Analysis of the yearly transition function in measles disease modeling.

Globally, there were an estimated 9.8 million measles cases and 207 500 measles deaths in 2019. As the effort to eliminate measles around the world continues, modeling remains a valuable tool for public health decision-makers and program implementers. This study presents a novel approach to the use of a yearly transition function that formulates mathematically the vaccine schedules for different age groups while accounting for the effects of the age of vaccination, the timing of vaccination, and disease seasonality on the yearly number of measles cases in a country. The methodology presented adds to an existing modeling framework and expands its analysis, making its utilization more adjustable for the user and contributing to its conceptual clarity. This article also adjusts for the temporal interaction between vaccination and exposure to disease, applying adjustments to estimated yearly counts of cases and the number of vaccines administered that increase population immunity. These new model features provide the ability to forecast and compare the effects of different vaccination timing scenarios and seasonality of transmission on the expected disease incidence. Although the work presented is applied to the example of measles, it has potential relevance to modeling other vaccine-preventable diseases.

Inorganic nitrate attenuates cardiac dysfunction: roles for xanthine oxidoreductase and nitric oxide.

BACKGROUND AND PURPOSE: NO is a vasodilator and independent modulator of cardiac remodelling. Commonly, in cardiac disease (e.g., heart failure), endothelial dysfunction (synonymous with NO deficiency) has been implicated in increased BP, cardiac hypertrophy and fibrosis. Currently, no effective therapies replacing NO have succeeded in the clinic. Inorganic nitrate (NO3 - ), through chemical reduction to nitrite and then to NO, exerts potent BP lowering, but whether it might be useful in treating undesirable cardiac remodelling is not known. EXPERIMENTAL APPROACH: We analysed demographics in a nested age- and sex-matched case-control study of hypertensive patients with or without left ventricular hypertrophy (NCT03088514) and assessed the effects of dietary nitrate in mouse models of cardiac dysfunction. KEY RESULTS: Lower plasma nitrite concentrations and vascular dysfunction accompanied cardiac hypertrophy and fibrosis in patients. In mouse models of cardiac remodelling, restoration of circulating nitrite levels using dietary nitrate improved endothelial dysfunction through targeting the xanthine oxidoreductase-driven increase in levels of H2 O2 and superoxide, and decreased cardiac fibrosis through NO-mediated block of SMAD phosphorylation leading to improvements in cardiac structure and function. CONCLUSIONS AND IMPLICATIONS: Dietary nitrate offers easily translatable therapeutic options for delivery of NO and thereby treatment of cardiac dysfunction.

Rivalry between Humans and Coronaviruses: Unanticipated Impact of Omicron.

With our prior Commentary we discussed the rivalry between ideation (humans) and mutations (viruses), (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8439168/), and more specifically, we described and compared two means of adaptability: collective and focused ideation for humans and self-serving mutation for viruses. The amazingly fast development of new effective and safe vaccines and drugs requires the humankind's most sophisticated form of ideation ability to respond to threatening stressors such as a dangerous virus like SARS-CoV-2. The essence of what makes us human is that human ideation requires a society of people working towards the same goal and is interdependent on socialization for the sustainability of humankind. In contrast, viruses mutate alone and "selfishly". The best fit virus for a particular environment, for a particular host, eliminates the competition through successive mutations. The Omicron variant of concern (VoC) is a great example for how higher transmissibility and perhaps, stochasticity, can drive the transmissive success of a virus across an entire host species like humans. With this review, we describe how Omicron has impacted the COVID-19 pandemic in an unanticipated way that could bring an end to it.

Rivalry between human ideation and virus mutation: two competing means of sustainability.

For the first time in human history, obtaining a COVID-19 vaccine has become essential for the sustainability of our species. As an amazing product of collective ideation, remarkably safe and efficient vaccines have been invented, tested, distributed, and administered to the population on a voluntary basis. The fast-mutating individual behavior of the virus is probably guided by a similar goal of the sustainability of the species. With this commentary, we analyze and compare two means of sustainability through adaptability: collective ideation in the case of humans and individual mutations in the case of viruses - two very different species whose behaviors are driven by sustainability.

