The APOBEC3B cytidine deaminase is an adenovirus restriction factor.

Human adenoviruses (HAdVs) are a large family of DNA viruses counting more than a hundred strains divided into seven species (A to G). HAdVs induce respiratory tract infections, gastroenteritis and conjunctivitis. APOBEC3B is a cytidine deaminase that restricts several DNA viruses. APOBEC3B is also implicated in numerous cancers where it is responsible for the introduction of clustered mutations into the cellular genome. In this study, we demonstrate that APOBEC3B is an adenovirus restriction factor acting through a deaminase-dependent mechanism. APOBEC3B introduces C-to-T clustered mutations into the adenovirus genome. APOBEC3B reduces the propagation of adenoviruses by limiting viral genome replication, progression to late phase, and production of infectious virions. APOBEC3B restriction efficiency varies between adenoviral strains, the A12 strain being more sensitive to APOBEC3B than the B3 or C2 strains. In A12-infected cells, APOBEC3B clusters in the viral replication centers. Importantly, we show that adenovirus infection leads to a reduction of the quantity and/or enzymatic activity of the APOBEC3B protein depending on the strains. The A12 strain seems less able to resist APOBEC3B than the B3 or C2 strains, a characteristic which could explain the strong depletion of the APOBEC3-targeted motifs in the A12 genome. These findings suggest that adenoviruses evolved different mechanisms to antagonize APOBEC3B. Elucidating these mechanisms could benefit the design of cancer treatments. This study also identifies adenoviruses as triggers of the APOBEC3B-mediated innate response. The involvement of certain adenoviral strains in the genesis of the APOBEC3 mutational signature observed in tumors deserves further study.

Antagonism of ALAS1 by the Measles Virus V protein contributes to degradation of the mitochondrial network and promotes interferon response.

Viruses have evolved countless mechanisms to subvert and impair the host innate immune response. Measles virus (MeV), an enveloped, non-segmented, negative-strand RNA virus, alters the interferon response through different mechanisms, yet no viral protein has been described as directly targeting mitochondria. Among the crucial mitochondrial enzymes, 5'-aminolevulinate synthase (ALAS) is an enzyme that catalyzes the first step in heme biosynthesis, generating 5'-aminolevulinate from glycine and succinyl-CoA. In this work, we demonstrate that MeV impairs the mitochondrial network through the V protein, which antagonizes the mitochondrial enzyme ALAS1 and sequesters it to the cytosol. This re-localization of ALAS1 leads to a decrease in mitochondrial volume and impairment of its metabolic potential, a phenomenon not observed in MeV deficient for the V gene. This perturbation of the mitochondrial dynamics demonstrated both in culture and in infected IFNAR-/- hCD46 transgenic mice, causes the release of mitochondrial double-stranded DNA (mtDNA) in the cytosol. By performing subcellular fractionation post infection, we demonstrate that the most significant source of DNA in the cytosol is of mitochondrial origin. Released mtDNA is then recognized and transcribed by the DNA-dependent RNA polymerase III. The resulting double-stranded RNA intermediates will be captured by RIG-I, ultimately initiating type I interferon production. Deep sequencing analysis of cytosolic mtDNA editing divulged an APOBEC3A signature, primarily analyzed in the 5'TpCpG context. Finally, in a negative feedback loop, APOBEC3A an interferon inducible enzyme will orchestrate the catabolism of mitochondrial DNA, decrease cellular inflammation, and dampen the innate immune response.

APOBEC3F Is a Mutational Driver of the Human Monkeypox Virus Identified in the 2022 Outbreak.

