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Some people remain healthier throughout life than others but the underlying reasons are poorly understood. Here we hypothesize this advantage is attributable in part to optimal immune resilience (IR), defined as the capacity to preserve and/or rapidly restore immune functions that promote disease resistance (immunocompetence) and control inflammation in infectious diseases as well as other causes of inflammatory stress. We gauge IR levels with two distinct peripheral blood metrics that quantify the balance between (i) CD8 +  and CD4 +  T-cell levels and (ii) gene expression signatures tracking longevity-associated immunocompetence and mortality-associated inflammation. Profiles of IR metrics in ~48,500 individuals collectively indicate that some persons resist degradation of IR both during aging and when challenged with varied inflammatory stressors. With this resistance, preservation of optimal IR tracked (i) a lower risk of HIV acquisition, AIDS development, symptomatic influenza infection, and recurrent skin cancer; (ii) survival during COVID-19 and sepsis; and (iii) longevity. IR degradation is potentially reversible by decreasing inflammatory stress. Overall, we show that optimal IR is a trait observed across the age spectrum, more common in females, and aligned with a specific immunocompetence-inflammation balance linked to favorable immunity-dependent health outcomes. IR metrics and mechanisms have utility both as biomarkers for measuring immune health and for improving health outcomes., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Rift Valley fever virus (RVFV) is an economically devastating, zoonotic arbovirus endemic across Africa with potential to cause severe disease in livestock and humans. Viral spread is primarily driven by movement of domestic ruminants and there is a high potential for transboundary spread. Despite influx of livestock to urban areas in response to the high demand for meat and animal products, RVFV has not been detected in any urban center. The objectives of this study were to determine the feasibility of assessing risk of RVFV introduction to urban Kisumu, Kenya, by testing slaughtered livestock for RVFV exposure and mapping livestock origins. Blood was collected from cattle, sheep, and goats directly after slaughter and tested for anti-RVFV IgG antibodies. Slaughterhouse businessmen responded to a questionnaire on their individual animals' origin, marketplace, and transport means. Thereafter, we mapped livestock flow from origin to slaughterhouse using participatory methods in focus group discussions with stakeholders. Qualitative data on route choice and deviations were spatially integrated into the map. A total of 304 blood samples were collected from slaughtered livestock in October and November 2021. Most (99%) of animals were purchased from 28 different markets across eight counties in Western Kenya. The overall RVFV seroprevalence was 9% (19% cattle, 3% in sheep, and 7% in goats). Migori County bordering Tanzania had the highest county-level seroprevalence (34%) and 80% of all seropositive cattle were purchased at the Suba Kuria market in Migori County. Road quality and animal health influenced stakeholders' decisions for choice of transport means. Overall, this proof-of-concept study offers a sampling framework for RVFV that can be locally implemented and rapidly deployed in response to regional risk. This system can be used in conjunction with participatory maps to improve active livestock surveillance and monitoring of RVFV in Western Kenya, and these methods could be extrapolated to other urban centers or livestock diseases., Competing Interests: All authors included on of this manuscript declare that they have no conflicts of interest., (© 2022 The Authors.)

Background: Diffuse midline gliomas (DMGs), including diffuse intrinsic pontine gliomas (DIPGs), have a dismal prognosis, with less than 2% surviving 5 years postdiagnosis. The majority of DIPGs and all DMGs harbor mutations altering the epigenetic regulatory histone tail (H3 K27M). Investigations addressing DMG epigenetics have identified a few promising drugs, including the HDAC inhibitor (HDACi) panobinostat. Here, we use clinically relevant DMG models to identify and validate other effective HDACi and their biomarkers of response., Methods: HDAC inhibitors were tested across biopsy-derived treatment-naïve in vitro and in vivo DMG models with biologically relevant radiation resistance. RNA sequencing was performed to define and compare drug efficacy and to map predictive biomarkers of response., Results: Quisinostat and romidepsin showed efficacy with low nanomolar half-maximal inhibitory concentration (IC50) values (~50 and ~5 nM, respectively). Comparative transcriptome analyses across quisinostat, romidepsin, and panobinostat showed a greater degree of shared biological effects between quisinostat and panobinostat, and less overlap with romidepsin. However, some transcriptional changes were consistent across all 3 drugs at similar biologically effective doses, such as overexpression of troponin T1 slow skeletal type (TNNT1) and downregulation of collagen type 20 alpha 1 chain (COL20A1), identifying these as potential vulnerabilities or on-target biomarkers in DMG. Quisinostat and romidepsin significantly (P < 0.0001) inhibited in vivo tumor growth., Conclusions: Our data highlight the utility of treatment-naïve biopsy-derived models; establishes quisinostat and romidepsin as effective in vivo; illuminates potential mechanisms and/or biomarkers of DMG cell lethality due to HDAC inhibition; and emphasizes the need for brain tumor-penetrant versions of potentially efficacious agents., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Diffuse intrinsic pontine glioma (DIPG) is a universally fatal tumor of the brainstem, most commonly affecting young children. Due to its location, surgical resection is not achievable, but consideration of a biopsy has become standard practice at children's hospitals with the appropriate neurosurgical expertise. While the decision to obtain a biopsy should be directed by the presence of atypical radiographic features that call the diagnosis of DIPG into question or the requirement of biopsy tissue for clinical trial enrollment, once this precious tissue is available its use for research should be considered. The majority of DIPG and diffuse midline glioma, H3 K27M-mutant (DMG) models are autopsy-derived or genetically-engineered, each of which has limitations for translational studies, so the use of biopsy tissue for laboratory model development provides an opportunity to create unique model systems. Here, we present a detailed laboratory protocol for the generation of treatment-naïve biopsy-derived DIPG/DMG models., Competing Interests: Conflicts of Interest None.