Pregnancy, a unique case of heterochronic parabiosis and peripartum cardiomyopathy.

Introduction: A loss of endogenous stem cells capable of tissue repair and regeneration drives the biological process that we recognize as "aging". Recovery of stem cell-mediated repair and regenerative functions in aged animals has been reported in murine heterochronic parabiosis experiments. Objectives: Herein we will review how pregnancy is an unusual form of heterochronic parabiosis, as the placenta prevents the exchange of most blood cells between parabionts. Instead, plasma and its content, including small extracellular vesicles, can readily cross the placental barrier. These nanosized extracellular vesicles are readily produced by the placenta, amnion, fetus and mother, and are essential for fetal organogenesis, growth and the progression of a healthy pregnancy. If defective, these extracellular vesicles can cause havoc such as in the case of peripartum cardiomyopathy. We will also review how these extracellular vesicles impact the mother substantially (including cardiac function) in the parabiosis of pregnancy. Conclusion: Extracellular vesicles generated during the course of a healthy pregnancy are essential for organogenesis and fetal growth, and also for maternal tissue repair and regeneration, and might be defective or deficient in pregnancies that result in peripartum cardiomyopathy.

Timing of Early Complications Following Open Reduction and Internal Fixation of Closed Ankle Fractures.

Introduction: There is increasing interest in the early identification and treatment of adverse medical events following orthopaedic procedures. The purpose of this study is to characterize the timing of 8 early adverse events following open reduction and internal fixation of closed fractures of the ankle. Methods: A retrospective cohort study was conducted using the American College of Surgeons National Surgical Quality Improvement Program. A total of 17 318 patients undergoing open reduction and internal fixation of closed ankle fractures were identified. 48.4% of patients were discharged on the day of surgery. For each of 8 different early adverse events, the median postoperative day of diagnosis, interquartile range for day of diagnosis, and middle 80% for day of diagnosis were determined. Timing was compared between unimalleolar and bi-/trimalleolar fractures and between inpatient and outpatient procedures. Results: The median day of diagnosis (and interquartile range; middle 80%) for myocardial infarction was 2 (1-5; 0-17), pneumonia 3 (2-7; 1-19), acute kidney injury 6.5 (2-18; 2-20), urinary tract infection 7 (2-14; 0-24), pulmonary embolism 10 (3-21; 0-27), sepsis 15 (4-22; 1-28), deep vein thrombosis 17 (10-22; 3-27), and surgical site infection 19 (14-25; 8-28). Patients with bi-/trimalleolar fractures had earlier occurrence of myocardial infarction (day 2 vs 10), urinary tract infection (day 6.5 vs 9.5), and sepsis (day 10 vs 20.5). Inpatients had later occurrence of acute kidney injury (day 7 vs 3), but earlier occurrence of urinary tract infection (day 6 vs 15). Conclusions: These precisely described time periods for occurrence of specific adverse events enable heightened awareness among orthopaedic surgeons during the first month following open reduction and internal fixation of the ankle. Orthopaedic surgeons should have the lowest threshold for testing for each adverse event during the time period of greatest risk.Levels of Evidence: Therapeutic, Level III: Retrospective cohort study.

A Warm, Stratified, and Restricted Labrador Sea Across the Middle Eocene and Its Climatic Optimum.

