Abstract Background Extended-release naltrexone (XR-NTX), is an effective treatment for opioid use disorder but is rarely initiated in US prisons or with criminal justice populations. Mobile ...treatment for chronic diseases h
as
been implemented in a variety of settings. Mobile treatment may provide an opportunity to expand outreach to parolees to surmount barriers to traditional clinic treatment. Methods Male and female prisoners (240) with pre-incarceration histories of opioid use disorder who are within one month of release from prison will be enrolled in this randomized clinical trial. Participants are randomized to one of two study arms: 1) XR-NTX-OTx One injection of long-acting naltrexone in prison, followed by 6 monthly injections post-release at a community opioid treatment program; or 2) XR-NTX + MMTx One injection of long-acting naltrexone in prison followed by 6 monthly injections post-release at the patient
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s place of residence utilizing mobile medical treatment. The primary outcomes are: treatment adherence; opioid use; criminal activity; re-arrest; reincarceration; and HIV risk-behaviors. Results We describe the background and rationale for the study, its aims, hypotheses, and study design. Conclusions The use of long-acting injectable naltrexone may be a promising form of treatment for pre-release prisoners. Finally, as many individuals in the criminal justice system drop out of treatment, this study will assess whether treatment at their place of residence will improve adherence and positively affect treatment outcomes. ClinicalTrials.gov : NCT02867124
COVID-19 caused by the SARS-CoV-2 virus has become a global pandemic. 3CL protease is a virally encoded protein that is essential across a broad spectrum of coronaviruses with no close human analogs. ...PF-00835231, a 3CL protease inhibitor, has exhibited potent in vitro antiviral activity against SARS-CoV-2 as a single agent. Here we report, the design and characterization of a phosphate prodrug PF-07304814 to enable the delivery and projected sustained systemic exposure in human of PF-00835231 to inhibit coronavirus family 3CL protease activity with selectivity over human host protease targets. Furthermore, we show that PF-00835231 has additive/synergistic activity in combination with remdesivir. We present the ADME, safety, in vitro, and in vivo antiviral activity data that supports the clinical evaluation of PF-07304814 as a potential COVID-19 treatment.
•Drug-catalyzed lipid degradation is a concern that is unique to irinotecan liposomes.•Intraliposomal salt form and extraliposomal pH impact storage stability.•Liposomes containing doxorubicin and ...vinorelbine, two drugs that are not in the camptothecin class, do not show this hydrolytic phospholipid degradation.•Liposomal irinotecan contains an insoluble amorphous stoichiometric salt of irinotecan with the liposome-loading aid sucrose octasulfate.•Exhausting the membrane-traversing cation gradient during loading of the drug into the liposomes was possible owing to the stoichiometric nature of irinotecan sucrose octasulfate and was instrumental in preventing phospholipid degradation.
Therapeutics at or close to the nanoscale, such as liposomal irinotecan, offer significant promise for the treatment of solid tumors. Their potential advantage over the unencapsulated or free form of the drug is due in part to their altered biodistribution. For slow and sustained release, significant optimization of formulation is needed to achieve the required level of stability and allow long-term storage of the drug product. Gradient-based liposomal formulation of camptothecins such as irinotecan poses unique challenges owing to the camptothecin- and acid-catalyzed hydrolysis of phospholipid esters in the inner monolayer of the liposomal membrane. We demonstrated that a narrow set of conditions related to the external pH, temperature, intraliposomal concentration, identity of the drug-trapping agent, physical form of the drug inside the liposomes, and final drug load have a marked impact on the stability of the liposome phospholipid membrane. The physical form of the drug inside the liposome was shown to be an insoluble gel with an irinotecan-to-sulfate ratio approximating 1:1, reducing the potential for irinotecan-catalyzed phospholipid hydrolysis in the internal phospholipid monolayer. As a result of this work, a stable and active liposome formulation has been developed that maintains phospholipid chemical stability following long-term storage at 2-8°C.
