies. The article further evaluates the results from the revisited model on the dynamics of exchange rate, inflation, and output following macro-policy shocks, and appraises the implications of the PTI for macro-policy effectiveness when due consideration is given to stock variables, as opposed to flow variables only, in the context of highly internationally financially integrated economies. Finally, the article considers what is new about the PTI as a theory of inflation and clarifies some of its possible misinterpretations.

Over the last decade economists have debated whether a country's exchange rate regime explains how it weathered the Great Recession. As Denmark is the only OECD country with a conventional currency peg, its experience brings unique perspective to the debate. After the collapse of Lehman Brothers in the fall of 2008, the Danish central bank raised the policy rate to defend the euro peg. The spread to the euro area was not normalized until the summer of 2009. Using the synthetic control method, I ask whether Denmark performed worse during 2009-2018 than the synthetic doppelganger, where the doppelganger is made up of comparable OECD countries with flexible exchange rates. I find that Danish real GDP per capita as a percentage of doppelganger ditto has on average been around 95 % to 98 % . Results are consistent across different specifications and samples. [ABSTRACT FROM AUTHOR]

How was Romania able to borrow cheaply on the international capital markets before World War I? We explore this within the context of its three southeast European neighbours, Bulgaria, Greece and Serbia, using a novel dataset of monthly bond prices from the Berlin and London stock exchanges. A comparison of country characteristics and panel data analysis suggests that Romania was able to borrow under more favourable conditions due to its abundant natural resources and desirable exports. [ABSTRACT FROM AUTHOR]

We develop a novel, risk-based theory of the effects of exchange rate stabilization. In our model, the choice of exchange rate regime allows policymakers to make their currency, and by extension, the firms in their country, a safer investment for international investors. Policies that induce a country's currency to appreciate when the marginal utility of international investors is high lower the required rate of return on the country's currency and increase the world-market value of domestic firms. Applying this logic to exchange rate stabilizations, we find a small economy stabilizing its bilateral exchange rate relative to a larger economy can increase domestic capital accumulation, domestic wages, and even its share in world wealth. In the absence of policy coordination, small countries optimally choose to stabilize their exchange rates relative to the currency of the largest economy in the world, which endogenously emerges as the world's "anchor currency", Larger economies instead optimally choose to float their exchange rates. The model therefore predicts an equilibrium pattern of exchange rate arrangements that is remarkably similar to the one in the data. [ABSTRACT FROM AUTHOR]

ABSTRACT High-risk human papillomaviruses (PV) account for approximately 600,000 new cancers per year. The early protein E8^E2 is a conserved repressor of PV replication, whereas E4 is a late protein that arrests cells in G2 and collapses keratin filaments to facilitate virion release. While inactivation of the Mus musculus PV1 (MmuPV1) E8 start codon (E8-) increases viral gene expression, surprisingly, it prevents wart formation in FoxN1nu/nu mice. To understand this surprising phenotype, the impact of additional E8^E2 mutations was characterized in tissue culture and mice. MmuPV1 and HPV E8^E2 similarly interact with cellular NCoR/SMRT-HDAC3 co-repressor complexes. Disruption of the splice donor sequence used to generate the E8^E2 transcript or E8^E2 mutants (mt) with impaired binding to NCoR/SMRT-HDAC3 activates MmuPV1 transcription in murine keratinocytes. These MmuPV1 E8^E2 mt genomes also fail to induce warts in mice. The phenotype of E8^E2 mt genomes in undifferentiated cells resembles productive PV replication in differentiated keratinocytes. Consistent with this, E8^E2 mt genomes induced aberrant E4 expression in undifferentiated keratinocytes. In line with observations for HPV, MmuPV1 E4-positive cells displayed a shift to the G2 phase of the cell cycle. In summary, we propose that in order to enable both expansion of infected cells and wart formation in vivo, MmuPV1 E8^E2 inhibits E4 protein expression in the basal keratinocytes that would otherwise undergo E4-mediated cell cycle arrest. IMPORTANCE Human papillomaviruses (PVs) initiate productive replication, which is characterized by genome amplification and expression of E4 protein strictly within suprabasal, differentiated keratinocytes. Mus musculus PV1 mutants that disrupt splicing of the E8^E2 transcript or abolish the interaction of E8^E2 with cellular NCoR/SMRT-HDAC3 co-repressor complexes display increased gene expression in tissue culture but are unable to form warts in vivo. This confirms that the repressor activity of E8^E2 is required for tumor formation and genetically defines a conserved E8 interaction domain. E8^E2 prevents expression of E4 protein in basal-like, undifferentiated keratinocytes and thereby their arrest in G2 phase. Since binding of E8^E2 to NCoR/SMRT-HDAC3 co-repressor is required to enable expansion of infected cells in the basal layer and wart formation in vivo, this interaction represents a novel, conserved, and potentially druggable target.