Several studies indicate that North Atlantic Deep Water (NADW) formation might have initiated during the globally warm Eocene (56-34 Ma). However, constraints on Eocene surface ocean conditions in source regions presently conducive to deep water formation are sparse. Here we test whether ocean conditions of the middle Eocene Labrador Sea might have allowed for deep water formation by applying (organic) geochemical and palynological techniques, on sediments from Ocean Drilling Program (ODP) Site 647. We reconstruct a long-term sea surface temperature (SST) drop from ~30°C to ~27°C between 41.5 to 38.5 Ma, based on TEX86. Superimposed on this trend, we record ~2°C warming in SST associated with the Middle Eocene Climatic Optimum (MECO; ~40 Ma), which is the northernmost MECO record as yet, and another, likely regional, warming phase at ~41.1 Ma, associated with low-latitude planktic foraminifera and dinoflagellate cyst incursions. Dinoflagellate cyst assemblages together with planktonic foraminiferal stable oxygen isotope ratios overall indicate low surface water salinities and strong stratification. Benthic foraminifer stable carbon and oxygen isotope ratios differ from global deep ocean values by 1-2‰ and 2-4‰, respectively, indicating geographic basin isolation. Our multiproxy reconstructions depict a consistent picture of relatively warm and fresh but also highly variable surface ocean conditions in the middle Eocene Labrador Sea. These conditions were unlikely conducive to deep water formation. This implies either NADW did not yet form during the middle Eocene or it formed in a different source region and subsequently bypassed the southern Labrador Sea.

Total Ankle Arthroplasty Is Safer Than Total Hip and Knee Arthroplasty in the Early Postoperative Period.

BACKGROUND: Total hip and knee arthroplasty (THA and TKA) are performed more commonly than total ankle arthroplasty (TAA), so patients and the orthopaedic community are more familiar with the likelihood of complications after THA and TKA than after TAA. The present study places early complication rates after TAA in the context of those after THA and TKA. METHODS: Patients who underwent TAA, THA, or TKA during 2006 to 2016 as part of the National Surgical Quality Improvement Program were identified. Multivariate regression was used to compare procedures with adjustment for baseline and anesthesia characteristics. RESULTS: One hundred thirty-eight thousand three hundred twenty-five patients underwent THA, 223,587 TKA, and 839 TAA. The total complication rate was lower for TAA (2.98%) compared with THA (4.92%, P = 0.011) and TKA (4.56%, P = 0.049). Similarly, the rate of blood transfusion was lower for TAA (0.48%) compared with THA (9.66%) and TKA (6.44%, P < 0.001 for each). The rate of additional surgery was lower for TAA compared with THA (0.48% versus 1.79%, P = 0.007). Finally, the rate of readmission was lower for TAA (1.45%) compared with THA (3.66%, P = 0.002) and TKA (3.40%, P = 0.005). DISCUSSION: Patients can be counseled that relative to THA and TKA, TAA is safer in the perioperative period, with lower rates of adverse events, blood transfusion, additional surgery, and hospital readmission.

Patient Knowledge Regarding Radiation Exposure From Foot and Ankle Imaging.

Foot and ankle surgeons routinely prescribe diagnostic imaging that exposes patients to potentially harmful ionizing radiation. It is unclear how well patients understand the radiation to which they are exposed. In this study, 946 consecutive new patients were surveyed regarding medical imaging and radiation exposure prior to their first appointment. Respondents compared the amount of radiation associated with chest X-rays (CXRs) with various types of foot and ankle imaging. Results were compared with actual values of radiation exposure from the published literature. Of 946 patients surveyed, 841 (88.9%) participated. Most had private insurance (82.8%) and a bachelor's degree or higher (60.6%). Most believed that foot X-ray, ankle X-ray, "low dose" foot and ankle computed tomography (CT) scan (alluding to cone-beam CT), and traditional foot and ankle CT scan contain similar amounts of ionizing radiation to CXR. This contradicts the published literature that suggests that the actual exposure to patients is 0.006, 0.006, 0.127, and 0.833 CXR equivalents of radiation, respectively. Of patients who had undergone an X-ray, 55.9% thought about the issue of radiation prior to the study, whereas 46.1% of those undergoing a CT scan considered radiation prior to the exam. Similarly, 35.2% and 27.6% reported their doctor having discussed radiation with them prior to obtaining an X-ray and CT scan, respectively. Patients greatly overestimate the radiation exposure associated with plain film X-rays and cone-beam CT scans of the foot and ankle, and may benefit from increased counseling regarding the relatively low radiation exposure associated with these imaging modalities.Level of Evidence: Level III: Prospective questionnaire.