Many of the specific functions of intrinsically disordered protein segments are mediated by Short Linear Motifs (SLiMs) interacting with other proteins. Well known examples include SLiMs that ...interact with 14-3-3, PDZ, SH2, SH3, and WW domains but the true extent and diversity of SLiM-mediated interactions is largely unknown. Here, we attempt to expand our knowledge of human SLiMs by applying in silico SLiM prediction to the human interactome. Combining data from seven different interaction databases, we analysed approximately 6000 protein-centred and 1600 domain-centred human interaction datasets of 3+ unrelated proteins that interact with a common partner. Results were placed in context through comparison to randomised datasets of similar size and composition. The search returned thousands of evolutionarily conserved, intrinsically disordered occurrences of hundreds of significantly enriched recurring motifs, including many that have never been previously identified (). In addition to True Positive results for at least 25 different known SLiMs, a striking number of "off-target" proteins/domains also returned significantly enriched known motifs. Often, this was due to the non-independence of the datasets, with many proteins sharing interaction partners or contributing interactions to multiple domain datasets. The majority of these motif classes, however, were also found to be significantly enriched in one or more randomised datasets. This highlights the need for care when interpreting motif predictions of this nature but also raises the possibility that SLiM occurrences may be successfully identified independently of interaction data. Although not as compositionally biased as previous studies, patterns matching known SLiMs tended to cluster into a few large groups of similar sequence, while novel predictions tended to be more distinctive and less abundant. Whether this is due to ascertainment bias or a true functional composition bias of SLiMs is not clear and warrants further investigation.
The practical utility of ionic liquids (ILs) makes the absence (heretofore) of reported examples from nature quite puzzling, given the facility with which nature produces many other types of exotic ...but utilitarian substances. In that vein, we report here the identification and characterization of a naturally occurring protic IL. It can be formed during confrontations between the ants S. invicta and N. fulva. After being sprayed with alkaloid‐based S. invicta venom, N. fulva detoxifies by grooming with its own venom, formic acid. The mixture is a viscous liquid manifestly different from either of the constituents. Further, we find that the change results as a consequence of formic acid protonation of the N centers of the S. invicta venom alkaloids. The resulting mixed‐cation ammonium formate milieu has properties consistent with its classification as a protic IL.
Crazy about ionic liquids: Throughout the southern United States, the invasive ant species S. invicta (fire ants) and N. fulva (tawny crazy ants) vie for resources. During confrontations, N. fulva is sprayed by S. invicta with a lipophilic, piperidine‐based venom. The former defeats this chemical attack by grooming with its own venom, formic acid. The combination forms a protic ionic liquid, which is the first naturally occurring ionic liquid to be reported.
Whether attending physicians, residents, nurses, and medical students agree on what constitutes medical student abuse, its severity, or influencing factors is unknown.
We surveyed 237 internal ...medicine attending physicians, residents, medical students, and nurses at 13 medical schools after viewing five vignettes depicting potentially abusive behaviors.
The majority of each group felt the belittlement, ethnic insensitivity, and sexual harassment scenarios represented abuse but that excluding a student from participating in a procedure did not. Only a majority of attending physicians considered the negative feedback scenario as abuse. Medical students rated abuse severity significantly lower than other groups in the belittlement scenario (p<.05). Respondents who felt abused as students were more likely to rate behaviors as abusive (p<.05).
The groups generally agree on what constitutes abuse, but attending physicians and those abused as students may perceive more behaviors as abusive.
With the increasing manufacture of expensive systems for the measurement of ambulatory blood pressure there is a need for potential purchasers to be able to satisfy themselves that the systems have ...been evaluated according to agreed criteria. The British Hypertension Society has, therefore, drawn up a protocol of requirements for the evaluation of these devices. This protocol incorporates many features of the American National Standard for Non-Automated Sphygmomanometers but includes many additional features, such as strict criteria for observer training, interdevice variability testing before and after a month of ambulatory use, and a new system of analysis which permits the test system to be graded. It is recommended that manufacturers of ambulatory blood pressure measuring devices should obtain an unbiased evaluation according to a recognized standard before a device is marketed.
In order to determine reference values for ambulatory blood pressure, a sample of 815 healthy bank employees (399 men and 416 women), aged 17-79 years, were investigated. Ambulatory blood pressure ...was recorded over 24 h, taking measurements at 30-min intervals. Blood pressure was also measured by trained observers in the clinic. Ambulatory blood pressure in the 815 subjects averaged 118/72 mmHg over 24 h, 124/78 mmHg during the day (1000-2259 h) and 106/61 mmHg at night (0100-0659 h). Office blood pressure, measured by an observer, was 4/2 mmHg lower (p less than 0.0001) than daytime ambulatory pressure. The 95th centiles for the daytime ambulatory pressure in men were: 114/88 mmHg for the age group 17-29 years (n = 107); 143/91 mmHg from 30-39 years (n = 123); 150/98 mmHg from 40-49 years (n = 109); and 155/103 mmHg in 50-79 year old men (n = 60); for the corresponding age groups in women, the 95th centiles of the daytime pressure were: 131/83 mmHg (n = 174); 132/85 mmHg (n = 149); 150/94 mmHg (n = 55); and 177/97 mmHg (n = 38).
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