An association between testosterone therapy (TT) and cardiovascular disease has been reported and TT use is increasing rapidly.
We conducted a cohort study of the risk of acute non-fatal myocardial ...infarction (MI) following an initial TT prescription (N = 55,593) in a large health-care database. We compared the incidence rate of MI in the 90 days following the initial prescription (post-prescription interval) with the rate in the one year prior to the initial prescription (pre-prescription interval) (post/pre). We also compared post/pre rates in a cohort of men prescribed phosphodiesterase type 5 inhibitors (PDE5I; sildenafil or tadalafil, N = 167,279), and compared TT prescription post/pre rates with the PDE5I post/pre rates, adjusting for potential confounders using doubly robust estimation.
In all subjects, the post/pre-prescription rate ratio (RR) for TT prescription was 1.36 (1.03, 1.81). In men aged 65 years and older, the RR was 2.19 (1.27, 3.77) for TT prescription and 1.15 (0.83, 1.59) for PDE5I, and the ratio of the rate ratios (RRR) for TT prescription relative to PDE5I was 1.90 (1.04, 3.49). The RR for TT prescription increased with age from 0.95 (0.54, 1.67) for men under age 55 years to 3.43 (1.54, 7.56) for those aged ≥ 75 years (p trend = 0.03), while no trend was seen for PDE5I (p trend = 0.18). In men under age 65 years, excess risk was confined to those with a prior history of heart disease, with RRs of 2.90 (1.49, 5.62) for TT prescription and 1.40 (0.91, 2.14) for PDE5I, and a RRR of 2.07 (1.05, 4.11).
In older men, and in younger men with pre-existing diagnosed heart disease, the risk of MI following initiation of TT prescription is substantially increased.
Patients with HIV infection are at increased risk for cancer. Cancer is the leading cause of death among non-AIDS-defining illnesses in these patients. Immune checkpoint inhibitor (ICI) therapy has ...transformed the treatment of cancer. However, clinical trials of ICIs have historically excluded patients with HIV infection. The safety and efficacy profile of ICIs is unknown in this underrepresented population.
To summarize results on the safety and efficacy of ICI therapy in HIV-infected patients with advanced-stage cancer.
This systematic review was conducted in accordance with PRISMA guidelines. A literature search of PubMed was performed on April 16, 2018, using the keyword HIV and the names of ICIs approved by the US Food and Drug Administration (ipilimumab, nivolumab, pembrolizumab, avelumab, atezolizumab, and durvalumab). Patients with HIV infection who were being treated with ICIs for advanced-stage cancer were included. In addition, abstracts and posters from major oncology and AIDS society annual meetings from 2016 through 2018 were reviewed.
Seventy-three patients (66 90.4% male; mean age, 56.1 years range, 30.0-77.0 years) were identified from 13 articles (11 case reports and 2 case series) and 4 meeting abstracts. Sixty-two patients were treated with anti-programmed cell death 1 (anti-PD-1) therapy, 6 with anti-cytotoxic T-lymphocyte antigen 4 (anti-CTLA-4) therapy, 4 with anti-PD-1/CTLA-4 therapy, and 1 with sequential ipilimumab and nivolumab therapy. Immune checkpoint inhibitor therapy was generally well tolerated, with grade 3 or higher immune-related adverse events noted in 6 of 70 patients (8.6%). Among 34 patients with known paired pretreatment and posttreatment HIV loads, HIV remained suppressed in 26 of the 28 (93%) with undetectable HIV load. Among the 25 with paired pretreatment and posttreatment CD4 cell counts, the counts increased (mean SD change, 12.3 28.5 /μL). Objective response rates were 30% for non-small cell lung cancer, 27% for melanoma, and 63% for Kaposi sarcoma.
Immune checkpoint inhibitor therapy for the treatment of advanced-stage cancer in patients with HIV infection was associated with no new safety signals. Immune checkpoint inhibitors may be a safe and efficacious treatment option in this patient population. Several ongoing prospective clinical trials will shed further light on the safety and efficacy of ICI therapy in HIV-infected patients with cancer.
DNA double-strand break (DSB) repair pathway choice is governed by the opposing activities of 53BP1 and BRCA1. 53BP1 stimulates nonhomologous end joining (NHEJ), whereas BRCA1 promotes end resection ...and homologous recombination (HR). Here we show that 53BP1 is an inhibitor of BRCA1 accumulation at DSB sites, specifically in the G1 phase of the cell cycle. ATM-dependent phosphorylation of 53BP1 physically recruits RIF1 to DSB sites, and we identify RIF1 as the critical effector of 53BP1 during DSB repair. Remarkably, RIF1 accumulation at DSB sites is strongly antagonized by BRCA1 and its interacting partner CtIP. Lastly, we show that depletion of RIF1 is able to restore end resection and RAD51 loading in BRCA1-depleted cells. This work therefore identifies a cell cycle-regulated circuit, underpinned by RIF1 and BRCA1, that governs DSB repair pathway choice to ensure that NHEJ dominates in G1 and HR is favored from S phase onward.
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► 53BP1 inhibits BRCA1 recruitment to DSB sites in G1 ► RIF1 is the effector of 53BP1 during DSB repair ► Class-switch recombination requires RIF1 ► RIF1 recruitment to DSB sites in S/G2 is inhibited by BRCA1-CtIP
The administration of probiotic bacteria as nutraceuticals is an area that has rapidly expanded in recent years, with a global market worth $32.6 billion predicted by 2014. Many of the health ...promoting claims attributed to these bacteria are dependent on the cells being both viable and sufficiently numerous in the intestinal tract. The oral administration of most bacteria results in a large loss of viability associated with passage through the stomach, which is attributed to the high acid and bile salt concentrations present. This loss of viability effectively lowers the efficacy of the administered supplement. The formulation of these probiotics into microcapsules is an emerging method to reduce cell death during GI passage, as well as an opportunity to control release of these cells across the intestinal tract. The majority of this technology is based on the immobilization of bacteria into a polymer matrix, which retains its structure in the stomach before degrading and dissolving in the intestine, unlike the diffusion based unloading of most controlled release devices for small molecules. This review shall provide an overview of progress in this field as well as draw attention to areas where studies have fallen short. This will be followed by a discussion of emerging trends in the field, highlighting key areas in which further research is necessary.