Papilloedema from Dural Venous Sinus Compression by Meningiomas.

Intracranial mass lesions may cause intracranial hypertension secondary to venous hypertension when they compress the dural venous sinuses (DVS) and may present with isolated papilloedema, mimicking idiopathic intracranial hypertension. We report a series of 16 patients with isolated papilloedema related to meningiomas compressing the DVS seen from 2012 to 2016 at three institutions. Correct diagnosis was delayed in 10/16 patients and treatment required a multidisciplinary approach, often with multiple sequential interventions, including combinations of acetazolamide, cerebrospinal fluid-shunt, optic nerve sheath fenestration, surgical resection of the meningioma, radiation therapy, and endovascular venous stenting. Two patients also received anticoagulation for venous thrombosis secondary to venous sinus compression.

Endogenously generated arachidonate-derived ligands for TRPV1 induce cardiac protection in sepsis.

The severity of cardiac dysfunction predicts mortality in sepsis. Activation of transient receptor potential vanilloid receptor type (TRPV)-1, a predominantly neuronal nonselective cation channel, has been shown to improve outcome in sepsis and endotoxemia. However, the role of TRPV1 and the identity of its endogenous ligands in the cardiac dysfunction caused by sepsis and endotoxemia are unknown. Using TRPV1-/- and TRPV1+/+ mice, we showed that endogenous activation of cardiac TRPV1 during sepsis is key to limiting the ensuing cardiac dysfunction. Use of liquid chromatography-tandem mass spectrometry lipid analysis and selective inhibitors of arachidonic metabolism suggest that the arachidonate-derived TRPV1 activator, 20-hydroxyeicosateraenoic acid (20-HETE), underlies a substantial component of TRPV1-mediated cardioprotection in sepsis. Moreover, using selective antagonists for neuropeptide receptors, we show that this effect of TRPV1 relates to the activity of neuronally released cardiac calcitonin gene-related peptide (CGRP) and that, accordingly, administration of CGRP can rescue cardiac dysfunction in severe endotoxemia. In sum activation of TRPV1 by 20-HETE leads to the release of CGRP, which protects the heart against the cardiac dysfunction in endotoxemia and identifies both TRPV1 and CGRP receptors as potential therapeutic targets in endotoxemia.-Chen, J., Hamers, A. J. P., Finsterbusch, M., Massimo, G., Zafar, M., Corder, R., Colas, R. A., Dalli, J., Thiemermann, C., Ahluwalia, A. Endogenously generated arachidonate-derived ligands for TRPV1 induce cardiac protection in sepsis.

Imaging Features of Idiopathic Intracranial Hypertension in Children.

Magnetic resonance imaging (MRI) signs of elevated intracranial pressure and idiopathic intracranial hypertension have been well characterized in adults but not in children. The MRIs of 50 children with idiopathic intracranial hypertension and 46 adults with idiopathic intracranial hypertension were reviewed for optic nerve head protrusion, optic nerve head enhancement, posterior scleral flattening, increased perioptic cerebrospinal fluid, optic nerve tortuosity, empty or partially empty sella, tonsillar herniation, enlargement of Meckel's cave meningoceles, and transverse venous sinus stenosis(TSS). Compared to adolescents (11-17 years, n = 40) and adults (>17 years, n = 46), prepubescent children (<11 years, n = 10) had lower frequencies of scleral flattening (50% vs 89% and 85%, P = .02), increased perioptic cerebrospinal fluid (60% vs 84% and 89%, P = .08), optic nerve tortuosity (20% vs 46% and 59%, P = .07), empty or partially empty sella (56% vs 78% and 93%, P = .007), and TSS (67% vs 93% and 96%, P = .04). Children with idiopathic intracranial hypertension have similar MRI findings as adults, but they are less frequent in prepubescent children.