BACKGROUND: On May 6, 2022, a powerful outbreak of monkeypox virus (MPXV) had been reported outside of Africa, with many continuing new cases being reported around the world. Analysis of mutations among the 2 different lineages present in the 2021 and 2022 outbreaks revealed the presence of G->A mutations occurring in the 5'GpA context, indicative of APOBEC3 cytidine deaminase activity. METHODS: By using a sensitive polymerase chain reaction (differential DNA denaturation PCR) method allowing differential amplification of AT-rich DNA, we analyzed the level of APOBEC3-induced MPXV editing in infected cells and in patients. RESULTS: We demonstrate that G->A hypermutated MPXV genomes can be recovered experimentally from APOBEC3 transfection followed by MPXV infection. Here, among the 7 human APOBEC3 cytidine deaminases (A3A-A3C, A3DE, A3F-A3H), only APOBEC3F was capable of extensively deaminating cytidine residues in MPXV genomes. Hyperedited genomes were also recovered in ∼42% of analyzed patients. Moreover, we demonstrate that substantial repair of these mutations occurs. Upon selection, corrected G->A mutations escaping drift loss contribute to the MPXV evolution observed in the current epidemic. CONCLUSIONS: Stochastic or transient overexpression of the APOBEC3F gene exposes the MPXV genome to a broad spectrum of mutations that may be modeling the mutational landscape after multiple cycles of viral replication.

CsAr, CsXe, and RbXe B2Σ1/2+ Interatomic Potentials Determined from Absorption Spectra and Calculations of Franck-Condon Factors for Free-Free Optical Transitions of Atomic Collision Pairs.

Interatomic potentials for the B2Σ1/2+ states of CsAr, CsXe, and RbXe have been determined through comparisons of experimental B ← X absorption spectra for alkali vapor-rare gas mixtures with calculations of the Franck-Condon factors (FCFs) associated with free-free transitions of thermal atomic pairs. Simulations of optical transitions of alkali-rare gas atomic pairs between the thermal and vibrational continua of the X2Σ1/2+ and B2Σ1/2+ states of the molecule, responsible for the blue satellites of the Cs and Rb D2 resonance lines in a rare gas background, require the incorporation of ground-state J values above ∼400 into the FCF calculations and proper normalization of the free-particle wave functions. Absorption spectra computed on the basis of several X and B state interatomic potentials available in the literature were found to be sensitive to the height of the B2Σ1/2+ state barrier, as well as the X2Σ1/2+ state repulsive wall contour and the location of the van der Waals minimum. Other spectral simulations entailed iterative modifications to a selected B2Σ1/2+ interatomic potential, again coupled with comparison to experimental B ← X spectra. Comparisons of calculated spectra with experiment yield a CsXe B2Σ1/2+ potential, for example, exhibiting a barrier height of 76 cm-1 at 5.2 Å and yet is nearly flat at smaller values of internuclear separation (R). The latter contrasts with previous theoretical calculations of VB(R) in the vicinity of the barrier maximum. For the CsAr molecule, the B2Σ1/2+ barrier height was found to be 221 cm-1, which is within 3% of the value determined from pseudopotential calculations incorporating the spin-orbit effect. Reproducing Cs-rare gas experimental absorption spectra also requires the existence of a broad, shallow potential well lying beyond the B2Σ1/2+ barrier that, for CsAr, has a dissociation energy (De ∼ 24 cm-1) a factor of 3 larger than values predicted by theory. Similar results are obtained for the RbXe and CsXe complexes.

The Influence of Diabetes on Labor Induction with Dinoprostone Vaginal Inserts.

OBJECTIVE: The aim of this study was to compare duration of labor induction between diabetic and nondiabetic women receiving dinoprostone vaginal insert (10 mg). STUDY DESIGN: This is a secondary analysis of two large randomized controlled trials using dinoprostone vaginal inserts for labor induction. We compare time to active labor, overall delivery, and vaginal delivery between diabetic and nondiabetic women undergoing induction of labor with a 10-mg dinoprostone vaginal insert. RESULTS: Diabetic women receiving dinoprostone vaginal insert had a longer time to onset of active labor, overall delivery, and vaginal delivery than their nondiabetic counterparts. There was no difference in abnormal labor affecting fetal heart rate pattern in diabetic women compared with nondiabetic women. The rates of neonatal hyperbilirubinemia were higher in diabetic women. CONCLUSION: Diabetes may represent an independent factor associated with prolonged induction among women undergoing induction of labor with dinoprostone. Dinoprostone is well tolerated in both diabetic and nondiabetic women. KEY POINTS: · Diabetic women receiving DVI have slower labor curves than nondiabetic women.. · Nulliparous diabetic women took longer to achieve active labor, overall delivery, and vaginal delivery than nondiabetic women.. · Parous diabetic women took longer to achieve vaginal delivery than nondiabetic women..

