Immunomodulatory Effects of Domoic Acid Differ Between In vivo and In vitro Exposure in Mice

The immunotoxic potential of domoic acid (DA), a well-characterized neurotoxin, has not been fully investigated. Phagocytosis and lymphocyte proliferation were evaluated following in vitro and in vivo exposure to assay direct vs indirect effects. Mice were injected intraperitoneally with a single dose of DA (2.5 μg/g b.w.) and sampled after 12, 24, or 48 hr. In a separate experiment, leukocytes and splenocytes were exposed in vitro to 0, 1, 10, or 100 μM DA. In vivo exposure resulted in a significant increase in monocyte phagocytosis (12-hr), a significant decrease in neutrophil phagocytosis (24-hr), a significant decrease in monocyte phagocytosis (48-hr), and a significant reduction in T-cell mitogen-induced lymphocyte proliferation (24-hr). In vitro exposure significantly reduced neutrophil and monocyte phagocytosis at 1 μM. B- and T-cell mitogen-induced lymphocyte proliferation were both significantly increased at 1 and 10 μM, and significantly decreased at 100 μM. Differences between in vitro and in vivo results suggest that DA may exert its immunotoxic effects both directly and indirectly. Modulation of cytosolic calcium suggests that DA exerts its effects through ionotropic glutamate subtype surface receptors at least on monocytes. This study is the first to identify DA as an immunotoxic chemical in a mammalian species

Assessing the utility of a quality-of-care assessment tool used in assessing comprehensive care services provided by community health workers in South Africa

Background: Few studies exist on the tools for assessing quality-of-care of community health worker (CHW) who provide comprehensive care, and for available tools, evidence on the utility is scanty. We aimed to assess the utility components of a previously-reported quality-of-care assessment tool developed for summative assessment in South Africa. Methods: In two provinces, we used ratings by 21 CHWs and three team leaders in two primary health care facilities per province regarding whether the tool covered everything that happens during their household visits and whether they were happy to be assessed using the tool (acceptability and face validity), to derive agreement index (≥85%, otherwise the tool had to be revised). A panel of six experts quantitatively validated 11 items of the tool (content validity). Content validity index (CVI), of individual items (I-CVI) or entire scale (S-CVI), should be >80% (excellent). For the inter-rater reliability (IRR), we determined agreement between paired observers' assigned quality-of-care messages and communication scores during 18 CHW household visits (nine households per site). Bland and Altman plots and multilevel model analysis, for clustered data, were used to assess IRR. Results: In all four CHW and team leader sites, agreement index was ≥85%, except for whether they were happy to be assessed using the tool, where it was <85% in one facility. The I-CVI of the 11 items in the tool ranged between 0.83 and 1.00. For the S-CVI, all six experts agreed on relevancy (universal agreement) in eight of 11 items (0.72) whereas the average of I-CVIs, was 0.95. The Bland-Altman plot limit of agreements between paired observes were −0.18 to 0.44 and −0.30 to 0.44 (messages score); and −0.22 to 0.45 and −0.28 to 0.40 (communication score). Multilevel modeling revealed an estimated reliability of 0.77 (messages score) and 0.14 (communication score). Conclusion: The quality-of-care assessment tool has a high face and content validity. IRR was substantial for quality-of-care messages but not for communication score. This suggests that the tool may only be useful in the formative assessment of CHWs. Such assessment can provide the basis for reflection and discussion on CHW performance and lead to change

The effect of a roving nurse mentor on household coverage and quality of care provided by community health worker teams in South Africa : a longitudinal study with a before, after and 6 months post design

Objective: Community health workers (CHW) are undertaking more complex tasks as part of the move towards universal health coverage in many low- and middle-income settings. They are expected to provide promotive and preventative care, make referrals to the local clinic, and follow up on non-attendees for a range of health conditions. CHW programmes can improve access to care for vulnerable communities, but many such programmes struggle due to inadequate supervision, low levels of CHW literacy, and the marginalized status of CHW in the health system. In this paper, we assess the effect of a roving nurse mentor on the coverage and quality of care of the CHW service in two vulnerable communities in South Africa. Participants: CHW, their supervisors, household members. Intervention: Roving professional nurse mentor to build skills of supervisors and CHW teams. Methods: Three household surveys to assess household coverage of the CHW service (baseline, end of the intervention, and 6 months after end of intervention); structured observations of CHW working in households to assess quality of care. Results: The intervention led to a sustained 50% increase in the number of households visited by a CHW in the last year. While the proportion of appropriate health messages given to household members by CHW remained constant at approximately 50%, CHW performed a greater range of more complex tasks. They were more likely to visit new households to assess health needs and register the household in the programme, to provide care to pregnant women, children and people who had withdrawn from care. CHW were more likely to discuss with clients the barriers they were facing in accessing care and take notes during a visit. Conclusion: A nurse mentor can have a significant effect both on the quantity and quality of CHW work, allowing them to achieve their potential despite their marginalised status in the health system and their limited prior educational achievement. Supportive supervision is important in enabling the benefit of having a health cadre embedded in marginalised communities to be realised

