Microbial metabolomic responses to changes in temperature and salinity along the western Antarctic Peninsula.

Seasonal cycles within the marginal ice zones in polar regions include large shifts in temperature and salinity that strongly influence microbial abundance and physiology. However, the combined effects of concurrent temperature and salinity change on microbial community structure and biochemical composition during transitions between seawater and sea ice are not well understood. Coastal marine communities along the western Antarctic Peninsula were sampled and surface seawater was incubated at combinations of temperature and salinity mimicking the formation (cold, salty) and melting (warm, fresh) of sea ice to evaluate how these factors may shape community composition and particulate metabolite pools during seasonal transitions. Bacterial and algal community structures were tightly coupled to each other and distinct across sea-ice, seawater, and sea-ice-meltwater field samples, with unique metabolite profiles in each habitat. During short-term (approximately 10-day) incubations of seawater microbial communities under different temperature and salinity conditions, community compositions changed minimally while metabolite pools shifted greatly, strongly accumulating compatible solutes like proline and glycine betaine under cold and salty conditions. Lower salinities reduced total metabolite concentrations in particulate matter, which may indicate a release of metabolites into the labile dissolved organic matter pool. Low salinity also increased acylcarnitine concentrations in particulate matter, suggesting a potential for fatty acid degradation and reduced nutritional value at the base of the food web during freshening. Our findings have consequences for food web dynamics, microbial interactions, and carbon cycling as polar regions undergo rapid climate change.

Treatment with a retinoic acid-inducible gene I (RIG-I) agonist as monotherapy and in combination with pembrolizumab in patients with advanced solid tumors: results from two phase 1 studies.

BACKGROUND: We evaluated MK-4621, an oligonucleotide that binds and activates retinoic acid-inducible gene I (RIG-I), as monotherapy (NCT03065023) and in combination with the anti-programmed death 1 antibody pembrolizumab (NCT03739138). PATIENTS AND METHODS: Patients were ≥ 18 years with histologically/cytologically confirmed advanced/metastatic solid tumors with injectable lesions. MK-4621 (0.2‒0.8 mg) was administered intratumorally as a stable formulation with jetPEI™ twice weekly over a 4-week cycle as monotherapy and weekly in 3-week cycles for up to 6 cycles in combination with 200 mg pembrolizumab every 3 weeks for up to 35 cycles. Primary endpoints were dose-limiting toxicities (DLTs), treatment-related adverse events (AEs), and treatment discontinuation due to AEs. RESULTS: Fifteen patients received MK-4621 monotherapy and 30 received MK-4621 plus pembrolizumab. The only DLT, grade 3 pleural effusion that subsequently resolved, occurred in a patient who received MK-4621/jetPEI™ 0.8 mg plus pembrolizumab. 93% of patients experienced ≥ 1 treatment-related AE with both monotherapy and combination therapy. No patients experienced an objective response per RECIST v1.1 with MK-4621 monotherapy; 4 (27%) had stable disease. Three (10%) patients who received combination therapy had a partial response. Serum and tumor biomarker analyses provided evidence that MK-4621 treatment induced an increase in gene expression of interferon signaling pathway members and associated chemokines and cytokines. CONCLUSIONS: Patients treated with MK-4621 monotherapy or in combination with pembrolizumab experienced tolerable safety and modest antitumor activity, and there was evidence that MK-4621 activated the RIG-I pathway. At the doses tested, MK-4621 did not confer meaningful clinical benefit. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03065023 and NCT03739138.

Trauma-Focused Cognitive Behavioral Therapy in 13 Urban Public Schools: Mixed Methods Results of Barriers, Facilitators, and Implementation Outcomes.

Trauma-focused cognitive behavioral therapy (TF-CBT) is an evidence-based intervention to treat Post-traumatic Stress Disorder among youth ages 3-18 years. In this pilot study, 31 clinicians in 13 urban public schools received TF-CBT training to improve access to a high-quality trauma treatment for youth in need. A mixed methods design was used to assess implementation barriers, facilitators and outcomes to examine initial feasibility, acceptability, and appropriateness of TF-CBT delivered in school settings. Although 70% of clinicians reported confidence in the evidence-base of TF-CBT and its potential to support their students who have a very high prevalence of lifetime trauma exposure, implementation practice outcomes suggest a wide range of TF-CBT use (Range = 0 to 11 students enrolled per clinician, Mean = 1.4 students) with 23 clinicians implementing the TF-CBT model with at least one case. Results point to the potential value of training school mental health clinicians in TF-CBT based on its compatibility with student needs. Yet, by connecting focus group results to top-rated barriers and facilitators, we identify several adjustments that should be made to improve intervention-setting fit in future studies. Specifically, school setting-specific intervention adaptations, school-tailored implementation support and thoughtful consideration of school-based clinicians' roles and responsibilities are needed to enhance future implementation success.

