Although parathyroid hormone-related protein (PTHrP) was discovered as a cancer-derived hormone, it has been revealed as an important paracrine/autocrine regulator in many tissues, where its effects ...are context dependent. Thus its location and action in the vasculature explained decades-long observations that injection of PTH into animals rapidly lowered blood pressure by producing vasodilatation. Its roles have been specified in development and maturity in cartilage and bone as a crucial regulator of endochondral bone formation and bone remodeling, respectively. Although it shares actions with parathyroid hormone (PTH) through the use of their common receptor, PTHR1, PTHrP has other actions mediated by regions within the molecule beyond the amino-terminal sequence that resembles PTH, including the ability to promote placental transfer of calcium from mother to fetus. A striking feature of the physiology of PTHrP is that it possesses structural features that equip it to be transported in and out of the nucleus, and makes use of a specific nuclear import mechanism to do so. Evidence from mouse genetic experiments shows that PTHrP generated locally in bone is essential for normal bone remodeling. Whereas the main physiological function of PTH is the hormonal regulation of calcium metabolism, locally generated PTHrP is the important physiological mediator of bone remodeling postnatally. Thus the use of intermittent injection of PTH as an anabolic therapy for bone appears to be a pharmacological application of the physiological function of PTHrP. There is much current interest in the possibility of developing PTHrP analogs that might enhance the therapeutic anabolic effects.
Bone remodeling is essential for the repair and replacement of damaged and old bone. The major principle underlying this process is that osteoclast-mediated resorption of a quantum of bone is ...followed by osteoblast precursor recruitment; these cells differentiate to matrix-producing osteoblasts, which form new bone to replace what was resorbed. Evidence from osteopetrotic syndromes indicate that osteoclasts not only resorb bone, but also provide signals to promote bone formation. Osteoclasts act upon osteoblast lineage cells throughout their differentiation by facilitating growth factor release from resorbed matrix, producing secreted proteins and microvesicles, and expressing membrane-bound factors. These multiple mechanisms mediate the coupling of bone formation to resorption in remodeling. Additional interactions of osteoclasts with osteoblast lineage cells, including interactions with canopy and reversal cells, are required to achieve coordination between bone formation and resorption during bone remodeling.
A number of recent studies have shown that the nonradiative voltage losses in organic solar cells can be suppressed in systems with low energetic offsets between donor and acceptor molecular states, ...but the physical reasons underpinning this remain unclear. Here, we present a systematic study of 18 different donor/acceptor blends to determine the effect that energetic offset has on both radiative and nonradiative recombination of the charge-transfer (CT) state. We find that, for certain blends, low offsets result in hybridization between charge-transfer and lowest donor or acceptor exciton states, which leads to a strong suppression in the nonradiative voltage loss to values as low as 0.23 V associated with an increase in the luminescence of the CT state. Further, we extend a two-state CT-state recombination model to include the interaction between CT and first excited states, which allows us to explain the low nonradiative voltage losses as an increase in the effective CT to ground state oscillator strength due to the intensity borrowing mechanism. We show that low nonradiative voltage losses can be achieved in material combinations with a strong electronic coupling between CT and first excited states and where the lower band gap material has a high oscillator strength for transitions from the excited state to the ground state. Finally, from our model we propose that achieving very low nonradiative voltage losses may come at a cost of higher overall recombination rates, which may help to explain the generally lower FF and EQE of highly hybridized systems.
The changing prevalence and patterns of tobacco use, the advent of novel nicotine delivery devices, and the development of new biomarkers prompted an update of the 2002 Society for Research on ...Nicotine and Tobacco (SRNT) report on whether and how to apply biomarker verification for tobacco use and abstinence.
The SRNT Treatment Research Network convened a group of investigators with expertise in tobacco biomarkers to update the recommendations of the 2002 SNRT Biochemical Verification Report.
Biochemical verification of tobacco use and abstinence increases scientific rigor and is recommended in clinical trials of smoking cessation, when feasible. Sources, appropriate biospecimens, cutpoints, time of detection windows and analytic methods for carbon monoxide, cotinine (including over the counter tests), total nicotine equivalents, minor tobacco alkaloids, and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol are reviewed, as well as biochemical approaches to distinguishing cigarette smoking from use of electronic nicotine delivery devices (ENDS).