Brodalumab in psoriatic arthritis: results from the randomised phase III AMVISION-1 and AMVISION-2 trials.

OBJECTIVE: To compare the efficacy and safety of brodalumab, an interleukin-17 receptor subunit A inhibitor, with placebo, in patients with psoriatic arthritis (PsA). METHODS: Adult patients with active PsA and inadequate response to, or intolerance to, conventional treatment were enrolled into two phase III studies (NCT02029495 and NCT02024646) and randomised 1:1:1 to receive subcutaneous brodalumab 140 mg or 210 mg or placebo at weeks 0, 1 and every 2 weeks up to 24 weeks. About 30% of patients had prior use of biologics. The primary endpoint for both studies was the American College of Rheumatology 20 (ACR20) response at week 16. RESULTS: 962 patients were randomised across the studies prior to early termination due to sponsor decision. The primary endpoint was met in both studies. Based on comparable design and eligibility criteria, data from both studies were pooled. Significantly more patients achieved ACR20 at week 16 in both brodalumab treatment groups (45.8% and 47.9% for 140 mg and 210 mg, respectively) versus placebo (20.9%) (p<0.0001). Similar results were observed at week 24. Significantly higher proportions of patients receiving brodalumab achieved ACR50/70, Psoriasis Area and Severity Index 75/90/100 and resolution of dactylitis and enthesitis versus placebo (p<0.01). Adverse event rates were similar across treatments at week 16 (54.4%, 51.6% and 54.5% for placebo, brodalumab 140 mg and 210 mg, respectively). No new safety signals were reported. CONCLUSION: Brodalumab was associated with rapid and significant improvements in signs and symptoms of PsA versus placebo. Brodalumab was well tolerated, with a safety profile consistent with other interleukin-17 inhibitors.

µ-Lat: A mouse model to evaluate human immunodeficiency virus eradication strategies.

A critical barrier to the development of a human immunodeficiency virus (HIV) cure is the lack of a scalable animal model that enables robust evaluation of eradication approaches prior to testing in humans. We established a humanized mouse model of latent HIV infection by transplanting "J-Lat" cells, Jurkat cells harboring a latent HIV provirus encoding an enhanced green fluorescent protein (GFP) reporter, into irradiated adult NOD.Cg-Prkdcscid Il2rgtm1Wjl /SzJ (NSG) mice. J-Lat cells exhibited successful engraftment in several tissues including spleen, bone barrow, peripheral blood, and lung, in line with the diverse natural tissue tropism of HIV. Administration of tumor necrosis factor (TNF)-α, an established HIV latency reversal agent, significantly induced GFP expression in engrafted cells across tissues, reflecting viral reactivation. These data suggest that our murine latency ("µ-Lat") model enables efficient determination of how effectively viral eradication agents, including latency reversal agents, penetrate, and function in diverse anatomical sites harboring HIV in vivo.

Lean body mass change over 6 years is associated with dietary leucine intake in an older Danish population.

Higher protein intake, and particularly higher leucine intake, is associated with attenuated loss of lean body mass (LBM) over time in older individuals. Dietary leucine is thought to be a key mediator of anabolism. This study aimed to assess this relationship over 6 years among younger and older adult Danes. Dietary leucine intake was assessed at baseline and after 6 years in men and women, aged 35-65 years, participating in the Danish cohort of the WHO-MONICA (Multinational MONItoring of trends and determinants in CArdiovascular disease) study (n 368). Changes in LBM over the 6 years were measured by bioelectrical impedance using equations developed for this Danish population. The association between leucine and LBM changes was examined using multivariate linear regression and ANCOVA analyses adjusted for potential confounders. After adjustment for baseline LBM, sex, age, energy intake and physical activity, leucine intake was associated with LBM change in those older than 65 years (n 79), with no effect seen in those younger than 65 years. Older participants in the highest quartile of leucine intake (7·1 g/d) experienced LBM maintenance, whereas lower intakes were associated with LBM loss over 6 years (for trend: ß=0·434, P=0·03). Sensitivity analysis indicated no effect modification of sex or the presence of CVD. Greater leucine intake in conjunction with adequate total protein intake was associated with long-term LBM retention in a healthy older Danish population. This study corroborates findings from laboratory investigations in relation to protein and leucine intakes and LBM change. A more diverse and larger sample is needed for confirmation of these results.

