Pharmacokinetics and Pharmacodynamics in HIV Prevention; Current Status and Future Directions: A Summary of the DAIDS and BMGF Sponsored Think Tank on Pharmacokinetics (PK)/Pharmacodynamics (PD) in HIV Prevention

Thirty years after its beginning, the HIV/AIDS epidemic is still raging around the world. According to UNAIDS, in 2011 alone 1.7M deaths were attributable to AIDS, and 2.5M people were newly infected by the virus. Despite the success in treating HIV-infected people with potent antiretroviral drugs, preventing HIV infection is the key to ending the epidemic. Recently, the efficacy of topical and systemic antiviral chemoprophylaxis (i.e., preexposure prophylaxis or “PrEP”), using the same drugs used for HIV treatment, has been demonstrated in a number of clinical trials. However, results from other trials have been inconsistent, especially those evaluating PrEP in women. These inconsistencies may result from our incomplete understanding of pharmacokinetics (PK)/pharmacodynamics (PD) at the mucosal sites of sexual transmission: the male and female gastrointestinal and reproductive tracts. The drug concentrations used in these trials were derived from those used for treatment; however, we still do not know the relationship between the therapeutic and the preventive dose. This article presents the first comprehensive review of the available data in the HIV pharmacology field from animal models to human studies, and outlines gaps, challenges, and future directions. Addressing these pharmacological gaps and challenges will be critical in selecting and advancing future PrEP candidates and strategies with the greatest impact on the HIV epidemic

Utilización de las cánulas nasales de alto flujo en las unidades neonatales españolas

Neonate; Respiratory therapy; SurveyNeonato; Terapia respiratoria; EncuestaNounat; Teràpia respiratòria; EnquestaIntroduction The use of high-flow cannula therapy (HFNC) in neonatal units has increased in recent years, but there are no consensus guidelines on its indications and application strategies. Our aim was to know the rate of use of HFNC, their indications and the management variability among Spanish neonatal units. Material and methods Twenty-five-question survey for medical and nursing staff. Level II and III units were contacted by phone and sent in Google forms between September 2016 and December 2018. Results Ninety-seven responses (63.9% medical, 36.1% nursing), from 69 neonatal units representing 15 autonomous communities (87% level of care III; 13% level II). All units except one have HFNC with a humidified and heated system. Their most frequent indications are: non-invasive ventilation weaning (79.4%), bronchiolitis (69.1%), respiratory distress of the term newborn (58.8%), after extubation (50.5%). Minimum flow (1–5 L/min) and maximum flow (5–15 L/min) are variable between units. 22.7% have experienced some adverse effect from its use (9 air leak, 12 nasal trauma). Less than half have an employment protocol, but all the answers agree on the usefulness of national recommendations. Conclusions HFNC therapy is widely used in Spanish units, but there is great variability in its indications and strategies of use. National recommendations would be applicable in most units and would allow unifying its use.Introducción El uso de la terapia con cánulas de alto flujo (CNAF) en las unidades neonatales ha experimentado un incremento en los últimos años, pero no existen guías de consenso sobre sus indicaciones y estrategias de aplicación. Nuestro objetivo fue conocer la tasa de empleo de CNAF, sus indicaciones y la variabilidad de uso entre las unidades neonatales españolas. Material y métodos Encuesta de 25 preguntas dirigida a personal médico y de enfermería. Se contactó telefónicamente con unidades de nivel II y III y se envió en formato Google Forms entre septiembre 2016 y diciembre 2018. Resultados Se recibieron 97 respuestas (63,9% medicina, 36,1% enfermería), de 69 unidades neonatales que representan a 15 comunidades autónomas (87% nivel asistencial III; 13% nivel II). Todas las unidades, salvo una, disponen de CNAF con sistema humidificado y caliente. Sus indicaciones más frecuentes son: destete de ventilación no invasiva (VNI) (79,4%), bronquiolitis (69,1%), distrés respiratorio del recién nacido a término (RNT) (58,8%), tras extubación (50,5%). El flujo mínimo varía entre 1–5 lpm y el flujo máximo entre 5–15 lpm. El 22,7% ha experimentado algún efecto indeseado por su uso (9 fuga aérea, 12 traumatismo nasal). Menos de la mitad tiene protocolo de empleo, pero todas las respuestas coinciden en la utilidad de unas recomendaciones nacionales. Conclusiones La terapia con CNAF está ampliamente extendida en las unidades españolas, pero existe gran variabilidad en sus indicaciones y estrategias de utilización. Unas recomendaciones a nivel nacional serían aplicables en la mayoría de las unidades y permitirían unificar su empleo