Recommendations are provided for whether and how to use biochemical verification of tobacco use and abstinence. Guidelines are provided on which biomarkers to use, which biospecimens to use, optimal cutpoints, time windows to detection, and methodology for biochemical verifications. Use of combinations of biomarkers is recommended for assessment of ENDS use.
Biochemical verification increases scientific rigor, but there are drawbacks that need to be assessed to determine whether the benefits of biochemical verification outweigh the costs, including the cost of the assays, the feasibility of sample collection, the ability to draw clear conclusions based on the duration of abstinence, and the variability of the assay within the study population. This paper provides updated recommendations from the 2002 SRNT report on whether and how to use biochemical markers in determining tobacco use and abstinence.
Not all nanopores are created equal. By definition, nanopores have characteristic diameters or conduit widths between ∼1 and 100 nm. However, the narrowest of such pores, perhaps best called Single ...Digit Nanopores (SDNs) and defined as those with regular diameters less than 10 nm, have only recently been accessible experimentally for precision transport measurements. This Review summarizes recent experiments on pores in this size range that yield surprising results, pointing toward extraordinary transport efficiencies and selectivities for SDN systems. These studies have identified critical gaps in our understanding of nanoscale hydrodynamics, molecular sieving, fluidic structure, and thermodynamics. These knowledge gaps are, in turn, an opportunity to discover and understand fundamentally new mechanisms of molecular and ionic transport at the nanometer scale that may inspire a host of new technologies, from novel membranes for separations and water purification to new gas-permeable materials and energy storage devices. Here we highlight seven critical knowledge gaps in the study of SDNs and identify the need for new approaches to address these topics.
IMPORTANCE: Estimates from claims-based analyses suggest that the incidence of sepsis is increasing and mortality rates from sepsis are decreasing. However, estimates from claims data may lack ...clinical fidelity and can be affected by changing diagnosis and coding practices over time. OBJECTIVE: To estimate the US national incidence of sepsis and trends using detailed clinical data from the electronic health record (EHR) systems of diverse hospitals. DESIGN, SETTING, AND POPULATION: Retrospective cohort study of adult patients admitted to 409 academic, community, and federal hospitals from 2009-2014. EXPOSURES: Sepsis was identified using clinical indicators of presumed infection and concurrent acute organ dysfunction, adapting Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) criteria for objective and consistent EHR-based surveillance. MAIN OUTCOMES AND MEASURES: Sepsis incidence, outcomes, and trends from 2009-2014 were calculated using regression models and compared with claims-based estimates using International Classification of Diseases, Ninth Revision, Clinical Modification codes for severe sepsis or septic shock. Case-finding criteria were validated against Sepsis-3 criteria using medical record reviews. RESULTS: A total of 173 690 sepsis cases (mean age, 66.5 SD, 15.5 y; 77 660 42.4% women) were identified using clinical criteria among 2 901 019 adults admitted to study hospitals in 2014 (6.0% incidence). Of these, 26 061 (15.0%) died in the hospital and 10 731 (6.2%) were discharged to hospice. From 2009-2014, sepsis incidence using clinical criteria was stable (+0.6% relative change/y 95% CI, −2.3% to 3.5%, P = .67) whereas incidence per claims increased (+10.3%/y 95% CI, 7.2% to 13.3%, P < .001). In-hospital mortality using clinical criteria declined (−3.3%/y 95% CI, −5.6% to −1.0%, P = .004), but there was no significant change in the combined outcome of death or discharge to hospice (−1.3%/y 95% CI, −3.2% to 0.6%, P = .19). In contrast, mortality using claims declined significantly (−7.0%/y 95% CI, −8.8% to −5.2%, P < .001), as did death or discharge to hospice (−4.5%/y 95% CI, −6.1% to −2.8%, P < .001). Clinical criteria were more sensitive in identifying sepsis than claims (69.7% 95% CI, 52.9% to 92.0% vs 32.3% 95% CI, 24.4% to 43.0%, P < .001), with comparable positive predictive value (70.4% 95% CI, 64.0% to 76.8% vs 75.2% 95% CI, 69.8% to 80.6%, P = .23). CONCLUSIONS AND RELEVANCE: In clinical data from 409 hospitals, sepsis was present in 6% of adult hospitalizations, and in contrast to claims-based analyses, neither the incidence of sepsis nor the combined outcome of death or discharge to hospice changed significantly between 2009-2014. The findings also suggest that EHR-based clinical data provide more objective estimates than claims-based data for sepsis surveillance.