MaKing and justitying capital expenditures can be a difficult part of a supervi- sory or managerial position. Understanding more advanced accounting tools for justifying these expenditures, like Internal Rate of Return (IRR) and Net Present Value (NPV), can improve the chances of receiving necessary funding. NPV avoids the weaknesses of the IRR method by allowing decision makers to specify when cash flows will occur instead of assuming that net cash flows will be equal each year ofa project. Taking the time to learn basic account- ing definitions and tools can improve your ability to manage and provide greater opportunities to help patients, staff, and the community.

Understanding the principles behind the time value of money can help individuals succeed in both business and personal long-term planning. The Internal Rate of Return (IRR) method provides a straightforward way to analyze long-term financial decisions. The result, the project's IRR, is a simple percentage that is easy to explain and compare with the results from other projects. When considering multiple investments, it is relatively simple to rank them by their IRRs, make minor adjustments to the list for qualitative issues, and invest down the list until the funds for the year have been spent.

Making and justifying capital expenditures can be a difficult part of a supervisory or managerial position. Understanding some basic tools for making estimates and calculating values can help simplify this process. Breaking down some of the most common accounting methods into a six-step, intuitive process allows everyone, even those with little or no accounting background, to use and understand the results of these tools. Accounting tools can seem complex when they are first used, but after walking through them step-by-step and practicing them, they can become an essential tool in working with executives and other administrators.

Accounting terminology and methods are essential parts of management and can be used to improve the efficacy of communication with other managers and executives. While learning these terms and methods can seem daunting, the rewards are well worth the effort. Accounting terminology can seem almost as complex as medical terminology: revenues, expenses, iRR, net pres- ent value, and profit. However, manag- ers and supervisors don't need to understand all of those terms, just those most commonly used. Once those basics have been mastered, they will provide sufficient background to understand the many forms, information requests, and questions accounting and finance lead- ers will provide and request. Imaging supervisors and directors can use these terms and methods to success- fully communicate with management about resources needed and their impact on the community and the bottom line of the organization. The reward for the time spent is well worth the effort.

Sixty-nine patients with first episodes and 111 with recurrent episodes of genital herpes simplex virus (HSV) infection were enrolled in a double-blind trial comparing a 5 percent topical acyclovir ointment versus placebo, polyethylene glycol (PEG). Among acyclovir recipients with first episodes of genital herpes, the mean duration of viral shedding from genital lesions, 2.0 days, mean duration of local pain or itching, 3.6 days, and mean time to healing of lesions, 11.2 days, were less than in placebo recipients 4.6, 6.7, and 15.8 days, respectively (p less than 0.05 for each comparison). Among patients with recurrent genital herpes, the mean duration of viral shedding from genital lesions was 0.8 days in acyclovir recipients compared with 1.7 days in placebo recipients (p less than 0.001). Among men with recurrent genital herpes, the mean time to crusting and healing of lesions was 3.5 and 7.5 days in acyclovir recipients compared with 5.0 and 9.7 days in placebo recipients, p = 0.03 and 0.07, respectively. No significant differences in the duration of symptoms or healing times were noted between acyclovir- and placebo-treated women with recurrent genital herpes. Acyclovir therapy was not associated with a decrease in frequency of clinical recurrences or an increase in the time of the next recurrence in patients with either first or recurrent genital herpes. Topical acyclovir appears effective in shortening some of the clinical manifestations of genital HSV infections.

Thirty-one patients with first episodes of genital herpes were randomized in a double-blind fashion to intravenous treatment with saline placebo or acyclovir, 5 mg/kg body weight at 8-hour intervals, for 5 days. The median duration of viral shedding from genital lesions after the onset of therapy was significantly shorter for patients given acyclovir (2 days) than for those given placebo (13 days), p less than 0.001. Viral shedding from the pharynx, cervix, urethra, and urine were also shorter in acyclovir-treated patients. (p less than or equal to 0.01 for each comparison). Local and systemic symptoms were shortened by a mean of 5 days and healing of genital lesions by a mean of 12 days in acyclovir-treated patients. (p less than 0.01). Complications during treatment, such as extragenital lesions or urinary retention requiring catheterization, developed in four patients given placebo and in none given acyclovir. (p less than 0.05). Intravenous acyclovir substantially decreases the symptoms, duration of lesions, and complications of primary genital herpes.