Association between dairy intake and caries among children and adolescents. results from the Danish EYHS follow-up study.

The aim of this paper was to investigate associations between the intake of dairy products and the development in caries (DMFS, decayed, missing and filled surfaces) among children/adolescents over a period of 3 and 6 years, and to investigate whether dairy intake protects against caries incidence. A total of 68.9% of the children were caries free at the age of 9 compared with 34.0% of the adolescents at the age of 15 (measured as DMFS = 0). A larger percentage of children/adolescents with a dairy intake above the mean were caries free compared with the group of children/adolescents with an intake below the mean (72.8 vs. 65.8% at age 9 and 41.1 vs. 30.7% at age 15). The results from the generalized estimation equation showed that dairy and milk intake, as well as intakes of components of dairy such as dairy calcium, whey and casein, was generally inversely associated with childhood/adolescent caries experience (measured as DMFS). With regard to caries incidence, the same inverse association was found for incidence over a period of 3 years and for incidence over 6 years, but the results were only statistically significant for the 3-year incidence and for the unadjusted models of the 6-year incidence. This study found that previous dairy intake, as well as milk intake or intake of dairy components, may be a predictor of future risk of caries measured by the DMFS count level. This relationship was inverse, meaning that a high intake of dairy products was associated with less future caries development. However, more studies on larger cohorts are needed to confirm these findings.

High-resolution Inference of Multiplexed Anti-HIV Gene Editing using Single-Cell Targeted DNA Sequencing.

Gene therapy-based HIV cure strategies typically aim to excise the HIV provirus directly, or target host dependency factors (HDFs) that support viral persistence. Cure approaches will likely require simultaneous co-targeting of multiple sites within the HIV genome to prevent evolution of resistance, and/or co-targeting of multiple HDFs to fully render host cells refractory to HIV infection. Bulk cell-based methods do not enable inference of co-editing within individual viral or target cell genomes, and do not discriminate between monoallelic and biallelic gene disruption. Here, we describe a targeted single-cell DNA sequencing (scDNA-seq) platform characterizing the near full-length HIV genome and 50 established HDF genes, designed to evaluate anti-HIV gene therapy strategies. We implemented the platform to investigate the capacity of multiplexed CRISPR-Cas9 ribonucleoprotein complexes (Cas9-RNPs) to simultaneously 1) inactivate the HIV provirus, and 2) knockout the CCR5 and CXCR4 HDF (entry co-receptor) genes in microglia and primary monocyte-derived macrophages (MDMs). Our scDNA-seq pipeline revealed that antiviral gene editing is rarely observed at multiple loci (or both alleles of a locus) within an individual cell, and editing probabilities across sites are linked. Our results demonstrate that single-cell sequencing is critical to evaluate the true efficacy and therapeutic potential of HIV gene therapy.

The influence of early exposure to vitamin D for development of diseases later in life.

BACKGROUND: Vitamin D deficiency is common among otherwise healthy pregnant women and may have consequences for them as well as the early development and long-term health of their children. However, the importance of maternal vitamin D status on offspring health later in life has not been widely studied. The present study includes an in-depth examination of the influence of exposure to vitamin D early in life for development of fractures of the wrist, arm and clavicle; obesity, and type 1 diabetes (T1D) during child- and adulthood. METHODS/DESIGN: The study is based on the fact that in 1961 fortifying margarine with vitamin D became mandatory in Denmark and in 1972 low fat milk fortification was allowed. Apart from determining the influences of exposure prior to conception and during prenatal life, we will examine the importance of vitamin D exposure during specific seasons and trimesters, by comparing disease incidence among individuals born before and after fortification. The Danish National databases assure that there are a sufficient number of individuals to verify any vitamin D effects during different gestation phases. Additionally, a validated method will be used to determine neonatal vitamin D status using stored dried blood spots (DBS) from individuals who developed the aforementioned disease entities as adults and their time and gender-matched controls. DISCUSSION: The results of the study will contribute to our current understanding of the significance of supplementation with vitamin D. More specifically, they will enable new research in related fields, including interventional research designed to assess supplementation needs for different subgroups of pregnant women. Also, other health outcomes can subsequently be studied to generate multiple health research opportunities involving vitamin D. Finally, the results of the study will justify the debate of Danish health authorities whether to resume vitamin D supplementation policies.