Background: APOE variants are strongly associated with abnormal amyloid aggregation and additional direct effects of APOE on tau aggregation are reported in animal and human cell models. The degree to which these effects are present in humans when individuals are clinically unimpaired (CU) but have abnormal amyloid (Aβ+) remains unclear. Methods: We analyzed data from CU individuals in the Anti-Amyloid Treatment in Asymptomatic AD (A4) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies. Amyloid PET data were available for 4486 participants (3163 Aβ-, 1323 Aβ+) and tau PET data were available for a subset of 447 participants (55 Aβ-, 392 Aβ+). Linear models examined APOE (number of e2 and e4 alleles) associations with global amyloid and regional tau burden in medial temporal lobe (entorhinal, amygdala) and early neocortical regions (inferior temporal, inferior parietal, precuneus). Consistency of APOE4 effects on regional tau were examined in 220 Aβ + CU and mild cognitive impairment (MCI) participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Results: APOE2 and APOE4 were associated with lower and higher amyloid positivity rates, respectively. Among Aβ+ CU, e2 and e4 were associated with reduced (−12 centiloids per allele) and greater (+15 centiloids per allele) continuous amyloid burden, respectively. APOE2 was associated with reduced regional tau in all regions (-0.05 to -0.09 SUVR per allele), whereas APOE4 was associated with greater regional tau (+0.02 to +0.07 SUVR per allele). APOE differences were confirmed by contrasting e3/e3 with e2/e3 and e3/e4. Mediation analyses among Aβ+ s showed that direct effects of e2 on regional tau were present in medial temporal lobe and early neocortical regions, beyond an indirect pathway mediated by continuous amyloid burden. For e4, direct effects on regional tau were only significant in medial temporal lobe. The magnitude of protective e2 effects on regional tau was consistent across brain regions, whereas detrimental e4 effects were greatest in medial temporal lobe. APOE4 patterns were confirmed in Aβ+ ADNI participants. Conclusions: APOE influences early regional tau PET burden, above and beyond effects related to cross-sectional amyloid PET burden. Therapeutic strategies targeting underlying mechanisms related to APOE may modify tau accumulation among Aβ+ individuals. [ABSTRACT FROM AUTHOR]

We aim to describe the relationship between the immunohistochemical expression patterns of HPV E4 markers and the presence of HPV major capsid protein (L1) in cervical tissues obtained by biopsy of patients with abnormal liquid-based cytology (LBC) results, HR HPV infections, or clinically suspicious cervix. A novel HPV-encoded marker, SILgrade-E4 (XR-E4-1), and an HPV (clone K1H8) antibody were used to demonstrate the expression in terminally differentiated epithelial cells with a productive HPV infection in the material. A semiquantitative analysis was performed based on light microscope images. The level of E4 protein decreased with the disease severity. Patients with LSIL-CIN 1 and HSIL-CIN 2 diagnoses had significantly lower levels of HPV major capsid protein (L1) than those without confirmed cervical lesions. Our analysis confirms a higher incidence of L1 in patients with molecularly diagnosed HPV infections and excluded lesions of LSIL-CIN 1 and HSIL-CIN 2. Further studies on the novel biomarkers might help assess the chances of the remission of lesions such as LSIL-CIN 1 and HSIL-CIN 2. Higher levels of E4 protein and L1 may confirm a greater probability of the remission of lesions and incidental infections. In the cytological verification or HPV-dependent screening model, testing for E4 protein and L1 expression may indicate a group with a lower risk of progression of histopathologically diagnosed lesions. [ABSTRACT FROM AUTHOR]