A method is described for testing analgesia for narcotic or nonnarcotic drugs in rats injected with Freund's adjuvant in the tail, by manipulation of the tail the day after injection, or of the feet after the development of adjuvant arthritis. The method is responsive to a behavioral depressant or an anti-inflammatory steroid. Diflunisal (MK-647; 5-(2,4-difluorophenyl)salicylic acid] exhibited activity in this assay after oral administration with potency about 25 times greater than that of aspirin, about 3 times that of glafenine and twice that of zomepirac. The onset of activity was within a 1/2 hour for narcotic analgesics but required about an hour for non-narcotic compounds. With the latter, the peak of activity was not attained until 2 to 4 hr, depending on the compound. The peak for diflunisal was delayed until the 3rd or 4th hour, but the onset of action was more prompt and the duration greater as the dose was increased. [14C]Diflunisal was concentrated to some extent in the inflamed tissue after adjuvant injection. Peak levels both in plasma and tissue appeared about 2 hr before peak analgesic effect. Repeated administration of large doses produced neither tolerance nor sensitization to the analgesic action of diflunisal. Naloxone and naltrexone did not antagonize the action of the compound, but when morphine and diflunisal were given together, the overall effect was enhanced.

Evidence is presented to show that nonsteroidal antiinflammatory drugs react with two sites on the cyclooxygenase (8,11,14-eicosatrienoate, hydrogen-donor:oxygen oxidoreductase, EC 1.14.99.1). Although the degree of interaction with the catalytic site determines the potency of such compounds, interaction with the supplementary site is also obligatory for efficacy as cyclooxygenase inhibitors and may explain the selectivity of such drugs in inhibiting the cyclooxygenase but not the lipoxygenase pathway. Drugs that interact more effectively with the supplementary site than with the catalytic site--i.e., those of weak to moderate activity as cyclooxygenase inhibitors--are shown to prevent inhibition of the enzyme by indomethacin. Compounds in this class are also capable of blocking the ulcerogenic action of indomethacin, which suggests that this antiulcerogenic property stems from a direct action at the level of the cyclooxygenase in the stomach.

Amniotic fluid is rarely used in the evaluation of syphilis during pregnancy but was available from a woman with positive serologic tests in the 30th week of gestation. Nonmotile intra-amniotic spirochetes were seen by dark-field microscopy 20 hr after treatment with benzathine penicillin G. The identity of the organism in amniotic fluid was confirmed by immunofluorescent staining. Less than 0.5 units/ml of penicillin was present in the amniotic fluid at this time. The amniotic fluid was positive in the Venereal Disease Research Laboratory (VDRL; Atlanta, GA) test, and the concentration of IgM was elevated as was the ratio of lecithin to sphyngomyelin. Phosphatidyl inositol and phosphatidyl glycerol were also present in the amniotic fluid. After treatment the lecithin-sphyngomyelin ratio declined; phosphatidyl glycerol disappeared, whereas phosphatidyl inositol was still present. Despite evidence of intrauterine growth retardation at 30 weeks, the infant born at 37 weeks was of normal weight and length; however, the head circumference was below the tenth percentile. These studies suggest that analysis of amniotic fluid may provide new insights into the biology of syphilis in pregnancy, but does not constitute a recommendation for routine examination of the amniotic fluid in mothers with reactive serologic tests for syphilis.

A technique is described for measuring objectively and quantitatively the reaction of sensitized guinea pigs when exposed to an aerosol of specific antigen. The principle involves registration by semi-automatic means of the number of coughs produced in animals passively sensitized with known amounts of antibody. The number of coughs is shown to be linearly related to log dose of antibody within a limited range and a dose-response curve is presented. The cough produced by this procedure is not inhibited by the antitussive drugs, codeine and propadrine, but can be inhibited by anti-allergic agents, such as cortisone and an antihistaminic drug. It is also inhibited by narcotine. The last is the only compound so far tested which suppresses both the cough produced by this procedure and that produced by a simple irritant. The action of cortisone and the antihistaminic drug, pyrilamine, is shown to be synergistic. A small dose of pyrilamine in animals pretreated with cortisone gives a degree of inhibition which cannot be obtained by increasing the dose of pyrilamine in animals not treated with cortisone.

The external symptoms of suprarenal insufficiency in cats with diabetes insipidus are the same as in those animals with only the suprarenals removed, except that the symptoms develop more rapidly in the former. The serum electrolyte changes, however, are different; there is no consistent or marked decrease in the concentration of sodium or chloride following suprarenalectomy in cats with diabetes insipidus, but there is the usual increase in the concentration of potassium. It is suggested that this indicates that changes in sodium are less characteristic of suprarenal insufficiency than are disturbances of potassium metabolism or distribution. A possible inter-relationship between the suprarenal cortex and the posterior lobe of the pituitary as salt-regulating mechanisms is discussed.