Environmental enrichment models a naturalistic form of maternal separation and shapes the anxiety response patterns of offspring.

Environmental enrichment (EE) mimics positive life experiences by providing enhanced social and physical stimulation. Placement into EE following weaning, or in later life, confers beneficial outcomes on both emotional and cognitive processes. However, anxiety-like behavior is also reported, particularly in rats exposed to enhanced housing during early development. Notably, the quality of maternal behavior affects stress regulation and emotional stability in offspring, yet the impact of environmental context on maternal care has not been thoroughly evaluated, or are the influences of EE on their offspring understood. To investigate the role of EE on these factors we analyzed the details of mother-neonate interactions, and juvenile offspring performance on several anxiety measures. Additionally, we evaluated neurochemical differences (i.e. serotonin, corticosterone, GABA, glutamate) in prefrontal cortex and hippocampus as a function of EE, Communal Nesting (CN) and Standard Care (SC). Although EE dams spent significantly less time on the nest and had lower nursing frequencies compared to SC dams, there were no differences in maternal licking/grooming. In offspring, EE increased GLUR1 level and GABA concentrations in the prefrontal cortex of both juvenile male and female rats. A similar pattern for glutamate was only observed in males. Although EE offspring spent less time on the open arms of the elevated plus maze and had faster escape latencies in a light-dark test, there were no other indications of anxiety-like behavior on these measures or when engaged in social interaction with a conspecific. In the wild, rats live in complicated and variable environments. Consequently dams must leave their nest to defend and forage, limiting their duration of direct contact. EE exposure in early development may mimic this naturalistic maternal separation, shaping parental behavior and offspring resiliency to stressors.

Environmental enrichment mitigates the sex-specific effects of gestational inflammation on social engagement and the hypothalamic pituitary adrenal axis-feedback system.

Modest environmental enrichment (EE) is well recognized to protect and rescue the brain from the consequences of a variety of insults. Although animal models of maternal immune activation (MIA) are associated with several neurodevelopmental impairments in both the behavioral and cognitive functioning of offspring, the impact of EE in protecting or reversing these effects has not been fully evaluated. In the present study, female Sprague-Dawley rats were randomized into EE (pair-housed in a large multi-level cage with toys, tubes and ramps) or animal care control (ACC; pair-housed in standard cages) conditions. Each pair was bred, following assignment to their housing condition, and administered 100µg/kg of lipopolysaccharide (LPS) on gestational day 11. After birth, and until the end of the study, offspring were maintained in their respective housing conditions. EE protected against both the social and hypothalamic pituitary adrenal axis consequences of MIA in juvenile male rats, but surprisingly not against the spatial discrimination deficits or accompanying decrease in glutamate levels within the hippocampus (as measured via LCMS-MS). Based on these preliminary results, the mechanisms that underlie the sex-specific consequences that follow MIA appear to be dependent on environmental context. Together, this work highlights the importance of environmental complexity in the prevention of neurodevelopmental deficits following MIA.

Enterococcal urinary tract infections: eight years experience at a regional hospital in Trinidad, West Indies.