The hypoxia-regulated ectonucleotidase CD73 is a host determinant of HIV latency.

Deciphering the mechanisms underlying viral persistence is critical to achieving a cure for human immunodeficiency virus (HIV) infection. Here, we implement a systems approach to discover molecular signatures of HIV latently infected CD4+ T cells, identifying the immunosuppressive, adenosine-producing ectonucleotidase CD73 as a key surface marker of latent cells. Hypoxic conditioning, reflecting the lymphoid tissue microenvironment, increases the frequency of CD73+ CD4+ T cells and promotes HIV latency. Transcriptomic profiles of CD73+ CD4+ T cells favor viral quiescence, immune evasion, and cell survival. CD73+ CD4+ T cells are capable of harboring a functional HIV reservoir and reinitiating productive infection ex vivo. CD73 or adenosine receptor blockade facilitates latent HIV reactivation in vitro, mechanistically linking adenosine signaling to viral quiescence. Finally, tissue imaging of lymph nodes from HIV-infected individuals on antiretroviral therapy reveals spatial association between CD73 expression and HIV persistence in vivo. Our findings warrant development of HIV-cure strategies targeting the hypoxia-CD73-adenosine axis.

TCF-1 regulates HIV-specific CD8+ T cell expansion capacity.

Although many HIV cure strategies seek to expand HIV-specific CD8+ T cells to control the virus, all are likely to fail if cellular exhaustion is not prevented. A loss in stem-like memory properties (i.e., the ability to proliferate and generate secondary effector cells) is a key feature of exhaustion; little is known, however, about how these properties are regulated in human virus-specific CD8+ T cells. We found that virus-specific CD8+ T cells from humans and nonhuman primates naturally controlling HIV/SIV infection express more of the transcription factor TCF-1 than noncontrollers. HIV-specific CD8+ T cell TCF-1 expression correlated with memory marker expression and expansion capacity and declined with antigenic stimulation. CRISPR-Cas9 editing of TCF-1 in human primary T cells demonstrated a direct role in regulating expansion capacity. Collectively, these data suggest that TCF-1 contributes to the regulation of the stem-like memory property of secondary expansion capacity of HIV-specific CD8+ T cells, and they provide a rationale for exploring the enhancement of this pathway in T cell-based therapeutic strategies for HIV.

FOXO1 promotes HIV latency by suppressing ER stress in T cells.

Quiescence is a hallmark of CD4+ T cells latently infected with human immunodeficiency virus 1 (HIV-1). While reversing this quiescence is an effective approach to reactivate latent HIV from T cells in culture, it can cause deleterious cytokine dysregulation in patients. As a key regulator of T-cell quiescence, FOXO1 promotes latency and suppresses productive HIV infection. We report that, in resting T cells, FOXO1 inhibition impaired autophagy and induced endoplasmic reticulum (ER) stress, thereby activating two associated transcription factors: activating transcription factor 4 (ATF4) and nuclear factor of activated T cells (NFAT). Both factors associate with HIV chromatin and are necessary for HIV reactivation. Indeed, inhibition of protein kinase R-like ER kinase, an ER stress sensor that can mediate the induction of ATF4, and calcineurin, a calcium-dependent regulator of NFAT, synergistically suppressed HIV reactivation induced by FOXO1 inhibition. Thus, our studies uncover a link of FOXO1, ER stress and HIV infection that could be therapeutically exploited to selectively reverse T-cell quiescence and reduce the size of the latent viral reservoir.

Misoprostol vaginal insert versus dinoprostone vaginal insert: A comparison of labour and delivery outcomes.