The effect of early versus late treatment initiation after diagnosis on the outcomes of patients treated for multidrug-resistant tuberculosis: a systematic review.

BACKGROUND: Globally it is estimated that 480 000 people developed multidrug-resistant tuberculosis (MDR-TB) in 2014 and 190 000 people died from the disease. Successful treatment outcomes are achieved in only 50 % of patients with MDR-TB, compared to 86 % for drug susceptible disease. It is widely held that delay in time to initiation of treatment for MDR-TB is an important predictor of treatment outcome. The objective of this review was to assess the existing evidence on the outcomes of multidrug- and extensively drug-resistant tuberculosis patients treated early (≤4 weeks) versus late (>4 weeks) after diagnosis of drug resistance. METHODS: Eight sources providing access to 17 globally representative electronic health care databases, indexes, sources of evidence-based reviews and grey literature were searched using terms incorporating time to treatment and MDR-TB. Two-stage sifting in duplicate was employed to assess studies against pre-specified inclusion and exclusion criteria. Only those articles reporting WHO-defined treatment outcomes were considered for inclusion. Articles reporting on fewer than 10 patients, published before 1990, or without a comparison of outcomes in patient groups experiencing different delays to treatment initiation were excluded. RESULTS: The initial search yielded 1978 references, of which 1475 unique references remained after removal of duplicates and 28 articles published pre-1990. After title and abstract sifting, 64 papers underwent full text review. None of these articles fulfilled the criteria for inclusion in the review. CONCLUSIONS: Whilst there is an inherent logic in the theory that treatment delay will lead to poorer treatment outcomes, no published evidence was identified in this systematic review to support this hypothesis. Reports of programmatic changes leading to reductions in treatment delay exist in the literature, but attribution of differences in outcomes specifically to treatment delay is confounded by other contemporaneous changes. Further primary research on this question is not considered a high priority use of limited resources, though where data are available, improved reporting of outcomes by time to treatment should be encouraged.

Pronounced zonal heterogeneity in Eocene southern high-latitude sea surface temperatures.

Paleoclimate studies suggest that increased global warmth during the Eocene epoch was greatly amplified at high latitudes, a state that climate models cannot fully reproduce. However, proxy estimates of Eocene near-Antarctic sea surface temperatures (SSTs) have produced widely divergent results at similar latitudes, with SSTs above 20 °C in the southwest Pacific contrasting with SSTs between 5 and 15 °C in the South Atlantic. Validation of this zonal temperature difference has been impeded by uncertainties inherent to the individual paleotemperature proxies applied at these sites. Here, we present multiproxy data from Seymour Island, near the Antarctic Peninsula, that provides well-constrained evidence for annual SSTs of 10-17 °C (1σ SD) during the middle and late Eocene. Comparison of the same paleotemperature proxy at Seymour Island and at the East Tasman Plateau indicate the presence of a large and consistent middle-to-late Eocene SST gradient of ∼7 °C between these two sites located at similar paleolatitudes. Intermediate-complexity climate model simulations suggest that enhanced oceanic heat transport in the South Pacific, driven by deep-water formation in the Ross Sea, was largely responsible for the observed SST gradient. These results indicate that very warm SSTs, in excess of 18 °C, did not extend uniformly across the Eocene southern high latitudes, and suggest that thermohaline circulation may partially control the distribution of high-latitude ocean temperatures in greenhouse climates. The pronounced zonal SST heterogeneity evident in the Eocene cautions against inferring past meridional temperature gradients using spatially limited data within given latitudinal bands.

Reorganization of Southern Ocean plankton ecosystem at the onset of Antarctic glaciation.

The circum-Antarctic Southern Ocean is an important region for global marine food webs and carbon cycling because of sea-ice formation and its unique plankton ecosystem. However, the mechanisms underlying the installation of this distinct ecosystem and the geological timing of its development remain unknown. Here, we show, on the basis of fossil marine dinoflagellate cyst records, that a major restructuring of the Southern Ocean plankton ecosystem occurred abruptly and concomitant with the first major Antarctic glaciation in the earliest Oligocene (~33.6 million years ago). This turnover marks a regime shift in zooplankton-phytoplankton interactions and community structure, which indicates the appearance of eutrophic and seasonally productive environments on the Antarctic margin. We conclude that earliest Oligocene cooling, ice-sheet expansion, and subsequent sea-ice formation were important drivers of biotic evolution in the Southern Ocean.