Objective: To evaluate overall and subgroup efficacy of an estetrol (E4) 15 mg drospirenone (DRSP) 3 mg oral contraceptive in a 24/4-day regimen.Study Design: We pooled efficacy outcomes from 2 pivotal phase 3 contraceptive trials with E4/DRSP conducted in the United States/Canada and Europe/Russia. We assessed Pearl Index (PI; pregnancies per 100 participant-years) and 13-cycle life-table pregnancy rates in at-risk cycles (confirmed intercourse and no other contraceptive use) among participants 16 to 35 years. We calculated PI by age and further subcategorization (contraceptive history and body mass index [BMI]). We performed multivariable analysis using Cox regression to assess impact of potential confounding factors.Results: Analyses included 3027 participants, of whom 451 (14.9%) had a BMI ≥30 kg/m2. The pooled PI was 1.52 (95% confidence interval 1.04-2.16) and the 13-cycle life-table pregnancy rate was 1.28% (0.83%-1.73%). We calculated unadjusted pooled PI in participants 16 to 25 years and 26 to 35 years of 1.61 (0.94-2.57) and 1.43 (0.78-2.40), respectively; in new starters and switchers of 1.88 (1.09-3.00) and 1.24 (0.68-2.08), respectively; and by BMI <25 kg/m2, 25 to 29.9 kg/m2, and ≥30 kg/m2 of 1.14 (0.64-1.88), 2.19 (1.05-4.03), and 2.27 (0.83-4.94), respectively. In multivariable analysis, we found associations of prior pregnancy (hazard ratio [HR] 3.61[1.56-8.38]), Black race (HR 4.61[1.97-10.80]), age 16 to 25 years (HR 2.37[1.09-5.15]) and compliance <99% of expected pills (HR 4.21[2.04-8.66]) with conception.Conclusion: E4/DRSP is an effective oral contraceptive overall and across subgroups stratified by age, contraceptive history, and BMI. Other than compliance, predictors of contraceptive failure are nonmodifiable.Implications Statement: Pooled results from two phase 3 trials demonstrate high contraceptive efficacy of the novel estetrol-drospirenone oral contraceptive. Several non-modifiable risk factors, including prior pregnancy, race, and age, are associated with higher pregnancy risk. Additional research is needed to better understand predictors of combined oral contraceptive failure. [ABSTRACT FROM AUTHOR]

The aim of this study is to analyse the level and determinants of women farmers’ access to financial resources in agriculture in Kosovo. The study describes the socio-economic characteristics of women farmers and identifies the socio-economic factors that influence access to financial resources. Primary data were collected from one hundred forty-six (146) women farmers who had access to a source of finance using multistage random sampling. Data were analysed using descriptive statistics, Likert scores, and probit regression estimates. 61.94% of the women had a farm size between 0.2 and 1.0 hectares and had an average farming experience of 8.33 years. The majority, 40.48% of the respondents, had formal education. They had a relatively high number of sources of finance through “family savings” and did not have access to finance through “borrowing from family members”. The probit regression estimation showed that education level, gross annual income, and net worth each exerted a significant positive influence on the probability. This implies that the relevant institutions in the country should develop policies and programmes for women farmers with low levels of education, income, and net worth.