A radical solution is needed for the organ supply crisis, and the domestic pig is a promising organ source. In preparation for a clinical trial of xenotransplantation, we developed an in vivo ...pre‐clinical human model to test safety and feasibility tenets established in animal models. After performance of a novel, prospective compatible crossmatch, we performed bilateral native nephrectomies in a human brain‐dead decedent and subsequently transplanted two kidneys from a pig genetically engineered for human xenotransplantation. The decedent was hemodynamically stable through reperfusion, and vascular integrity was maintained despite the exposure of the xenografts to human blood pressure. No hyperacute rejection was observed, and the kidneys remained viable until termination 74 h later. No chimerism or transmission of porcine retroviruses was detected. Longitudinal biopsies revealed thrombotic microangiopathy that did not progress in severity, without evidence of cellular rejection or deposition of antibody or complement proteins. Although the xenografts produced variable amounts of urine, creatinine clearance did not recover. Whether renal recovery was impacted by the milieu of brain death and/or microvascular injury remains unknown. In summary, our study suggests that major barriers to human xenotransplantation have been surmounted and identifies where new knowledge is needed to optimize xenotransplantation outcomes in humans.
The authors report the development of an in vivo, pre‐clinical, human model to test safety and feasibility tenets and show that major barriers to human xenotransplantation have been surmounted. Kirk comments on page 1007.
In the bone remodeling process that takes place throughout the skeleton at bone multicellular units, intercellular communication processes are crucial. The osteoblast lineage has long been known to ...program osteoclast formation and hence resorption, but the preservation of bone mass and integrity requires tight control of remodeling. This needs local controls that ensure availability of mesenchymal precursors and the provision of local signals that promote differentiation through the osteoblast lineage. Some signals can come from growth factors released from resorbed bone matrix, and there is increasing evidence that the osteoclast lineage itself produces factors that can either enhance or inhibit osteoblast differentiation and hence bone formation. A number of such factors have been identified from predominantly in vitro experiments. The coupling of bone formation to resorption is increasingly recognized as a complex, dynamic process that results from the input of many local factors of cell and matrix origin that can either promote or inhibit bone formation.
Summary The two licensed bivalent and quadrivalent human papillomavirus (HPV) L1 (the major papillomavirus virion protein) virus-like particle (VLP) vaccines are regarded as safe, effective, and well ...established prophylactic vaccines. However, they have some inherent limitations, including a fairly high production and delivery cost, virus-type restricted protection, and no reported therapeutic activity, which might be addressed with the development of alternative dosing schedules and vaccine products. A change from a three-dose to a two-dose protocol for the licensed HPV vaccines, especially in younger adolescents (aged 9–13 years), is underway in several countries and is likely to become the future norm. Preliminary evidence suggests that recipients of HPV vaccines might derive prophylactic benefits from one dose of the bivalent vaccine. Substantial interest exists in both the academic and industrial sectors in the development of second-generation L1 VLP vaccines in terms of cost reduction—eg, by production in Escherichia coli or alternative types of yeast. However, Merck's nonavalent vaccine, produced via the Saccharomyces cerevisiae production system that is also used for their quadrivalent vaccine, is the first second-generation HPV VLP vaccine to be available on the market. By contrast, other pharmaceutical companies are developing microbial vectors that deliver L1 genes. These two approaches would add an HPV component to existing live attenuated vaccines for measles and typhoid fever. Prophylactic vaccines that are based on induction of broadly cross-neutralising antibodies to L2, the minor HPV capsid protein, are also being developed both as simple monomeric fusion proteins and as virus-like display vaccines. The strong interest in developing the next generation of vaccines, particularly by manufacturers in middle-to-high income countries, increases the likelihood that vaccine production will become decentralised with the hope that effective HPV vaccines will be made increasingly available in low-resource settings where they are most needed.
PDF