First measurement of the form factors in the decays D0 → ρ- e+ ν(e) and D+ → ρ0 e+ ν(e).

The beauty to up quark coupling constant |V(ub)| can be extracted from B → ρ e+ ν(e) combined with the form factors for D → K* e+ ν(e) and B → V ℓ+ ℓ- and D → ρ e+ ν(e). Using the entire CLEO-c ψ(3770) → DD event sample, corresponding to an integrated luminosity of 818 pb(-1) and approximately 5.4×10(6) DD events, we measure the form factors for the decays D0 → ρ- e+ ν(e) and D+ → ρ0 e+ ν(e) for the first time and the branching fractions with improved precision. A four-dimensional unbinned maximum likelihood fit determines the form factor ratios to be V(0)/A1(0)=1.48±0.15±0.05 and A2(0)/A1(0)=0.83±0.11±0.04. Assuming Cabibbo-Kobayashi-Maskawa unitarity, the known D meson lifetimes, and our measured branching fractions we obtain the form factor normalizations A1(0), A2(0), and V(0). We also present a measurement of the branching fraction for D+ → ω e+ ν(e) with improved precision.

Histone deacetylase inhibitors and their potential role in inflammatory bowel diseases.

IBDs (inflammatory bowel diseases) are lifelong manifestations that significantly impair the quality of life of those who suffer from them. Although many therapies are now available, including immunomodulatory drugs such as Infliximab which have efficacy in IBD, not all patients respond and some patients generate autoantibodies against these drugs. Hence the search for novel treatments is ongoing. HDACs (histone deacetylases) are responsible for condensation of chromatin in the nucleus of cells and inhibition of gene transcription and are often dysregulated during cancer. HDAC inhibitors allow normal gene transcription to be restored and provide attractive therapeutic options, as they have been shown to be anti-inflammatory and anti-proliferative in cancer. Indeed, two HDAC inhibitors have been recently approved for the treatment of cutaneous T-cell lymphoma in the U.S.A. Recent research using animal models has shown that HDAC inhibitors may have a beneficial effect in colitis by boosting levels of Foxp3+ (forkhead box P3+) T-regulatory cells that dampen inflammation. In the present paper, we outline the background to IBD, HDACs and their inhibitors as well as discussing their current use in models of IBD.

Progress toward measles and rubella elimination in Egypt.

Measles and rubella were common infectious diseases in Egypt during the prevaccine era. Monovalent measles vaccine was introduced in 1977, and measles vaccination coverage increased from <50% to >90% from 1980 to 1999; however, measles outbreaks continued to occur at 2- to 4-year intervals during this period. After the introduction of a second routine dose of measles vaccine as a combined measles-mumps-rubella (MMR) vaccine in 1999 and the implementation of measles immunization campaigns targeting 6- to 16-year-old children during 2000-2003, reported measles cases dramatically decreased by 2003. In 2002, Egypt established a goal to eliminate measles and rubella and to prevent congenital rubella syndrome (CRS) by 2010. Large-scale rubella and measles outbreaks in 2005-2007, however, led to a revision of the plan of action to achieve the 2010 goals. A nation-wide measles-rubella immunization campaign, targeting children, adolescents, and young adults 2-20 years old, was conducted in 2 phases during 2008-2009 and achieved coverage >95%. With the decrease to record low levels of cases of measles and rubella in 2009 and 2010, Egypt should achieve measles and rubella elimination in the near future, but high coverage(>95%) with 2 doses of measles-rubella vaccine needs to be maintained, measles-rubella surveillance strengthened, and CRS surveillance developed.