Disruptive technology has been prominent as a spotlight with countless innovations that improve human’s life efficiently. In Vietnam, COVID-19ʹs outbreak has reinforced citizens to adopt other types of payment without using cash, which easily diffuses virus. Till now, the number of studies related to continuance usage of mobile wallets in Vietnam has been rare. Hence, our purpose in this research is to study continuance usage in COVID-19 through determinants. This paper concentrates on Millennials and Zillennials living Ho Chi Minh City. PLS-SEM with data collected from questionnaires assesses the conceptual model that indicates the correlation between UTAUT2ʹs constructs, trust, price saving orientation, behavioral intention and continuance usage. As predicted, the findings show that there are positive relationships among all determinants. In the event of effort expectancy and social influence, despite unsatisfactory of statistical significance, they reflect current context. Besides, direct positive influences from two variables to behavioral intention lead to further research studies after the pandemic to conclude properly about their significance. From the study’s result, business strategies together with security’s policies have to be modified by providers as well as the government to motivate mobile wallet adoption in Vietnam, amplifying cashless society and financial inclusion targets.

This note provides a nontechnical summary of a research paper (Bullard and DiCecio [2021, Classical policy benchmarks for economies with substantial inequality, Federal Reserve Bank of St. Louis, unpublished manuscript]) that I presented as the NIESR 2021 Dow Lecture on 9 February 2021. In the paper, we construct a simple benchmark macroeconomic model with substantial heterogeneity among households, enough to generate empirically plausible Gini coefficients for the distributions of consumption, income and financial wealth. The model includes aggregate shocks as well as both permanent and temporary idiosyncratic uncertainties. Four policymakers—implementing monetary, fiscal, labour market and education policies—act in concert to achieve a first-best allocation of resources. We argue that the roles of these policymaker types are 'classic' and match up well with observed policymaker roles in OECD countries. We regard this simple economy as a benchmark for the study of other aspects of the interaction between policy and inequality. [ABSTRACT FROM AUTHOR]

After adopting an inflation targeting framework for monetary policy at the turn of the twenty-first century, Banco de la República, the Central Bank of Colombia, started actively using the monetary policy interest rate as its key policy tool. This paper examines the interest rate pass-through from the monetary policy rate to the retail rates in Colombia and explores asymmetries in the adjustment process within the framework of a nonlinear version of the autoregressive distributed lag (ARDL) and the non-linear autoregressive distributed lag (NARDL) models developed by Shin, Yo, and Greenwood-Nimmo (2014). The findings show that the policy rate plays a key role in determining deposit and lending retail rates, but the nature of the pass-through varies across different types of products. In the case of lending rates, the pass-through is nearly complete and takes around 12 months to be nearly complete. The results capture an asymmetric pass-through in deposit rates—i.e., greater when the policy rate is increased than when it is reduced—and an upward rigidity in the lending rates of consumer and ordinary corporate loans, implying that major retail lending rates respond more to policy rate cuts than to hikes, indicating that financial intermediaries are more reluctant to raise interest rates than to decrease them following policy adjustments. Results are robust to the inclusion of additional regressors.

Macroeconomic models typically focus on innovations in the level of fundamentals as driver of business cycles because modeling of volatility can be demanding. This paper suggests a simple methodology that can separate the level from the volatility factors without directly estimating the volatility processes. This is made possible by exploiting features in the second order approximation of equilibrium models and using information in a large panel of data to estimate the factors. Augmenting the factors to a VAR shed light on the effects of the level and volatility shocks and their relative importance.

We study the effects of monetary policy shocks on—and their historical contribution to—consumption and income inequality in the United States since 1980 as measured by the Consumer Expenditure Survey. Contractionary monetary policy systematically increases inequality in labor earnings, total income, consumption and total expenditures. Furthermore, monetary policy shocks account for a non-trivial component of the historical cyclical variation in income and consumption inequality. Using detailed micro-level data on income and consumption, we document some of the different channels via which monetary policy shocks affect inequality, as well as how these channels depend on the nature of the change in monetary policy.

We study the effects of monetary policy shocks on—and their historical contribution to—consumption and income inequality in the United States since 1980 as measured by the Consumer Expenditure Survey. Contractionary monetary policy systematically increases inequality in labor earnings, total income, consumption and total expenditures. Furthermore, monetary policy shocks account for a non-trivial component of the historical cyclical variation in income and consumption inequality. Using detailed micro-level data on income and consumption, we document some of the different channels via which monetary policy shocks affect inequality, as well as how these channels depend on the nature of the change in monetary policy.