Analysis of stimulant prescriptions and drug-related poisoning risk among persons receiving buprenorphine treatment for opioid use disorder

Importance: Stimulant medication use is common among individuals receiving buprenorphine for opioid use disorder (OUD). Associations between prescription stimulant use and treatment outcomes in this population have been understudied. Objectives: To investigate whether use of prescription stimulants was associated with (1) drug-related poisoning and (2) buprenorphine treatment retention. Design, Setting, and Participants: This retrospective, recurrent-event cohort study with a case-crossover design used a secondary analysis of administrative claims data from IBM MarketScan Commercial and Multi-State Medicaid databases from January 1, 2006, to December 31, 2016. Primary analyses were conducted from March 1 through August 31, 2021. Individuals aged 12 to 64 years with an OUD diagnosis and prescribed buprenorphine who experienced at least 1 drug-related poisoning were included in the analysis. Unit of observation was the person-day. Exposures: Days of active stimulant prescriptions. Main Outcomes and Measures: Primary outcomes were drug-related poisoning and buprenorphine treatment retention. Drug-related poisonings were defined using International Classification of Diseases, Ninth Revision, and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, codes; treatment retention was defined by continuous treatment claims until a 45-day gap was observed. Results: There were 13 778 567 person-days of observation time among 22 946 individuals (mean [SD] age, 32.8 [11.8] years; 50.3% men) who experienced a drug-related poisoning. Stimulant treatment days were associated with 19% increased odds of drug-related poisoning (odds ratio [OR], 1.19 [95% CI, 1.06-1.34]) compared with nontreatment days; buprenorphine treatment days were associated with 38% decreased odds of poisoning (OR, 0.62 [95% CI, 0.59-0.65]). There were no significant interaction effects between use of stimulants and buprenorphine. Stimulant treatment days were associated with decreased odds of attrition from buprenorphine treatment (OR, 0.64 [95% CI, 0.59-0.70]), indicating that stimulants were associated with 36% longer mean exposure to buprenorphine and its concomitant protection. Conclusions and Relevance: Among persons with OUD, use of prescription stimulants was associated with a modest increase in per-day risk of drug-related poisoning, but this risk was offset by the association between stimulant use and improved retention to buprenorphine treatment, which is associated with protection against overdose

Liver genomic responses to ciguatoxin: evidence for activation of Phase I and Phase II detoxification pathways following an acute hypothermic response in mice

Ciguatoxins (CTX) are polyether neurotoxins that target voltage-gated sodium channels and are responsible for ciguatera, the most common fish-borne food poisoning in humans. This study characterizes the global transcriptional response of mouse liver to a symptomatic dose (0.26 ng/g) of the highly potent Pacific ciguatoxin-1 (P-CTX-1). At 1 h post-exposure 2.4% of features on a 44K whole genome array were differentially expressed (p ≤ 0.0001), increasing to 5.2% at 4 h and decreasing to 1.4% by 24 h post-CTX exposure. Data were filtered (|fold change| ≥ 1.5 and p ≤ 0.0001 in at least one time point) and a trend set of 1550 genes were used for further analysis. Early gene expression was likely influenced prominently by an acute 4°C decline in core body temperature by 1 h, which resolved by 8 h following exposure. An initial downregulation of 32 different solute carriers, many involved in sodium transport, was observed. Differential gene expression in pathways involving eicosanoid biosynthesis and cholesterol homeostasis was also noted. Cytochrome P450s (Cyps) were of particular interest due to their role in xenobiotic metabolism. Twenty-seven genes, mostly members of Cyp2 and Cyp4 families, showed significant changes in expression. Many Cyps underwent an initial downregulation at 1 h but were quickly and strongly upregulated at 4 and 24 h post-exposure. In addition to Cyps, increases in several glutathione S-transferases were observed, an indication that both phase I and phase II metabolic reactions are involved in the hepatic response to CTX in mice

Loose regulation of medical marijuana programs associated with higher rates of adult marijuana use but not cannabis use disorder

Background and Aims Most US states have passed medical marijuana laws (MMLs), with great variation in program regulation impacting enrollment rates. We aimed to compare changes in rates of marijuana use, heavy use and cannabis use disorder across age groups while accounting for whether states enacted medicalized (highly regulated) or non-medical mml programs. Design Difference-in-differences estimates with time-varying state-level MML coded by program type (medicalized versus non-medical). Multi-level linear regression models adjusted for state-level random effects and covariates as well as historical trends in use. Setting Nation-wide cross-sectional survey data from the US National Survey of Drug Use and Health (NSDUH) restricted use data portal aggregated at the state level. Participants Participants comprised 2004–13 NSDUH respondents (n ~ 67 500/year); age groups 12–17, 18–25 and 26+ years. States had implemented eight medicalized and 15 non-medical MML programs. Measurements Primary outcome measures included (1) active (past-month) marijuana use; (2) heavy use (> 300 days/year); and (3) cannabis use disorder diagnosis, based on DSM-IV criteria. Covariates included program type, age group and state-level characteristics throughout the study period. Findings Adults 26+ years of age living in states with non-medical MML programs increased past-month marijuana use 1.46% (from 4.13 to 6.59%, P = 0.01), skewing towards greater heavy marijuana by 2.36% (from 14.94 to 17.30, P = 0.09) after MMLs were enacted. However, no associated increase in the prevalence of cannabis use disorder was found during the study period. Our findings do not show increases in prevalence of marijuana use among adults in states with medicalized MML programs. Additionally, there were no increases in adolescent or young adult marijuana outcomes following MML passage, irrespective of program type. Conclusions Non-medical marijuana laws enacted in US states are associated with increased marijuana use, but only among adults aged 26+ years. Researchers and policymakers should consider program regulation and subgroup characteristics (i.e. demographics) when assessing for population level outcomes. Researchers and policymakers should consider program regulation and subgroup characteristics (i.e. demographics) when assessing for population level outcomes