OBJECTIVE: To investigate the prevalence of significant enterococcal isolates from urine and determine what factors are associated with the increased prevalence, with particular reference to antibiotic susceptibilities. METHODS: Retrospective analysis over an 8-year period of hospital laboratory records of urinary isolates of enterococci was done. Species were identified via colony morphology, growth in 6.5% sodium chloride and their ability to hydrolyze esculin in the presence of 40% bile salts. Susceptibility testing via the disc diffusion technique with 9 commonly used antibiotics was also done as defined by the National Committee for Clinical Laboratory Standards. RESULTS: From 39,881 urine specimens, 9116 (22.9%) were culture positive. Of this 9116, 1001 (11.0%) were enterococci, the 4th most common urinary isolate. E. coli was the most common (36.2%). Most enterococci were from pediatric patients (28.4%) and the urology unit (24.5%). All enterococci were fully sensitive to ampicillin and augmentin (amoxicillin-clavulanic acid). Sensitivity to gentamicin decreased significantly from 79% in 1990 to 58% in 1997 (P < 0.005). Sensitivity to the cephalosporins and nitrofuratoin were relatively stable, but sensitivity to nalidixic acid varied. No resistance to vancomycin was detected during the study, and no cases of bacteremia complicated bacteriuria were seen. CONCLUSION: Isolation of enterococci was relatively stable during the 8-year period, and all isolates were fully sensitive to the older beta-lactams, ampicillin, cefaclor and augmentin, but displayed varying degrees of multi-resistance to other commonly used urinary agents such as nalidixic acid and co-trimoxazole (trimethoprim-sulfamethoxazole). Because of the emergence of multi-resistant enterococci in many countries, and the high cost of drugs in our society, it is imperative that vigilance be maintained in monitoring enterococcal infections in hospitals.

Relation between circadian patterns in levels of circulating lipoprotein(a), fibrinogen, platelets, and related lipid variables in men.

BACKGROUND: A correlation has been reported between lipoprotein(a) [Lp(a)] concentration and risk for coronary artery disease. High concentrations of Lp(a) might be markers for vascular or tissue injury or might be associated with other genetic or environmental factors that can cause acute myocardial infarction. METHODS: We measured the circadian characteristics of circulating Lp(a), fibrinogen, platelets, cholesterol, triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol for a group of adult male volunteers who had no clinical symptoms. We obtained samples every 3 hours around the clock to assess the normal degree of variation within a 24-hour period and to test for similarities in circadian patterns and correlations with level of Lp(a). RESULTS: Each variable displayed a highly significant circadian rhythm. Lp(a), fibrinogen, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol peaked in the morning. Cholesterol and platelets peaked in the late afternoon, and triglycerides peaked in the evening. CONCLUSIONS: Although peak levels of Lp(a) and fibrinogen coincide with reported morning peak frequencies of myocardial infarction and stroke, the platelet peak appears to coincide with late afternoon peak frequencies of sudden cardiac death and fatal stroke. The data suggest that proper timing of single samples may improve the usefulness and accuracy of diagnosis, risk assessment, and therapy.

Arranged marriages, unlikely partners. How will their offspring look?

In the new era of managed care, many religious healthcare providers are making "arranged marriages"--permanent partnerships with secular organizations. As they do so, the religious partners naturally ponder how best to ensure that their values permeate the new entity and thus prevail in later organizational "offspring." The organizations most likely to perpetuate their values are those with ethical corporate cultures and climates. These include religiously based healthcare providers, but such providers seem to lack confidence today in their ability to maintain culture and climate in newly formed partnerships. That may be fortunate because it prevents them from trying to impose their values on secular partners. Nevertheless, such values are often attractive to a prospective partner. A religious healthcare provider will need market leverage, as well as attractive values, to make a good "marriage." Even so, religious providers and secular investor-owned organizations are unlikely partners, because their motives and incentives differ radically. But religious providers can form solid relationships with secular, not-for-profit healthcare organizations if they take care to negotiate a binding commitment to maintain an ethical culture and climate. However, Catholic providers are at a disadvantage in such negotiations because Catholic religious congregations are unlikely to continue as owner-sponsors much beyond another decade. It is crucial that a stable source of influence develop to ensure a religious presence in the offspring of new partnerships.

Health status of the community becoming focus of MHS (Mercy Health Services) system. Interview by Donald E.L. Johnson.

Since hospitals exist to stabilize and improve the health of the people they serve, they should form community health care systems that offer the full spectrum of services in an organized way, says Edward J. Connors, president of Mercy Health Services, in the following interview with Donald E.L. Johnson, editor and publisher of Health Care Strategic Management. Skills in epidemiology are desperately needed to accomplish this, as well as skills in statistics, information systems and outcomes measurement. Connors believes that a consensus has formed on the core content of health status measurement. Hospitals should start building the information base needed to improve the health status of their target population.