OBJECTIVES: To compare Misoprostol Vaginal Insert (MVI), a vaginal insert containing 200 µg of misoprostol) versus Dinoprostone Vaginal Insert (DVI), a vaginal insert containing 10 mg of dinoprostone), in the induction of labour. STUDY DESIGN: We performed a retrospective analysis of the data between February 2016 and September 2017 of women induced with MVI (n = 100) and DVI in UK (n = 100) at NHS Fife. MVI was used for the same indications as DVI, but specifically indicated in women with a Modified Bishops score ≤ 4. Outcome measures included: the incidence of tachysystole and hyperstimulation; further use of prostaglandins; use of pre-delivery oxytocin; mode of delivery; median insertion-to-delivery-interval; and admission to the neonatal unit. Statistical data analysis was performed. A logistic regression analysis was also performed, adjusting for potential confounders such as body mass index (BMI), gestational age, parity and baseline Modified Bishops score. RESULTS: Demographics such as parity, BMI, baseline Modified Bishops score and gestational age were assessed. A significantly higher rate of tachysystole and hyperstimulation was noted in the MVI group as compared to the DVI group. Only 8% of women in the MVI group as compared to a third (33%) of women in the DVI group required further prostaglandins. There was no difference in the modes of birth in either group and this result was statistically significant. The median induction to delivery interval was 15 h in the MVI group compared to 33 h in the DVI group. There was no difference in neonatal outcomes in either group. There was no significant difference in the use of pre-delivery oxytocin for subsequent augmentation of labour in either group. All the results, when adjusted to potential confounders using logistic regression, were in keeping with the unadjusted statistical analysis. CONCLUSION: The results of this study suggest that MVI significantly reduces the induction to delivery interval, has a similar caesarean section rate and neonatal outcomes, when compared with DVI.

Associations of hypertensive disorders of pregnancy and outcomes of labor induction with prostaglandin vaginal inserts.

OBJECTIVE: To evaluate the association between hypertensive (HTNsive) disorders of pregnancy and outcomes of labor induction, in two cohorts of women induced with either misoprostol vaginal insert (MVI) or dinoprostone vaginal insert (DVI). STUDY DESIGN: This investigation was a post-hoc analysis of data from three Phase II and III, multi-center, double blind, randomized controlled trials of women induced with identical efficacy endpoints. A competing risk framework investigated the association between HTNsive disorders of pregnancy and the time-to-event endpoints of onset of active labor and vaginal delivery. We analyzed the overall incidence of the competing risk, cesarean delivery, by logistic regression to identify potential differences between the proportion of patients with cesarean and vaginal deliveries for each cohort. RESULTS: 401 women with HTNsive disorders during pregnancy underwent induction of labor in these studies (175 with DVI and 226 with MVI). Significant differences were noted in the cumulative incidence of vaginal delivery 24 hours following insertion between the non-HTNsive and HTNsive groups for both treatments, (57.1% vs. 47.4% (p=0.023) among MVI patients and 39.9% vs. 27.2% (p=0.017) among DVI patients). However, upon adjusting for potential confounders, the estimated relative rates of vaginal delivery among HTNsive vs. non-HTNsive patients was 0.947 (95% CI (0.637, 1.371), p=0.631) and 0.904 (95% CI (0.735, 1.113) p=0.341) within the MVI and DVI sub-groups respectively. CONCLUSION: After adjustment for confounders, such as BMI, baseline modified Bishop score and gestational age, time-to-event outcomes for induction of labor using MVI or DVI in HTNsive women are not significantly different from non-HTNsive women.

Low-dose Desmopressin and Tolterodine Combination Therapy for Treating Nocturia in Women with Overactive Bladder: A Double-blind, Randomized, Controlled Study.