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The ability to trigger changes to material properties with external stimuli, so‐called “smart” behavior, has enabled novel technologies for a wide range of healthcare applications. Response to small ...changes in temperature is particularly attractive, where material transformations may be triggered by contact with the human body. Thermoreversible gelators are materials where warming triggers reversible phase change from low viscosity polymer solution to a gel state. These systems can be generated by the exploitation of macromolecules with lower critical solution temperatures included in their architectures. The resultant materials are attractive for topical and mucosal drug delivery, as well as for injectables. In addition, the materials are attractive for tissue engineering and 3D printing. The fundamental science underpinning these systems is described, along with progress in each class of material and their applications. Significant opportunities exist in the fundamental understanding of how polymer chemistry and nanoscience describe the performance of these systems and guide the rational design of novel systems. Furthermore, barriers to translating technologies must be addressed, for example, rigorous toxicological evaluation is rarely conducted. As such, applications remain tied to narrow fields, and advancements will be made where the existing knowledge in these areas may be applied to novel problems of science.
Thermoreversible gelators that exhibit a reversible switch from a liquid to gel state upon heating have driven groundbreaking innovations in healthcare. These materials may act as in situ gelators for forming drug depots, scaffolds for cells, or in bioprinting. This review concerns the latest progress in this field, highlighting opportunities for future research.
A micro analytical, interdisciplinary informed framework is presented to postulate why and how some cooperatives endure for long periods of time. This five-phase framework was developed through an ...extended research process employing inductive and deductive approaches. The paper concludes that cooperative longevity is associated with multiple factors, primarily among them, ability to adapt and ameliorate frictions and subgroup factions. This adaptability leads to multi “life cycles”. Cooperative multi life cycle regeneration is facilitated by a learned and embedded process called “cooperative genius”.
Lyme borreliosis is increasing rapidly in many parts of the world and is the most commonly occurring vector-borne disease in Europe and the USA. The disease is transmitted by ticks of the genus ...Ixodes. They require a blood meal at each stage of their life cycle and feed on a wide variety of wild and domestic animals as well as birds and reptiles. Transmission to humans is incidental and can occur during visits to a vector habitat, when host mammals and their associated ticks migrate into the urban environment, or when companion animals bring ticks into areas of human habitation. It is frequently stated that the risk of infection is very low if the tick is removed within 24-48 hours, with some claims that there is no risk if an attached tick is removed within 24 hours or 48 hours. A literature review has determined that in animal models, transmission can occur in <16 hours, and the minimum attachment time for transmission of infection has never been established. Mechanisms for early transmission of spirochetes have been proposed based on their presence in different organs of the tick. Studies have found systemic infection and the presence of spirochetes in the tick salivary glands prior to feeding, which could result in cases of rapid transmission. Also, there is evidence that spirochete transmission times and virulence depend upon the tick and Borrelia species. These factors support anecdotal evidence that Borrelia infection can occur in humans within a short time after tick attachment.
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In situ gelling formulations are drug delivery systems which typically exist in a liquid form at room temperature and change into gel state after application to the body in response ...to various stimuli such as changes in temperature, pH and ionic composition. Their biomedical application can further be improved by incorporating drug nanoparticles into in situ gelling systems in order to prolong drug release, reduce dosing frequency and improve therapeutic outcomes of patients, developing highly functional but challenging dosage forms. The composition of in situ gelling formulations influence factors relating to performance such as their syringeability, rheology, drug release profile and drug bioavailability at target sites, amongst other factors. The inclusion of mucoadhesive polymeric constituents into in situ gelling formulations has also been explored to ensure that the therapeutic agents are retained at target site for extended period of time. This review article will discuss traditional techniques (water bath-based vial inversion and viscometry) as well as advanced methodology (rheometry, differential scanning calorimetry, Small Angle Neutron Scattering, Small Angle X-ray Scattering, etc.) for evaluating in situ gel forming systems for topical drug delivery. The clinical properties of in situ gelling systems that have been studied for potential biomedical applications over the last ten years will be reviewed to highlight current knowledge in the performance of these systems. Formulation issues that have slowed the translation of some promising drug formulations from the research laboratory to the clinic will also be detailed.
Intravaginal drug delivery can elicit a local effect, or deliver drugs systemically without hepatic first pass metabolism. There are a number of emerging areas in intravaginal drug delivery, but the ...vagina is a challenging route of administration, due to the clearance mechanisms present which result in poor retention of dosage forms, and the potential for irritation and other adverse reactions. Gel formulations are desirable due to the ease of application, spreading and that they cause little to no discomfort to the patient. However, these dosage forms, in particular, are poorly retained and traditional gels typically have little control over drug release rates. This has led to a large number of studies on improving the retention of vaginal gels and modulating the controlled release of drugs from the gel matrix.
This review outlines the anatomy and physiology of the vagina, focussing on areas relevant to drug delivery. Medical applications of vaginally administered medicines is then discussed, followed by an overview of polymeric gels in intravaginal drug delivery. The sensorial properties of intravaginal gels, and how these relate to user compliance are also summarised. Finally, some important barriers to marketing approval are described.
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