Household coverage, quality and costs of care provided by community health worker teams and the determining factors : findings from a mixed methods study in South Africa

Objective: Community health workers (CHWs) are undertaking more complex tasks as part of the move towards universal health coverage in South Africa. CHW programmes can improve access to care for vulnerable communities, but many such programmes struggle with insufficient supervision. In this paper, we assess coverage (proportion of households visited by a CHW in the past year and month), quality of care and costs of the service provided by CHW teams with differing configurations of supervisors, some based in formal clinics and some in community health posts. Participants: CHW, their supervisors, clinic staff, CHW clients. Methods: We used mixed methods (a random household survey, focus group discussions, interviews and observations of the CHW at work) to examine the performance of six CHW teams in vulnerable communities in Sedibeng, South Africa. Results: A CHW had visited 17% of households in the last year, and we estimated they were conducting one to two visits per day. At household registration visits, the CHW asked half of the questions required. Respondents remembered 20%–25% of the health messages that CHW delivered from a visit in the last month, and half of the respondents took the action recommended by the CHW. Training, supervision and motivation of the CHW, and collaboration with other clinic staff, were better with a senior nurse supervisor. We estimated that if CHW carried out four visits a day, coverage would increase to 30%–90% of households, suggesting that some teams need more CHW, as well as better supervision. Conclusion: Household coverage was low, and the service was limited. Support from the local facility was key to providing a quality service, and a senior supervisor facilitated this collaboration. Greater investment in numbers of CHW, supervisors, training and equipment is required for the potential benefits of the programme to be delivered

The complex behavior of the satellite footprints at Jupiter: the result of universal processes?

At Jupiter, some auroral emissions are directly related to the electromagnetic interaction between the moons Io, Europa and Ganymede on one hand and the rapidly rotating magnetospheric plasma on the other hand. Out of the three, the Io footprint is the brightest and the most studied. Present in each hemisphere, it is made of at least three different spots and an extended trailing tail. The variability of the brightness of the spots as well as their relative location has been tentatively explained with a combination of Alfvén waves’ partial reflections on density gradients and bi-directional electron acceleration at high latitude. Should this scenario be correct, then the other footprints should also show the same behavior. Here we show that all footprints are, at least occasionally, made of several spots and they all display a tail. We also show that these spots share many characteristics with those of the Io footprint (i.e. some significant variability on timescales of 2-3 minutes). Additionally, we present some Monte-Carlo simulations indicating that the tails are also due to Alfvén waves electron acceleration rather than quasi-static electron acceleration. Even if some details still need clarification, these observations strengthen the scenario proposed for the Io footprint and thus indicate that these processes are universal. In addition, we will present some early results from Juno-UVS concerning the location and morphology of the footprints during the first low-altitude observations of the polar aurorae. These observations, carried out in previously unexplored longitude ranges, should either confirm or contradict our understanding of the footprints

Live to cheat another day: bacterial dormancy facilitates the social exploitation of beta-lactamases

The breakdown of antibiotics by β-lactamases may be cooperative, since resistant cells can detoxify their environment and facilitate the growth of susceptible neighbours. However, previous studies of this phenomenon have used artificial bacterial vectors or engineered bacteria to increase the secretion of β-lactamases from cells. Here, we investigated whether a broad-spectrum β-lactamase gene carried by a naturally occurring plasmid (pCT) is cooperative under a range of conditions. In ordinary batch culture on solid media, there was little or no evidence that resistant bacteria could protect susceptible cells from ampicillin, although resistant colonies could locally detoxify this growth medium. However, when susceptible cells were inoculated at high densities, late-appearing phenotypically susceptible bacteria grew in the vicinity of resistant colonies. We infer that persisters, cells that have survived antibiotics by undergoing a period of dormancy, founded these satellite colonies. The number of persister colonies was positively correlated with the density of resistant colonies and increased as antibiotic concentrations decreased. We argue that detoxification can be cooperative under a limited range of conditions: if the toxins are bacteriostatic rather than bacteridical; or if susceptible cells invade communities after resistant bacteria; or if dormancy allows susceptible cells to avoid bactericides. Resistance and tolerance were previously thought to be independent solutions for surviving antibiotics. Here, we show that these are interacting strategies: the presence of bacteria adopting one solution can have substantial effects on the fitness of their neighbours