OBJECTIVE: Evaluation of safety and efficacy of desmopressin/tolterodine combination therapy in women. METHODS: This double-blind, randomized, proof-of-concept study enrolled 106 patients (≥18 years), with overactive bladder (OAB) and nocturia, with ≥2 nocturnal voids, receiving a 3-month once-daily combination (desmopressin 25 µg, orally-disintegrating tablets [ODT]/tolterodine 4 mg [Detrol® LA]; n = 49) or monotherapy (tolterodine 4 mg/placebo ODT; n = 57). Primary endpoint was change from baseline in mean number of nocturnal voids. Secondary endpoints were change from baseline in nocturnal voided volume, time to first nocturnal void, and quality-of-life. Post-hoc exploratory analysis were performed for patients with and without baseline nocturnal polyuria (NP, n = 47 each). RESULTS: Overall population showed a non-significant reduction in mean number of nocturnal voids with combination versus monotherapy (full analysis set: adjusted treatment contrast [TC], -0.34; P = 0.112). Change in mean nocturnal void volume (TC, -64.16 mL; P = 0.103), mean time to first nocturnal void (TC, 18.00 min; P = 0.385) and Nocturia Impact (NI) Diary© scores were comparable. In post-hoc analysis, NP patients showed a benefit with combination versus monotherapy for nocturnal void volume (P = 0.034) and time to first nocturnal void (P = 0.045), and a non-significant improvement in NI Diary© scores. Safety profile was comparable between treatments. A single transient event of asymptomatic clinically significant hyponatremia in combination group resolved subsequently. CONCLUSION: Low-dose desmopressin could be safely combined with tolterodine for treating nocturia in women with OAB, with a significant benefit in women with NP. Further, prospective validation studies of combination therapy are warranted in mixed NP/OAB population, based on this favorable proof-of-concept finding.

Association between periodontal disease and overweight and obesity: a systematic review.

BACKGROUND: Periodontitis and obesity are among the most common chronic disorders affecting the world's populations, and recent reviews suggest a potential link between overweight/obesity and periodontitis. However, because of the scarcity of prospective evidence, previous reviews were primarily based on cross-sectional studies, with only a few longitudinal or intervention studies included. This study's objective is to examine the time-dependent association between obesity and periodontitis and how weight changes may affect the development of periodontitis in the general population. Therefore, longitudinal and experimental studies that assessed the association among overweight, obesity, weight gain, waist circumference, and periodontitis are reviewed. METHODS: Intervention and longitudinal studies with overweight or obesity as exposure and periodontitis as outcome were searched through the platforms PubMed/Medline and Web of Knowledge. RESULTS: Eight longitudinal and five intervention studies were included. Two of the longitudinal studies found a direct association between degree of overweight at baseline and subsequent risk of developing periodontitis, and a further three studies found a direct association between obesity and development of periodontitis among adults. Two intervention studies on the influence of obesity on periodontal treatment effects found that the response to non-surgical periodontal treatment was better among lean than obese patients; the remaining three studies did not report treatment differences between obese and lean participants. Among the eight longitudinal studies, one study adjusted for C-reactive protein (CRP) and biologic markers of inflammation such as CRP, interleukin-6, and tumor necrosis factor-α, and inflammation markers were analyzed separately in three of the five intervention studies. CONCLUSION: This systematic review suggests that overweight, obesity, weight gain, and increased waist circumference may be risk factors for development of periodontitis or worsening of periodontal measures.

Secular trends in seasonal variation in birth weight.

BACKGROUND: Many environmental factors have been shown to influence birth weight (BW) and one of these are season of birth. AIM: The aim of the present study was to investigate the seasonal variation in BW in Denmark during 1936-1989, and to see if the variation could be explained by sunshine exposure during pregnancy. METHODS: The study population was selected from the Copenhagen School Health Records Register and included 276 339 children born between 1936 and 1989. Seasonal variation was modeled using a non-stationary sinusoidal model that allowed the underlying trend in BW and the amplitude and phase of the yearly cycles to change. RESULTS: There was a clear seasonal pattern in BW which, however, changed gradually across the study period. The highest BWs were seen during fall (September - October) from 1936 to 1963, but a new peak gradually grew from the early 1940s during early summer (May - June) and became the highest from 1964 to 1989. The amplitude of the fall peak started at 25.5 (95%CI 24.6; 25.9) grams and gradually disappeared. The amplitude of the early summer peak gradually arose from nothing to a peak of 18.6 (95%CI 17.7; 19.6) grams in the mid 1980s where it started to decrease again. Sunshine did not explain the seasonal variation in BW. CONCLUSION: There was a clear seasonal pattern in BW in Denmark 1936-1989, which however changed across the study period. Throughout the study period we observed a peak in BW during the fall, but gradually, starting in the early 1940s, an additional early summer peak emerged and became the highest from 1964 and onwards.