A magnetar giant flare in the nearby starburst galaxy M82

Giant flares, short explosive events releasing up to 10$^{47}$ erg of energy in the gamma-ray band in less than one second, are the most spectacular manifestation of magnetars, young neutron stars powered by a very strong magnetic field, 10$^{14-15}$ G in the magnetosphere and possibly higher in the star interior. The rate of occurrence of these rare flares is poorly constrained, as only three have been seen from three different magnetars in the Milky Way and in the Large Magellanic Cloud in about 50 years since the beginning of gamma-ray astronomy. This sample can be enlarged by the discovery of extragalactic events, since for a fraction of a second giant flares reach peak luminosities above 10$^{46}$ erg/s, which makes them visible by current instruments up to a few tens of Mpc. However, at these distances they appear similar to, and difficult to distinguish from, regular short gamma-ray bursts (GRBs). The latter are much more energetic events, 10$^{50-53}$ erg, produced by compact binary mergers and originating at much larger distances. Indeed, only a few short GRBs have been proposed, with different levels of confidence, as magnetar giant flare candidates in nearby galaxies. Here we report the discovery of a short GRB positionally coincident with the central region of the starburst galaxy M82. Its spectral and timing properties, together with the limits on its X-ray and optical counterparts obtained a few hours after the event and the lack of an associated gravitational wave signal, qualify with high confidence this event as a giant flare from a magnetar in M82.Comment: Submitted version. New figures. Accepted for publication in Nature with minor modification

Supplement: "Localization and broadband follow-up of the gravitational-wave transient GW150914" (2016, ApJL, 826, L13)

This Supplement provides supporting material for Abbott et al. (2016a). We briefly summarize past electromagnetic (EM) follow-up efforts as well as the organization and policy of the current EM follow-up program. We compare the four probability sky maps produced for the gravitational-wave transient GW150914, and provide additional details of the EM follow-up observations that were performed in the different bands

Allergic manifestations and cutaneous histamine responses in patients with McCune Albright syndrome

Background McCune Albright syndrome (MAS) is a rare disorder characterized by precocious puberty, café-au-lait spots, and fibrous dysplasia. Its cause is an activating mutation in the GNAS gene, encoding a subunit of the stimulatory G protein, Gsalpha (Gsα). The action of any mediator that signals via Gsα and cyclic AMP can be up regulated in MAS. We had observed gastritis, gastroesophageal reflux, and anaphylaxis in McCune Albright patients.Objective As histamine is known to signal via histamine 1 (H1) and histamine 2 (H2) receptors, which couple with stimulatory G proteins, we attempted to mechanistically link histamine responsiveness to the activating GNAS mutation. We hypothesized that responsiveness to histamine skin testing would differ between MAS patients and healthy controls.Patients and methods After obtaining informed consent, we performed a systematic review of histamine responsiveness and allergic manifestations in 11 MAS patients and 11 sex-matched, Tanner-stage matched controls. We performed skin prick testing, quantifying the orthogonal diameters of wheals and erythema. We also quantitated G protein mRNA expression.Results The peak wheal and flare responses to histamine were significantly higher in MAS patients compared to controls.Conclusions This study suggests that MAS patients may be at risk for exaggerated histamine responsiveness compared to unaffected controls. Keywords: McCune Albright syndrome, Histamine responsiveness, Wheal and flare, Atopy, Anaphylaxi

Rural Cooperatives Magazine, March/April 2005

Features- Price crisis prompts potato growers to form national co-op; Low-carb, High Hopes; Farmer co-op business volume nears $117 billion; Unflappable; A Perfect Storm; Court of Preference; Upswing Continues; Perils & Pleasures of Partnership

Rural Cooperatives Magazine, March/April 2005

Features- Price crisis prompts potato growers to form national co-op; Low-carb, High Hopes; Farmer co-op business volume nears $117 billion; Unflappable; A Perfect Storm; Court of Preference; Upswing Continues; Perils & Pleasures of Partnership